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CAS No. : | 147127-20-6 | MDL No. : | MFCD00943794 |
Formula : | C9H14N5O4P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SGOIRFVFHAKUTI-ZCFIWIBFSA-N |
M.W : | 287.21 | Pubchem ID : | 464205 |
Synonyms : |
GS 1278;PMPA;TDF;(R)-PMPA;GS-1275
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.44 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 67.48 |
TPSA : | 146.19 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.19 cm/s |
Log Po/w (iLOGP) : | 0.41 |
Log Po/w (XLOGP3) : | -1.6 |
Log Po/w (WLOGP) : | -0.04 |
Log Po/w (MLOGP) : | -2.3 |
Log Po/w (SILICOS-IT) : | -1.93 |
Consensus Log Po/w : | -1.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.63 |
Solubility : | 66.8 mg/ml ; 0.233 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.96 |
Solubility : | 31.4 mg/ml ; 0.109 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.83 |
Solubility : | 42.4 mg/ml ; 0.148 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.39 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P270-P301+P310+P330-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: With triethylamine In 1-methyl-pyrrolidin-2-one at 63℃; for 0.5 h; Stage #2: at 63℃; for 4 h; Stage #3: at 50℃; for 0.5 h; |
In a tenofovir (PMPA) 4.0g prepared in Example 1 was added to the kettle and N- methylpyrrolidone 15 and triethylamine 5.8. The reaction solution was heated to about 63 and stirred for 30 minutes In the chloromethyl isopropyl carbonate 10gAnd then stirred for 4 hours at this temperature. After cooling the reaction solution to room temperature and again it cooled to 5°C ,Below 15°C cold water were added to maintain 25ml. At 15°C stirred for one hour, And extracted twice with methylene chloride 15ml.After washing twice, the organic layer was then partitioned with water 10ml and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the remaining filtrate tenofovir disoproxil (TD) as an oil.The tenofovir disoproxil (TD) of the oil phase Isopropyl alcohol 35ml And 1.6g of fumaric acid Added and the temperature was raised to about 50°C Dong was completely dissolved for 30 minutes.Then slowly cooled to about 25 the reaction solution was cooled, dissolved again in 3 was stirred for 4 hours and kept at this temperature.Crystals were filtered and washed with isopropyl alcohol and then dried in vacuo at about 40 10 desired compound of tenofovir disoproxil fumarate (TDF), 4.7g (yield: 53percent) was obtained.The obtained tenofovir disoproxil fumarate (TDF) in 4.7g In the 40ml and isopropyl alcohol and heated to about 50°C Open completely dissolved during 30 minutes.Then slowly cooled to about 25°C the reaction solution was cooled, dissolved again in 3°C kept at said temperature and stirred for 4 hours.Crystals were filtered, washed with isopropyl alcohol 100 mland vacuum-dried at about 40°C tenofovir disoproxil fumarate (TDF), 4.3g (Yield: 90percent) of the crystal form was obtained. |
63.6% | Stage #1: With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one; toluene at 45 - 55℃; for 5 h; Stage #2: at 50 - 55℃; for 2 h; |
25 g of the terpovorin anhydride obtained in the above example was dissolved in 100 ml of N-methyl-2-pyrrolidinone (NMP)Toluene (50 ml) was added and distilled under reduced pressure at 60 ° C to remove moisture. 50 ml of toluene was further added to distill once more.The reaction solution was cooled to 35 DEG C, and 35.2 g (4 equiv.) Of triethylamine was added thereto to produce crystals. However, homogenization was suspended with stirring, 28 g (1.0 Equiv.) Of tetrabutylammonium bromide was added RTI ID = 0.0 & gt; 45 C. & lt; / RTI & gt;To this was added 66.4 g (5.0 Equiv.) Of chloromethylisopropyl carbonate and stirring was continued at 45 to 55 .After 5 hours, the progress of the reaction was monitored by TLC and HPLC. When the reaction was completed and the viscous liquid turned transparent red, it was cooled to room temperature, 150 ml of cyclohexane was added thereto,The supernatant was removed with a vacuum syringe tube and again washed with 100 ml of cyclohexane to remove.300 ml of ethyl acetate and 100 ml of cold water were added to the reaction layer and the mixture was stirred to remove the aqueous layer. The aqueous layer was washed twice with 50 ml of ethyl acetate and added to the undiluted solution.The organic layer was washed with 50 ml of cold water and 50 ml of a saturated aqueous solution of sodium chloride, dehydrated with magnesium sulfate, and then vacuum-dried to obtain 53 g of crystalline sludge, Tenofovir disoproxil.The product was further cooled at a lower temperature for crystallization, and the content was analyzed by HPLC (purity 85percent, actual amount 45 g compared to area, yield 96percent).(0.087 mol) of terpovorbidisopropylsilane crystals were dissolved in 120 ml of isopropyl alcohol, 12.5 g (0.107 mol, 1.2 Equiv.) Of fumaric acid was added, and the mixture was stirred at 50 to 55 ° C for 2 hours .The reaction solution was cooled to 3 to 5 , and the resulting crystals were sufficiently stirred and then filtered.The crystals were suspended in 250 ml of ethyl acetate and stirred for 1 hour. The reaction solution was warmed to 10 DEG C or lower, filtered and washed. The crystals obtained in this way were vacuum-dried at 40 DEG C to obtain 35 g of terpovorbidisoproxyl fumarate (HPLC area Purity 98.5percent, yield 63.6percent). |
55 g | Stage #1: With triethylamine In cyclohexane at 80 - 85℃; for 2 h; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one at 50 - 55℃; for 4 h; Stage #3: at 50 - 55℃; for 0.833333 h; |
Example 9 Preparation of Tenofovir Disoproxil Fumarate [0092] To a clean 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20° C. to 35° C. Heated to 80° C. to 85° C. and stirred for 2 hours and simultaneously removed water liberated. The solvent was removed completely from the reaction mixture by distillation under vacuum at below 65° C. and to the obtained residue N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) were charged at 25° C. to 30° C. Heated to 50° C. to 55° C. and chloromethyl isopropyl carbonate (125 gms) was added at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20° C. to 25° C. and washed with cyclohexane (200 ml). Methylene chloride (500 ml) was charged into the organic layer and stirred for 1 hour at 10° C. to 15° C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10percent ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35° C. to obtain oily product and then the oily product was diluted with isopropanol (150 ml). [0093] In a clean another 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50° C. to 55° C. and stirred for 20 minutes and above obtained oily product solution was added at 50° C. to 55° C. Stirred for 30 minutes at this temperature and cooled to 0° C. to 5° C. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35° C. to 40° C. under reduced pressure to provide the title compound as crude (80 gms). [0094] In another clean 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10° C. to 15° C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35° C. to 40° C. for 6 hours under reduced pressure to provide the title compound. [0095] Yield: 55 gms. [0096] HPLC purity: 98.9percent |
35 g | Stage #1: at 60℃; Stage #2: at 45 - 55℃; for 5 h; Stage #3: at 50 - 55℃; for 2 h; |
25 g of the anhydrous tenofovir obtained in the Example was added to 100 ml of n-methyl-2-pyrrolidinone (NMP) and 50 ml of toluene, and the resultant solution was distilled under reduced pressure at 60° C. and removed of water. 50 ml of toluene was further added and distillation was performed. The reactant solution was cooled down to 35° C., and 35.2 g (4 eq.) of triethylamine was added to form crystals. Agitation was continued to make a homogeneous suspension. 28 g (1.0 eq.) of tetrabutylammonium bromide was added, and the resultant solution was heated up to 45° C. 66.4 g (5.0 eq.) of chloromethyl isopropyl carbonate was added to the solution, which was continuously stirred at 45-55° C. In 5 hours of the reaction, TLC and HPLC were used to estimate the progress of the reaction, and the reaction was terminated. As the sticky solution became clear and reddish, it was cooled down to the room temperature, mixed with 150 ml of cyclohexane, and vigorously stirred. The solution was removed of the supernatant using a low-pressure pipette and washed with 100 ml of cyclohexane. 300 ml of ethyl acetate and 100 ml of cold water were added to the reactant layer, which was then stirred and removed of the aqueous layer. The aqueous layer thus obtained was washed twice with 50 ml of ethyl acetate and combined with the crude solution. The organic layer was washed with 50 ml of cold water and 50 ml of saturated saline solution, dehydrated with magnesium sulfate and then isolated under reduced pressure to yield 53 g of tenofovir disoproxil in the form of crystalline sludge. The sludge was further cooled down to the lower temperature to form crystals and then subjected to quantitative analysis through HPLC (purity 85percent, actual amount per area 45 g, yield 96percent).[Synthesis Method for Tenofovir Disoproxil Fumarate (Teno-DF]53 g (actual 45 g) (0.087 mol) of tenofovir disoproxil coarse crystals were dissolved in 120 ml of isopropyl alcohol, and 12.5 g (0.107 mol, 1.2 eq.) of fumaric acid was added. The resultant solution was stirred at 50 to 55° C. for 2 hours and sufficiently cooled down to 3 to 5° C. to form crystals. After sufficient agitation, the crystals were filtered out and suspended with 250 ml of ethyl acetate. After one-hour agitation, the reactant solution was cooled down to 10° C. or below, filtered and washed. The crystals thus obtained were dried under vacuum at 40° C. to yield 35 g of tenofovir disoproxil fumarate (HPLC area purity 98.5percent, yield 63.6percent). |
72 g | Stage #1: With triethylamine In 1-methyl-pyrrolidin-2-one at 20 - 30℃; for 0.5 h; Inert atmosphere Stage #2: at 60 - 80℃; Inert atmosphere Stage #3: at 40℃; Inert atmosphere |
Diesterification reaction: Under a nitrogen atmosphere, 100 g Tenofovir (PMPA) And 300ml N-methylpyrrolidone (NMP), the control temperature at 25 ~ 30 , shaking 30min, To dissolve, and then add 106g triethylamine (TEA), 20 ~ 30 shaking 30min until uniform; The above mixture was warmed to 60 ~ 65 , and stirred, In 15 ~ 20min rapid dropping 266g chloromethyl isopropyl carbonate (CMIC) Then warmed to 75 ~ 80 , shaking reaction 60 ~ 70min, When TLC real-time monitoring of the basic reaction of the reaction material completely (3percent or less), and monoester content of 15percent or less, When the area of the main peak of the product is more than 80percent, the double esterification reaction is complete; Then the reaction system first use water bath cooling 5min, After using ice-water bath in 10-15 min the reaction system rapidly reduced to 10-15 ;Extraction and Separation: To the reaction system in step (1) was added 600 ml of ethyl acetate (EA) Heated at 10 ~ 15 , stirred for 15min and filtered, each time with 200ml ethyl acetate (EA) washed the filter cake three times, And the filtrate and the resulting filtrate was combined, to which was added 400ml 10 ~ 15 distilled cold water, Full shock, extraction and separation, the separated aqueous phase was extracted with ethyl acetate twice, The resulting organic phase was combined with the EA layer, washed twice with 1000 ml of distilled water, 300g of sodium chloride was added into the obtained water washing solution twice, dissolved with stirring and cooled down to 10 to 15 ° C, And then extracted with 500ml of ethyl acetate once, the organic phase was extracted and combined, Washed with 900 to 1000 ml of saturated saline (300 g of sodium chloride dissolved in 850 ml of distilled water) Finally, the organic phase was added 400g anhydrous sodium sulfate 60min after drying filtration;Salt-forming reaction: to step (2) dried and filtered about 2000ml filtrate was added to the reaction vessel, Then 32g fumaric acid (FMA) was added and the temperature was raised to 40 ° C in a nitrogen atmosphere and the reaction was stirred until the solution became clear. (4) Preparation of tenofovir disoproxil fumarate crude product: Step (3) The reaction solution was concentrated under reduced pressure at 40 ° C, most of the solvent was distilled off until a large amount of crystals were precipitated, Then the concentrate was naturally cooled to room temperature, and then placed in a -5 ° C freezer was allowed to cool more than 2h, filtered, The resulting filter cake was washed with a small amount of ethyl acetate 2 to 3 times, pumping dry weighed about 130g, 40 under blast drying 2h, weighed to give 85g Tenofovir disoproxil fumarate crude product, The HPLC detector purity of 98percent or more;Recrystallization: Under a nitrogen atmosphere, the reaction vessel was charged with step (4) 85 g crude Tenofovir disoproxil fumarate and 500 ml isopropanol (IPA) The nitrogen atmosphere was warmed to 55 ° C and stirred for 15 min to clarify the solution. If not, the filtrate should be filtered and the filtrate rapidly crystallized. After the resulting solution was left to cool to room temperature, Placed in a freezer at 4 frozen 2h above, so recrystallized, filtered, rinsed with cold isopropyl alcohol cake, Drained, to obtain white wet crystal 108g, at 40 blast drying 2h or 40 under reduced pressure drying 4h, 72 g of tenofovir disoproxil fumarate finished product was obtained. Tenofovir disoproxil fumarate obtained by the above method was tested by HPLC, Its purity is higher than 99.5percent, monoester is less than 0.5percent, the sum of other impurities is not more than 0.1percent, with tenofovir, The total molar yield is about 35-40percent. |
216.1 g | Stage #1: With triethylamine In N,N-dimethyl acetamide for 0.166667 h; Stage #2: at 55℃; for 7 h; Stage #3: at 55℃; |
120 g (0.418 mol) of tenofovir was heated to 80 ° C and dried under reduced pressure for 2 hours to remove water.After adding 600 g of DMAc (dimethylacetamide) and stirring uniformly, 120 g of triethylamine (1.186 mol) was added and stirred for 10 minutes, and then 280 g (1.835 mol) of CMIC (isopropylchloromethyl carbonate) was added.The reaction was incubated at 55 ° C for 7 hours.Sampling HPLC control,The reaction purity is 84.3percent,2.2percent of raw materials,Monoester 7.5percent.The reaction was cooled to 5 ° C and filtered.The filter cake was washed with 850 g of dichloromethane.Combine the filtrate,Add 1200g of purified water cooled to 5 ° C with stirring.Let stand, dispense,Collect the lower organic layer,The upper aqueous layer was extracted once with 400 g of dichloromethane.The combined organic layer solutions were washed twice with purified water.The methylene chloride solution was concentrated to a pale yellow oil and then was stirred at 30 ° C for 30 min with 200 g of isopropanol and 240 g of n-hexane.Then cool down to 0 ° C for 2 h,filter,Decofolvir dipivoxil wet product 231.2g (about 185.4g dry),The molar yield was 85.3percent and the purity was ≥99.8percent.231.2 g (0.445 mol) of tenofovir disoproxil wet product (about 185.4 g, 0.357 mol) and 55.4 g(0.477 mol) fumaric acid was added to 950 g of isopropanol and dissolved at 55 ° C.After being dissolved, it is filtered while hot.The filtrate was slowly cooled to 35-40 ° C. After crystallization for 2 h, the temperature was lowered to 0 ° C for 2 h.Filtered, pre-cooled isopropyl alcohol wash filter cake,About 120.6g of tenofovir disoproxil fumarateThe temperature was controlled to dry at 50 ° C for 10 hours under reduced pressure;Tenofovir disoproxil fumarate 216.1g,Molar yield 95.2percent,Purity ≥ 99.8percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrogenchloride In water at 130 - 140℃; Microwave irradiation; Sealed tube; | |
90% | With hydrogenchloride In water at 140℃; for 0.5h; Microwave irradiation; | 3 Example 3: Synthesis of (R)-9-[2-(phosphonomethoxy)propyl]adenine Method B: A mixture of diesters of (R)-9-[2-(phosphonomethoxy)propyl]adenine (18.6 g, 50 mmol) and aq. HCl (1 M, 100 mL) in a MW vial was irradiated at 140 °C for 30 min. The reaction mixture was evaporated to dryness at 50 °C in vacuo and crystallized from H2O, filtered, washed with H2O and acetone, and dried at 60°C for 4 days (under vacuum with P2O5) to give 12.97 g (90%) of the product (R)-9-[2-(phosphonomethoxy)propyl]adenine. The reaction was successfully carried our using several different MW reactors: 1) CEM Discover, single-mode cavity with focused MW heating (MW power supply 0-300 W, 1 W increments, IR temperature sensor, open or closed vessel mode, pressure range 0-20 bar, 10 ml or 80 ml vials); 2) Milestone BatchSYNTH, instrument for large scale procedures (MW power supply 0-1000 W, 10 W increments, internal temperature sensor, open or closed vessel mode, pressure range 0-30 bar, 250 ml vial); 3) Milestone FlowSYNTH, continuous flow microwave reactor for scale-up (MW power supply 0-1000 W, 10 W increments, two internal temperature sensors, continuous flow mode, pressure range 0-30 bar, 200 ml vessel, flow rate 10-100 ml/min). |
90% | With hydrogenchloride In water at 140℃; for 0.5h; Microwave irradiation; | 3 Example 3: Synthesis of (R)-9-[2-(phosphonomethoxy)propyl]adenine Method B: A mixture of diesters of (R)-9-[2-(phosphonomethoxy)propyl]adenine (18.6 g, 50 mmol) and aq. HCl (1 M, 100 mL) in a MW vial was irradiated at 140 °C for 30 min. The reaction mixture was evaporated to dryness at 50 °C in vacuo and crystallized from H2O, filtered, washed with H2O and acetone, and dried at 60°C for 4 days (under vacuum with P2O5) to give 12.97 g (90%) of the product (R)-9-[2-(phosphonomethoxy)propyl]adenine. The reaction was successfully carried our using several different MW reactors: 1) CEM Discover, single-mode cavity with focused MW heating (MW power supply 0-300 W, 1 W increments, IR temperature sensor, open or closed vessel mode, pressure range 0-20 bar, 10 ml or 80 ml vials); 2) Milestone BatchSYNTH, instrument for large scale procedures (MW power supply 0-1000 W, 10 W increments, internal temperature sensor, open or closed vessel mode, pressure range 0-30 bar, 250 ml vial); 3) Milestone FlowSYNTH, continuous flow microwave reactor for scale-up (MW power supply 0-1000 W, 10 W increments, two internal temperature sensors, continuous flow mode, pressure range 0-30 bar, 200 ml vessel, flow rate 10-100 ml/min). |
80% | With trimethylsilyl bromide In acetonitrile | |
47% | With trimethylsilyl bromide In acetonitrile Ambient temperature; | |
Multi-step reaction with 4 steps 1.1: bromine / tetrachloromethane; N,N-dimethyl-formamide / 48 h / 20 °C 2.1: trimethylsilyl bromide / acetonitrile / 20 °C 2.2: Co-distillation 3.1: tritium; 5% Pd-BaSO4; triethylamine / water / 1.5 h / 20 °C / 640 Torr 4.1: water / water-d2 / 20 °C / pH 7.4 / aq. phosphate buffer |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogenchloride In N,N-dimethyl-formamide at 130℃; for 0.0416667h; Inert atmosphere; | 1.3-3.3; 1-2 (3) 40 g of (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (VI) obtained in step (2) is dissolved in 160 g of DMF,Get a mixed solution; pass the mixed solution into the first reaction module of the microreactor to preheat to 130 ° C;Control the flow rate of the mixed solution at 30g / min; the second reaction module is fed with hydrogen chloride gas,The nitrogen back pressure in the microreactor, the control system pressure is 10 bar, and the hydrogen chloride gas flow rate is 900 ml / min.; The gas and the material liquid are fully mixed in the module, and the reaction is performed at 130 ° C for 150s,The molar ratio of the total flux of hydrogen chloride gas and the compound of formula VI is 2.25: 1;The resulting reaction solution was cooled to room temperature, and then dropped into a reaction bottle containing 400 ml of cold water.Reduce the temperature to 5-10 ° C. After the transfer of the liquid material is completed, add 200ml of dichloromethane.The layers were extracted by stirring, the aqueous phase was adjusted to pH 3.0 with sodium hydroxide, the temperature was lowered to 0 ° C, and the crystals were cultivated for 2 hours.Wet product was obtained by filtration and vacuum-dried at 80 ° C for 10 hours to obtain 32 g of product.The purity is greater than 99% and the molar yield is 95%. |
90% | With trimethylsilyl bromide In acetonitrile at 65℃; for 1h; | 2 Synthesis of tenopovir (PMPA) 7.3 ml of acetonitrile and 19.4 ml of bromotrimethylsilane were introduced into the obtained residue, and the mixture was stirred at 65 ° C for 1 hour. The reaction mixture was cooled to 25 ° C, concentrated under reduced pressure, completely dissolved by introducing 7.3 mL of water and 73 mL of methanol,A 20% aqueous sodium hydroxide solution To pH 3.0 Titration at 25 °C for 2 hours The crystals produced by stirring were filtered and washed with 36.3 mL of water and 14.5 mL of acetone to obtain 6.7 g (yield 62.2%) of crude tenofovir. To 6.7 g of the above crude flavopir (PMPA)124 mL of water was added, the temperature was raised to 95 C and completely dissolved.The mixture was slowly cooled to 0 to 5°C and stirred for 3 hours. The resulting crystals were filtered and washed with 34 mL of water and 13 mL of acetone to give 6.0 g (yield 90%) of tenopovir (PMPA). Purity: 99.4% by HPLC |
89% | With trimethylsilyl bromide In acetonitrile at 60 - 70℃; for 1h; | 1.3 Step 3: (R) Preparation of -9- [2- (phosphonomethoxy) propyl] adenine (PMPA) 100 ml of acetonitrile and 201 ml of bromotrimethylsilane were added to 142 g of oil (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine, and the mixture was stirred at about 60-70° C. for 1 hour. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure, and 100 ml of water and 1000 ml of methanol were added to completely dissolve. The pH was adjusted to 3.0 using 20% aqueous sodium hydroxide solution and stirred at room temperature for 2 hours. The resulting crystals were filtered, washed with water 300ml and acetone 200ml in that order, and then dried with nitrogen at room temperature, and 69g of the target compound (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) (yield) : 58%) was obtained.1.3L of water was added to 69g of PMPA obtained above, and the temperature was raised to about 90-100° C. and completely dissolved for 30 minutes. The dissolved reaction solution was slowly cooled to about 25° C., then cooled to 0-5° C., and then maintained at this temperature and stirred for 3 hours. The crystals were filtered, washed with water 300ml and acetone 200ml in that order, and then dried at room temperature with nitrogen to obtain 61 g of the target compound (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA) (yield: 89). %) was obtained.Purity: 98.2% by HPLC |
83.8% | With sulfuric acid at 90 - 110℃; | 2 Adenine (17.4 g, 0.13 mol),Sodium carbonate (15.9 g, 0.15 mol)1R-propylene carbonate (15.8 g, 0.15 mol)Was dissolved in 50 mL of N-methylpyrrolidone,Heated to 90 ~ 125 ° C,Insulation at 90 ~ 125 ° CReaction 3 ~ 6 hours;Down to room temperature,Under a argon atmosphere, magnesium tert-butoxide (23.8 g, 0.14 mol) was added,Heating up to 30 ~ 45,Insulation reaction 0.5 ~ 1 hour;DripP-toluenesulfonyloxymethylphosphonic acidDiethyl ester (48.3 g, 0.15 mol)Insulation at 30 ~ 45 ° C continue to react 4 ~ 6 hours; the system down to room temperature,The reaction system was concentrated under reduced pressure to give a viscous oily substance intermediate 2;To the resulting intermediate 2 was added 130 g of concentrated sulfuric acid,Heating up to 90 ~ 110 ° C,Insulation reaction 3 ~ 6 hours;Down to room temperature,The reaction was continued at room temperature for 1 to 2 hours,Filter,The filter cake was washed twice with 150 mL of 5 wt% dilute sulfuric acid aqueous solution, The filtrate with sodium hydroxide solution ρΗ = 2 ~ 3,Crystallization overnight, cooling to 0 ~ 3 ° C,So that the crystallization for 3 hours;Filter,The filter cake was washed once with 30 mL of water,50 mL of water and acetone (V / V = 1: 1) was washed twice,50mL acetone washed once;Vacuum drying,Tylenolide 31g,The total molar yield was 83.8%HPLC purity of 98.5% |
74% | With trimethylsilyl bromide In water at 20 - 90℃; | 2 2. Preparation of (R) -9- [2- (phosphonomethoxy) propyl] -adenine (abbreviated as PMPA): The PMPA diethyl ester obtained in the previous step and 9 g of water were added to a 250 ml four-necked flask, and 44.4 g of trimethylbromosilane was added dropwise at room temperature. The temperature was gradually increased from room temperature to 90 ° C. After completion of the dropwise addition, , The control sample in HPLC, when the PMPA monoethyl ester After adding 160 ml of water to the crude product, the solution was allowed to spontaneously crystallize at room temperature after dissolution. The filter cake was washed with 40 ml of acetone and dried to obtain 11.7 g of the product in 74% yield. |
74% | With hydrogenchloride In water; N,N-dimethyl-formamide at 25 - 75℃; Large scale; | 1-2; 1 SO42-/ZrO2-Nd2O3 type solid acid hydrolyzes (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine to prepare tenofovir (PMPA): Add 20LDMF and 7kg R-hydroxypropyl adenine to a 50L reactor, and stir for 10 minutes. Add 4 kg of magnesium isopropoxide in three portions. The internal temperature rose to 72±2°C. The reaction temperature was controlled to 72±2°C, and 15kg of diethyl p-toluenesulfonyl methoxyphosphonate was added dropwise to the reaction kettle. After the addition is complete, control the temperature to 72±2°C and keep stirring for 6 hours. After the reaction is over, the internal temperature drops to 25±5°C. Control the temperature of the reactor at 25±5°C, and add hydrochloric acid dropwise to the reactor to adjust the pH to 6.5. The internal temperature was raised to 75±5°C, and DMF was concentrated under reduced pressure until no liquid flowed out. After the concentration is completed, the internal temperature is reduced to 30°C, 30L of acetone is slowly added, and the mixture is stirred to dissolve. Stir for 1 hour at the internal temperature of 8±2°C, filter, filter to remove insolubles, collect the filtrate, add the filtrate to a 50L reactor, control the internal temperature to 35±5°C, and concentrate under reduced pressure until no liquid flows out. Add 2.4kg of SO42-/ZrO2-Nd2O3 solid acid, stir to raise the temperature of the oil bath in the jacket of the 50L reactor to 112±2, and slowly add 12L of deionized water to the reactor within 1 hour. After the feeding is completed, keep the temperature of the oil bath in the jacket of the 50L reactor at 112±2°C and stir and react for 12 hours. Filter while hot to filter out SO42-/ZrO2-Nd2O3 solid acid, wash the filter cake 10 times with 20L of hot deionized water at 80°C, and collect the filtrate. Transfer the filtrate to a 50L reaction kettle while it is hot, keep the temperature in the kettle at 65±5°C, add 1 kg of activated carbon with stirring, stir and decolorize for 1 hour, filter while hot, filter out the activated carbon, and collect the filtrate. Transfer the filtrate to a 50L reaction kettle while it is hot, keep the temperature inside the kettle at 65±5°C, add sodium hydroxide solution to the reaction kettle dropwise with stirring, adjust the pH to 2.01, after the addition is complete, slowly reduce the temperature in the reaction kettle 0°C. Stir for 1 hour. Centrifuge the material in the reaction kettle to dryness, wash the filter cake with 50L of water, and take out the filter cake after centrifugation to dryness to obtain a wet product of tenofovir. Control the temperature at 72±2 and dry under reduced pressure for 20 hours to obtain a white powder. Norfovir (PMPA) 7.8kg.The molar yield is 74%, and the HPLC purity is 99.6%. |
73% | With hydrogen bromide In water at 70 - 95℃; for 5h; | 2 Example2Preparation for the tenofovir 1) at 20 ~ 35 conditions, with stirring, 100 grams of HPA was suspended in 300 ml N, N- dimethyl formamide; at 0 ~ 5 , was added 116 g of potassium t-butoxide, stirred for half an hours; 25 ~ 30 , stirred for 2 hours, 49.2 g of magnesium chloride was added, stirred for 1 hour;After the mixture 2) in step 1) was incubated at 60 deg.] C obtained in 2 hours, and warmed to 75 ~ 80 , was added after 200 g DESMP at 75 ~ 80 , stirred for 5 hours;3) The reaction was incubated at 70 deg.] C the solvent was distilled off under reduced pressure, cooled to 25 ~ 35 , aqueous hydrobromic acid was added 600 ml, 90 ~ 95 incubated for 5 hours;4) Step 3) the resulting reaction was cooled to 25 ~ 35 , stirred for half an hour, filtered; the filter cake was washed with 300 ml of methylene chloride;5) After stirring for 1 hour and the filtrate layers were separated; the aqueous layer was neutralized with 50% sodium hydroxide to pH 2.5 ~ 3.0, at 20 ~ 25 conditions, for half hour; 0 ~ 5 , stirred for 4 hours;6) The filter cake was dispersed in 900 ml of water, stirred at 90 ~ 95 1 hour, cooled to room temperature, and then cooled to 0 ~ 5 stirred for 4 hours;7) and the filter cake washed with 50 ml of cold water, then washed with 100 ml of cold acetone, 70 ~ 75 dried to obtain 109 g tenofovir, yield 73%. |
67% | With hydrogen bromide; acetic acid at 75℃; for 3h; | |
33% | With hydrogen bromide at 80℃; for 8h; | 5.3 paration of tenofovir (IV) monohydrate The resulting pale yellow oil was dissolved in 40% hydrobromic acid solution (150.00 g), reacted at 80 ° C for 8 h, cooled to room temperature and washed with ethyl acetate (120 mL). The aqueous phase was partitioned between acetic acid Ethyl acetate (120 ml) and adjusted to pH 2.5 to 3.5 with sodium hydroxide solution. The mixture was cooled to 2 ° C, stirred and crystallized. The solid was filtered, washed with acetone and dried in vacuo to give the monohydrate tenofovir (IV) 18. 88 g, total yield of 33% in two-step reaction (Examples 3 and 5). |
24% | With chloro-trimethyl-silane; sodium bromide In 1-methyl-pyrrolidin-2-one at 0 - 75℃; for 16h; | Example I (OPRD route) Example I (OPRD route)A solution of PPA 2 (- 2.59 mmol) in NMP (2.5 ml) was treated with sodium bromide (0.933 g, 9.07 mmol, 3.5 eq). The solution was cooled to 0-5 °C and TMSCI (1.491 g, 1.74 ml, 13.73 mmol, 5.3 eq) was added over ten mm, and the reaction was then heated to 75 °C and stirred for 16 h at this temperature. The reaction mixture was cooled to 20-25 °C and diluted with water (5 m) and washed twice by extraction with ethyl acetate (2 x 5 ml). The aqueous layer was cooled to 5 °C, the pH adjusted to between 2.8 and 3.2 with 40% NaOH (aq) crystallizing the product. The resulting precipitate was stirred at 5 °C for 2 h and the product isolated by filtration. The solids were washed with chilled water (5 °C, 0.75 ml) and dried under vacuum below 65 °C to yield PMPA 3 as a white solid (178.9 mg, 24%). |
With trimethylsilyl bromide; water 1.) MeCN, RT, 2.) acetone, 4 deg C; Yield given. Multistep reaction; | ||
With sodium hydroxide; trimethylsilyl bromide 1.) acetonitrile, reflux, 2.) H2O, pH 3; Yield given. Multistep reaction; | ||
Multi-step reaction with 2 steps 1: chlorobenzene / 9 h / 125 °C 2: 30.3 g / water | ||
With trimethylsilyl bromide In acetonitrile at 50 - 75℃; for 2 - 4h; Heating / reflux; | ||
With trimethylsilyl bromide In acetonitrile at 70℃; for 4h; Inert atmosphere; | 4 Preparation of 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) Crude (R)-9-[2-(diethoxyphosphinylmethoxy)propyl]adenine (100 g) was dissolved in acetonitrile (122 ml), then bromotrimethylsilane (207 g) was added under nitrogen. The reaction mixture was refluxed for 4 hours at 70° C., solvent was distilled off under vacuum after TLC showed the complete disappearance of starting material, the residue was dissolved with 200 ml of water, cooled to 20° C. and washed with dichloromethane or ethyl acetate. The pH value of aqueous phase was adjusted to 3.13.5 by 50% aqueous sodium hydroxide solution, stirred slowly at room temperature for about 3 hours, the resulting solids were collected by filtration and washed by cold water (50 ml) and acetone (50 ml) respectively to give 60 g of crude PMPA. 200 ml of 90° C. pure water was added to crude PMPA, after efficient stirring, the mixture was cooled to room temperature and kept overnight. The solids that formed were collected by filtration and washed with cold water and acetone continuously, dried under vacuum at 50° C. to afford 45 g of PMPA with purity 99% by HPLC. | |
3.72 g | With chloro-trimethyl-silane; sodium bromide In 1-methyl-pyrrolidin-2-one at 0 - 75℃; | |
Stage #1: (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate With hydrogen bromide In water at 90 - 95℃; for 5h; Stage #2: With sodium hydroxide In water at 0 - 30℃; for 4h; | 2 Preparation of Tenofovir (using sodium hydride and magnesium chloride). EXAMPLE 2: Preparation of Tenofovir (using sodium hydride and magnesium chloride). To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged dimethyl formamide (500 ml) and 9-[2-(R)-(hydroxy)propyl] adenine of formula III (100 gms) at temperature 20°C to 35°C. Cooled to 0°C to 5°C and added sodium hydride (41.5 gms) and stirred for 60 minutes at same temperature. Heated to 25°C to 30°C and added magnesium chloride (56 gms) and stirred for 2 hours at 25°C to 30°C. To the reaction mass added diethyl p-toluene sulfonyloxy methyl phosphonate (225 gms) at 25°C to 30°C and stirred for 1 hour at same temperature. Heated to 70°C to 75°C and stirred for 4 hours at same temperature. Reaction was monitored by HPLC and observed 75% of the reaction product formed. Cooled the reaction temperature to 25°C to 30°C and added methanol (20 ml) and then solvent was removed from the reaction mixture by distillation under vacuum at below 70°C to obtain (R)-9-[2-(diethylphosphono methoxy) propyl] adenine of formula II as thick residue.Cooled the resultant residue to 25°C to 35°C and charged aqueous hydrobromic acid (524ml). Heated to 90°C to 95°C and stirred for 5 hours at same temperature. After completion of the reaction, the reaction mass was cooled to 25°C to 30°C and stirred for 30 minutes at same temperature. Filtered the salts formed and washed the salts with methylene chloride (300 ml). Taken filtrate and separated methylene chloride layer from the aqueous layer and then adjusted the aqueous layer pH to 2.5 to 3 with 50% sodium hydroxide solution at 20°C to 30°C. Cooled the solution to 0°C to 5°C and stirred for 4 hours. Filtered the precipitated product and washed with chilled water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product charged water (1200 ml), heated to 95°C to 100°C and stirred for 30 minutes at same temperature. Cooled to 25°C to 30°C and then to 0°C to 5°C and stirred for 4 hours. Filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70°C to 75°C under reduced pressure to provide the title compound. Yield: 85 gms. HPLC purity: 98.7% | |
Stage #1: (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate With hydrogen bromide In water at 90 - 95℃; for 2h; Stage #2: With water; sodium hydroxide at 0 - 30℃; for 5h; | 1 EXAMPLE 1 :Preparation of Tenofovir (using sodium amide and magnesium chloride).To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged dimethyl formamide (400 ml) and 9-[2-(R)- (hydroxy)propyl] adenine of formula III (100 gms) at temperature 20°C to 35°C. Cooled to 0°C to 5°C and added sodium amide (40.4 gms) at temperature 0°C to -10°C and stirred for 30 minutes at same temperature. Heated to 25°C to 30°C and stirred for 2 hours at same temperature. Added magnesium chloride (49.2 gms) and stirred for 1 hour at 25°C to 30°C. To the reaction mass was charged toluene (300 ml) and heated to 50°C to 55°C and stirred for 4 hours at same temperature and then again heated to 75 °C to 80°C. At this temperature added diethyl p-toluene sulfonyloxy methyl phosphonate (250 gms) and stirred for 2 hours at same temperature. After completion of the reaction, the solvent was removed from the reaction mixture by distillation under vacuum at below 70°C to obtain (R)-9-[2-(diethylphosphono methoxy) propyl] adenine of formula II as thick residue. Cooled the resultant residue to 25°C to 35°C and charged aqueous hydrobromic acid (650 ml). Heated to 90°C to 95°C and stirred for 2 hours at same temperature. After completion of the reaction, the reaction mass was cooled to 25°C to 30°C and stirred for 30 minutes at same temperature. Filtered the salts formed and washed the salts with methylene chloride (300 ml). Taken filtrate and separated methylene chloride layer from the aqueous layer and then adjusted the aqueous layer pH to 2.5 to 3 with 50% sodium hydroxide solution at 20°C to 30°C. Stirred the solution for 1 hour at 20°C to 25 °C and cooled to 0°C to 5°C and then stirred for 4 hours. Filtered the precipitated product and washed with chilled water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product charged water (900 ml), heated to 90°C to 95°C and stirred for 30 minutes at same temperature. Cooled to 25°C to 30°C and then to 0°C to 5°C and stirred for 4 hours. Filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70°C to 75°C under reduced pressure to provide the title compound.Yield: 90 gms.[0076] HF-LC purity: 98.5%[0077] HPA: Not detected[0078] The XRPD is set forth in Figure- 1 | |
With hydrogen bromide; acetic acid In 1-methyl-pyrrolidin-2-one; water at 90 - 95℃; | 2 EXAMPLE 2Preparation of TenofovirN-methyl-2-pyrrolidone (25 gm) was taken along with toluene (150 gm) into a reaction vessel. 1-(6-amino-purin-9-yl)-propan-2-ol (100 gm); toluene-4-sulfonic acid diethoxy phosphoryl methyl ester (200 gm) and magnesium ter-butoxide (71.2 gm) were also taken at 25-35° C. Temperature was raised to 74-75° C. and maintained for 5-6hrs. After completion of reaction, acetic acid (60 gm) was added and maintained for 1 hr. Later aq.HBr (332 gm) was taken and heated to 90-95° C. After reaction completion, salts were filtered and filtrate was subjected to washings with water and extracted into methylene dichloride. Later pH was adjusted using CS lye below 10° C. Tenofovir product was isolated using acetone.Yield: 110 gm. | |
82 g | With hydrogenchloride; N,N-dimethyl-formamide at 0 - 95℃; for 4h; | 2 EXAMPLE 2 Preparation of Tenofovir using dimethyl formamide-hydrochloric acid complex. To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel dimethyl formamide (200 ml), 9-[2-(R)- (hydroxy)propyl] adenine (HP A) (100 gms) and Magnesium t-butoxide (72gms)were charged at temperature 20°C to 35°C and stirred for 30 minutes at same temperature. Diethyl p-toluene sulfonyloxy methyl phosphonate (225gms) (DESMP) was added and temperature was raised to 75 °C to 80°C and stirred for 2 hours at same temperature. Reaction mass was cooled to 0°C to 5°C and dry hydrochloric acid gas was passed for 5 hours. Reaction mass was heated to 90°C to 95°C and maintained for 4 hours. After completion of the dealkylation and monitored by HPLC, the solvent was removed completely under vacuum below 70°C and water (400 ml) was added to the resultant residue at temperature 60°C to 65°C. Adjusted pH of the reaction mass to about 1 with Concentrated HQ. Filtered the salts formed and washed the salts with 10% HC1 solution. Filtrate was taken and pH was adjusted to about 2.5 with 50% NaOH solution and the reaction mass was cooled to 0° to 5°C. Filtered the precipitated product and washed with water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product water (800 ml) was charged and heated to 90°C to 95°C. Temperature was cooled to 25 °C to 30°C and filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70°C to 75°C under reduced pressure to provide the title compound. Yield: 82gms. HPLC purity: 99.2% |
With hydrogen bromide In water at 25 - 95℃; for 5h; | 2 EXAMPLE 2 Preparation of Tenofovir (Using Sodium Hydride and Magnesium Chloride) Cooled the resultant residue to 25° C. to 35° C. and charged aqueous hydrobromic acid (524 ml). Heated to 90° C. to 95° C. and stirred for 5 hours at same temperature. After completion of the reaction, the reaction mass was cooled to 25° C. to 30° C. and stirred for 30 minutes at same temperature. Filtered the salts formed and washed the salts with methylene chloride (300 ml). Taken filtrate and separated methylene chloride layer from the aqueous layer and then adjusted the aqueous layer pH to 2.5 to 3 with 50% sodium hydroxide solution at 20° C. to 30° C. Cooled the solution to 0° C. to 5° C. and stirred for 4 hours. Filtered the precipitated product and washed with chilled water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product charged water (1200 ml), heated to 95° C. to 100° C. and stirred for 30 minutes at same temperature. Cooled to 25° C. to 30° C. and then to 0° C. to 5° C. and stirred for 4 hours. Filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70° C. to 75° C. under reduced pressure to provide the title compound. Yield: 85 gms. HPLC purity: 98.7%. |
|
68 g | With hydrogen bromide In water at 95℃; for 5h; | Example RRN 26Preparation of Tenofovir Using Aqueous HBr (U.S. Pat. No. 8,049,009) Comparitive Example RRN 26Preparation of Tenofovir Using Aqueous HBr (U.S. Pat. No. 8,049,009) [0097] To a clean 3-necked 2 L round bottom flask dimethyl formamide (200 ml) and 9-[2-(R)-(hydroxy)propyl] adenine (100 gms) were charged at temperature 25° C. to 35° C. and stirred for 5 minutes. Magnesium tert-butoxide (72 gms) was charged and heated to 60° C. Maintained for 1 hour at 60° C. to 65° C. and again heated to 75° C. Diethyl p-toluene sulfonyloxy methyl phosphonate (200 gms) (DESMP) was added in 2 hours time and stirred for 5 hours at 75° C. to 80° C. Reaction mass was cooled to 25° C. to 35° C. and acetic acid (60 gms) was added. Distill off the solvent completely under vacuum at below 80° C. to obtain the residue. To the residue, water (200 ml) and methylene chloride (1000 ml) were charged and filtered the salts formed and washed the salts with methylene chloride (3×200 ml ). Filtrate was separated and aqueous layer was washed with methylene chloride (300 ml). Distill off the entire organic layer completely under vacuum up to 80° C. to obtain the tenofovir phosphonate diester residue. To the residue charged aqueous hydrobromic acid (470 ml) at 25° C. to 35° C. and heated to 95° C. and stirred for 5 hours at same temperature.The reaction mass was cooled to 25° C. to 35° C. and water (300 ml) was charged methylene chloride (300 ml) and stirred for 15 minutes. The methylene chloride layer was separated and adjusted the pH of aqueous layer to 2.5 to 3.0 with 50% NaOH solution at 25° C. to 30° C. Stirred for 4 hours at same temperature and cooled to 0° C. to 5° C. and stirred for 4 hours at same temperature. Precipitated product was filtered and washed with chilled water(100 ml) and then finally washed with chilled acetone(200 ml). The wet cake was dissolved in water (1000 ml) at temperature 95° C. to 100° C. The solution was cooled to 25° C. to 30° C. and then to 5° C. and stirred for 4 hours at 0° C. to 5° C.Precipitated product was filtered and washed with chilled water (50 ml) and chilled acetone (100 ml). The wet compound was dried at 70° C. to 75° C. under vacuum for 12 hours to obtain the title compound. [0098] Yield: 68 gms. [0099] HPLC purity: 98%. |
4.2g | Stage #1: (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate With trimethylsilyl bromide In acetonitrile at 65℃; for 1h; Stage #2: With water; sodium hydroxide at 20℃; for 2h; | 1 Example 1: Preparation of tenofovir (PMMA) Insert the acetonitrile and 5 bromo trimethylsilane 14 the oil on the (R) -9- [2- (diethyl phosphono-methoxy) propyl] adenine (DPPA) was stirred for 1 hour at about 65 °C . After cooling the reaction solution to room temperature it was concentrated under reduced pressure and dissolved completely by introducing the water and methanol 5 50. Using 20% sodium hydroxide aqueous solution adjusted to pH 3.0 and at room temperatureStirred for 2 hours. Filtering the crystal blank, and the target compound tenofovir nitrogen dried at room temperature and then washed with water and acetone 25 10 net (PMPA), 5.0g (yield: 67%). To give the obtained tenofovir (PMPA) in the water 90 to 4.9g and the temperature was raised to about 95 °C completely dissolved for 30 minutes. After cooling the reaction mixture gradually dissolved to about 25 was cooled again to 3 kept at said temperature and stirred for 3 hours. After filtering the crystals, washed with water and acetone 25 10 order to dry nitrogen at room temperature, tenofovir (PMPA)4.2g (yield: 86%) was obtained |
With hydrogen bromide for 10h; Reflux; | 2 Synthesis of tenofovir A solution of (R) -9- [2- (diethoxyphosphonoylmethoxy) propyl] adenine was added to a reaction vessel,450 g of hydrobromic acid was added,Stirring,Heated to reflux for 10 hours,The reaction was terminated.Vacuum distillation,Cooled to room temperature,Dichloromethane and water were added in an appropriate amount,Separation and extraction of methylene chloride layer, with 20% sodium hydroxide solution to adjust pH3.0, cooling to 10 ° C, crystallization for 12 hours, filtration, the tenofovir crude. Add the right amount of water, heated to dissolve the solid, cooling to 10 ° C, crystallization for 12 hours, filtration, tenofovir boutique. 55 decompression drying, was tenofovir dry goods. | |
45 g | With chloro-trimethyl-silane; potassium iodide In acetonitrile at 70℃; for 4h; | 1.4 Synthesis of (R) -9- [2- (phosphonic acid methoxy) propyl] adenine (PMPA) In 1000ml three bottles,A solution of 100 g of (R) -9- [2- (diethylphosphonoylmethoxy) propyl] adenine crude, 122 ml of acetonitrile, 50 g of potassium iodide and 207 g of trimethylchlorosilane was added and the mixture was heated to 70 ° C with stirring. 4 hours. And then distilled under reduced pressure to the oil. The residue was dissolved in 200 ml of water and cooled to 20 ° C. The lower aqueous phase was separated and the aqueous phase was washed with 30%The alkali was adjusted to pH 3.1 to 3.5, stirred at room temperature for about 3 hours, filtered and the filter cake was washed with 50 ml of ice water and 50 ml of acetone to obtain 60 g of crude PMPA.To the crude PMPA, add 200ml of pure water (preheated to 90 ). The mixture was stirred for 3 hours and then cooled to 25 . The filtrate was washed continuously with ice water and acetone. The filter cake was dried in vacuum at 50 ,Get 45 grams of PMPA. |
9 kg | With hydrogenchloride In water; N,N-dimethyl-formamide at 15℃; for 1h; Autoclave; Large scale; | 3 3) preparation of (PMPA) tynofovir Adding glass autoclave convenient replacement adenine (7.5 kg, 55 . 50mol), R-propylene carbonate (8.25 kg, 80 . 81mol), DMF (30 kg, 410 . 45mol) and NaOH (0.23 kg, 5 . 75mol), stirring the mixture at room temperature for 10 minutes, the system, to start-up of heating 120-130°C, thermal reaction, every 1 hour detecting TLC, the reaction is complete, to stop the reaction, cooling to 45-60°C, joins uncleding Chunmei in the reaction liquid (7.4 kg, 43 . 39mol), then heating to 60-80°C, start dropping paratoluene sulfonyloxy phosphoric acid diethyl ester (30 kg, 93 . 08mol), add reaction is preserved after the 6-hour, tracking of the reaction, to be (R) - 9 - (2-hydroxy-propyl) adenine after the reaction is complete, cooling to 60 °C, plus 4.5 kg acetic acid, stirring 10 minutes, to concentrated under reduced pressure, to obtain R-9 [(diethyl phosphinylidyne methoxy ) propyl] purine, cooling to 50 °C, by adding the mass concentration is 30% hydrochloric acid of 37.5 kg, stirring to dissolve, cooling to 15 °C the following stirring 1 hour, a large number of solid precipitation, filtration of the solid, the filtrate in the 85 °C sustained-access access 6kgHCL gas, reaction 18 hours, to after the reaction is complete, reaction solution is concentrated under reduced pressure to the slurry, by adding 45 kg water, stirring to dissolve, PH value is adjusted with ammonia water to the 3.0-3.5, obtained crude PMPA, filtering out the solid, using 10 times the crystallization is provided, to filter out solid and atmospheric drying is 9 kg of refined PMPA, ≥ 99% purity, the yield is 120%. |
With hydrogen bromide In N,N-dimethyl-formamide at 90 - 100℃; Inert atmosphere; | 1 Example 1 Preparation of high purity tenofovir (one pot method and acid and alkali method) In sequence under nitrogen protection, DMF (50g), R-propylene carbonate (17.2g, 168mmol), adenine (20g, 148mmol), and NaOH (0.2g, 5mmol), heating to 125-135°C, and thermal insulation reaction 6-8 hours; cooling to 60-70°C, ding Chunmeijoins uncle (20.3g, 119mmol), then dropwise DESMP (64g, 199mmol), the drop finishes, 60-70 °C insulation reaction 6-8 hours, esterification reaction is over, cooling, adds the second grade acid is neutralized, decompression does thickly DMF (80 °C, the [...] 5mmHg), added 48% hydrobromic acid of (160g) dissolves uniform, heating to 90-100 °C insulation reaction 3-5 hours, cooling to 20-25°C, then adding 40% NaOH solution regulating PH value to 3.0, cooling to 5-8 °C crystallization 3 hours, filtered, to crude PMPA 48g, PMPA crude in 20-25 °C with 5% hydrochloric acid (140g) dissolved, then using 5% sodium hydroxide (175g) adjusting PH value to 2.5, cooling to 0-5°C, thermal insulation 1h, filtering, washing two times with water, 100 °C -105 ° C drying to obtain the finished product 24.7g, HPLC purity 99.6%. (Molar yield to adenine as 58%). | |
33 g | With trimethylsilyl bromide In acetonitrile for 5h; Reflux; | 1 Synthesis of Tenofovir ((R)-9-[2-(phosphonomethoxy)propyl]adenine, Tenofovir) Tenofovir ester (DEPMPA) obtained in the above procedure was dissolved in 200 ml of acetonitrile, and 120 ml of bromotrimethylsilane was added thereto to effect a reflux reaction. After 5 hours reaction, the reaction was completed (14 hours) while checking the reaction process by TLC and HPLC. The reaction solution was diluted with 200 ml of cold purified water, and then washed with 200 ml of ethyl acetate twice to remove the trimethylsilane component. The aqueous solution was concentrated under reduced pressure at room temperature to build up a residual solvent amount in the vessel, Respectively.Next, the aqueous solution was neutralized with 50% sodium hydroxide to adjust pH to 3. The resultant crystals were filtered and washed with cold purified water (5 ) to obtain tenofovir 1 crystal water (H 2 O). The crystals were dried under reduced pressure (30 Torr) at 65 DEG C to obtain 35.2 g of the crystals (Yield: 55.6%). The crystals obtained above were further dried under reduced pressure at 100 ° C (30 Torr) to finally obtain 33 g of terpovorillone crystals (anhydrous yield: 55.4%). |
With trimethylsilyl bromide In 1-methyl-pyrrolidin-2-one at 70℃; for 19h; Large scale; | 1.2 2. To the NMP solution of TNF-2, 5.4 kg of trimethylbromosilane was added dropwise, About 1 hour drop finished, And then heated to 70 ° C, The reaction was carried out for 18 hours. After completion of the reaction, To the reaction solution was slowly added 10 L of water, After shaking, add 10L * 2 ethyl acetate to wash the aqueous phase. Aqueous phase at 2 deg C with 20% NaOH solution water phase pH of about 3, Slowly stir the crystal overnight. filter, Dry for 12 hours, TNF-2 crude, In the crude product by adding 30L reactor, Add 15 L of water, Stir, Heated to 100 ° C. The solution was naturally cooled to 0-5 ° C, A large number of white solid wash out, The crystals were allowed to stand at 0-5 ° C for 3-4 hours. filter, Dried to give TNF-2. | |
5.95 g | With trimethylsilyl bromide In 1-methyl-pyrrolidin-2-one at 0 - 77℃; for 8h; | 1 Preparation of tenofovir 20 ml of 1-methyl-2-pyrrolidone (ΝΜΡ) was added to the reaction flask, adding (R) -9- [2- (light) propyl] adenosine (4.0 g, 21.0 mmol, 1 eq.) under stirring and heated to 65 ° C. To the mixture was added magnesium tert-butoxide (3.0g, 17.3mmol, 0.8eq.) over a period of 1 hour, maintaining the temperature at 78 ° C, A solution of diethyl p-fluorobenzenesulfonyloxymethyl phosphonate (10 · 14g, about 31 · 1mmol, 1.5 eq.).was added slowly over 2 hours. At 75~80 ° C The reaction was stirred for 7 hours, cooled to room temperature, ice-cooled to 0~5 ° C, was added dropwise trimethylsilyl bromide (12.9g, 84.3mmo 1,4. 0eq.), Then the reaction mixture was heated at 77 ° C for 8 hours. The reaction was stopped, 20 ml of water was added to the reaction solution, and the mixture was extracted twice with 50 mol of ethyl acetate. The aqueous layer was stirred under ice-cooling, adjusted to pH 2.5 to 3.1 with 50% NaOH solution and precipitated as an off-white solid for at least 3 hours. Filtration, drying of tenofovir 5.95g, yield 64% |
45 g | With trimethylsilyl bromide In acetonitrile for 5h; Reflux; | The tenofovir ester (DEPMPA) was dissolved in 200 ml of acetonitrile and then refluxed with 120 ml of bromotrimethylsilane. In 5 hours of the reaction, the reaction process was examined through TLC and HPLC and terminated (taking 12 hours). 200 ml of cold purified water was carefully added to dilute the reactant solution, which was then washed twice with 200 ml of ethyl acetate to remove the trimethylsilane component. The aqueous solution thus obtained was concentrated under slightly reduced pressure at the room temperature to eliminate the remaining solvent in the container and cooled down to 5° C. Subsequently, the aqueous solution was neutralized with a 40% solution of sodium hydroxide to pH 3.5, and a reverse ion-exchange resin (Dowex 50W cation exchange resin) was used to precisely control the pH value to 3.2. The crystals thus obtained were collected through filtration and washed with cold purified water (5° C.) to obtain tenofovir crystals. The crystals were dissolved in 400 ml of methanol, filtered to remove the ion-exchange resin and concentrated under reduced pressure. The residual crystals were dried at the internal temperature of ° C. in a drier under vacuum (30 Torr) to obtain 48.0 g of tenofovir crystals (yield 75.9%). The crystals thus obtained were dried at 95° C. under reduced pressure (30 Torr) again to yield 45 g of anhydrous tenofovir crystals (anhydrous yield 75.7%). The anhydrous tenofovir was used to synthesize tenofovir disoproxil (Teno-D) according to the following procedures. |
With hydrogen bromide | ||
With trimethylsilyl bromide In 1-methyl-pyrrolidin-2-one at 75℃; Large scale; | 1.S02-10.S02; 1.S02-10.S02 S02 hydrolysis: (R)-9-(2-phosphonomethoxypropyl)adenine di(ethyl) esterThe N-methylpyrrolidone solution is added to the reaction kettle.9.25 kg of trimethylbromosilane was added with stirring, and the addition was completed in about 1 hour.Reheat at 75 ° C, stir the reaction, vacuum and concentrate under reduced pressure; after concentration, cool down,Add 15 L of purified water, wash twice with 20 L of ethyl acetate, and adjust the pH of the aqueous layer to 3 with 40 wt% NaOH solution.The mixture was cooled to 0-5 ° C and slowly stirred for crystallization. After 3 hours, it was centrifuged and washed with 2 L of ice water.The obtained solid was beaten by centrifugation with a 70% ethanol aqueous solution to obtain a crude solid tenofovir. | |
With trimethylsilyl bromide In 1-methyl-pyrrolidin-2-one at 75℃; for 1h; | 1.02 S02 hydrolysis:(R)-9-(2-phosphonomethoxypropyl) adenine di(ethyl) ester N-methylpyrrolidone solution was added to the reaction kettle, and 9.25 kg of trimethylbromosilane was added with stirring. After about 1 hour, the addition was completed, and the mixture was further heated at 75 ° C. The reaction was stirred and concentrated under vacuum. After concentration, the temperature was lowered, 15 L of purified water was added, and the mixture was washed twice with 20 L of ethyl acetate, and the aqueous layer was adjusted with a 40 wt% NaOH solution. The value is 3, the temperature is lowered to 0-5 ° C, the mixture is slowly stirred, and after 3 hours, it is centrifuged and washed with 2 L of ice water.The obtained solid was beaten by centrifugation with a 70% ethanol aqueous solution to obtain a crude solid tenofovir. | |
Stage #1: (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate With trimethylsilyl bromide In acetonitrile at 60 - 75℃; Large scale; Stage #2: With sodium hydroxide In water at 22 - 50℃; Large scale; | 1.5 Step 5. (R)-9-[ 2-(Phosphonomethoxy) propyl]adenine, crude: Bromotrimethylsilane (1.56 kg) was added to a solution of crude (R) -9- [2- (diethylphosphonomethoxy) propyl] adenine (1.0 kg based on the adenine charge from step 4 above) and acetonitrile (0.9 kg) Is added to the reactor containing the mixture with cooling so as to maintain a temperature of only about 50 ° C. The tubing was rinsed with acetonitrile (0.3 kg) and the mixture was refluxed at about 60-75 ° C. for about 2-4 hours, with medium stirring to prevent splashing of the contents of the reactor. Completion of the reaction is monitored by showing the residual of total monoethyl PMPA and diethyl PMPA where the area normalized HPLC is only about 3%. When the reaction is complete, additional bromotrimethylsilane (0.04 kg) is placed in the reactor and the reaction is refluxed with moderate stirring for at least about 1 hour. Volatiles are removed by distillation at a temperature of only about 70 ° C., initially at atmospheric pressure and then at a temperature of only about 70 ° C. in a vacuum (about 24-27 inches Hg (in Hg)). The reactor was then cooled to about 20 ° C. (typically about 15-25 ° C.) and water (1.9 kg) was added to the residue (exothermic addition) while maintaining the temperature at about 50 ° C. )did. The mixture is cooled to 20 ° C. and washed with dichloromethane (1.7 kg) while stirring for about 30 minutes. The isolated aqueous phase is then filtered through a 1 μm cartridge filter, diluted with water (3.2 kg), heated to about 40 ° C. (typically about 35 to 50 ° C.) and heated to about 45 ° C. While maintaining the temperature, adjust the pH to about 1.1 (typically about 0.9 to 1.3) with aqueous sodium hydroxide solution (about 0.15 kg NaOH as a 50% solution). PMPA seed crystals are added to the mixture and while maintaining the temperature at about 45 ° C. (typically about 35 ° C. to 50 ° C.), the pH is reduced to about 50% with an aqueous 50% sodium hydroxide solution (required about 0.15 kg NaOH) Adjust to 2.8 (typically about 2.6 to 3.0). Prevent splashing of the contents with slow to moderate agitation and cool the solution to about 22 ° C. (typically about 15-25 ° C.) for about 3 to 20 hours. Meanwhile, the product starts precipitating at about 35 ° C. Adjust the pH of the slurry to about 3.2 (typically about 3.1 to 3.3) (typically using 50% aqueous sodium hydroxide or concentrated hydrochloric acid as needed). Cool the slurry to about 5 ° C. (typically about 0 to 10 ° C.) and slowly stir at that temperature range for at least about 3 hours. The solid is collected by filtration and washed successively with cold water (0.35 kg) and acetone (0.3 kg) to give crude PMPA as a wet solid, typically about 97% pure. Heat the product to about 50 ° C. and dry under vacuum to a water content of less than 10%. The amount of diethyl PMPA is calculated from the amount of adenine used in the step prior to synthesis (estimated yield 100%) and calculated from the net weight of crude diethyl PMPA (which may contain other compounds) It is not done. | |
36.33 g | With hydrogenchloride In water at 75℃; for 11h; | 5.3; 6.3 The third step: preparation of anhydrous tenofovir (IV) The pale yellow oil obtained in Example 3 was dissolved in 61% (0.725 mol) of 36% concentrated hydrochloric acid solution, and reacted at 75 ° C for 11 h.After cooling to 45 ° C, the concentrate was washed with ethyl acetate (320 ml) and water (160 ml).The layers were separated and the aqueous phase was washed with ethyl acetate (320 ml).The aqueous phase is then cooled to 5 ° C.And use 40% sodium hydroxide solution to adjust the pH to 2.8 ~ 3.2,The mixture was decanted at the same temperature for 8 h, and the solid was filtered and washed with 150 ml of cold water.Vacuum drying at 80 ° C for 12 hgetTenofovir (IV) 36.33g anhydrous(0.127 mol), two-step reaction (Examples 3 and 5)The total molar yield was 61%. |
With trimethylsilyl bromide at 0 - 80℃; for 10h; Industrial scale; | 2 Step 2, Preparation of Intermediate TN03 The 200L glass-lined reaction tank equipped with TN02 is cooled to 0 °C.Connect the exhaust gas absorption device,48kg of trimethylbromosilane was added dropwise, and the exotherm was drastic during the addition.Control the internal temperature does not exceed 60 ° C, drop, heat up,The internal temperature was controlled at 60-80 ° C, stirred for 10 h, and sampled by HPLC.After the reaction was completed, the pressure was concentrated under reduced pressure until no significant fraction was obtained.Continue to cool down to the internal temperature of 0 ~ 20 ° C,Start adding 20kg of purified water; when the system has no obvious exotherm,Then, 100 kg of purified water was directly taken in.Transfer the reaction solution to a 300 L reaction tank, add 80 kg of ethyl acetate, and stir for 30 min.Allow to layer and collect the water layer.Transfer the water layer to a clean 300L glass-lined reaction tank and start stirring.Cool down to an internal temperature of 0 to 20 ° C,Start slowly adding the prepared 50% aqueous sodium hydroxide solution.Adjust the pH to 3~5, adjust and stir for 2h. The TN03 crude product can be obtained by diafiltration. Add 300 kg of purified water to a 500 L glass-lined reaction tank.The mixture was stirred, and the crude TN03 was added, and the mixture was heated to reflux for 1 h.Then cool down to 0 ° C,Stir for 3 to 6 hours with heat preservation.The filter cake is evenly spread and placed in a hot air circulating oven for drying.After 24~36h, the material is weighed.Calculate the yield; then TN03 can be obtained.The HPLC purity was 99.5% and the two-step yield was 64%. | |
With trimethylsilyl bromide at 60℃; for 0.416667h; | 1.C; 2.C; 3.C C) Preparation of tenofovir: step B)a solution of (R)-9(2-phosphonomethoxypropyl)adenine di(ethyl) ester in a mixing kettle,Add in agitated stateTrimethylbromosilane, then heated to 60 ° C, stirred for 25 min,Then it was naturally cooled to room temperature, and water and ethyl acetate were added, and the mixture was stirred for 10 min, and then layered.The water layer is cooled and added to the NaOH solution to adjust the pH to 4, followed by stirring and crystallization.After the crystal quality is no longer increased, centrifugation is performed, and the crystal is washed with water.Then add the mixing kettle to heat to 95 ° C, until the solid is completely dissolved,The mixture is naturally cooled to room temperature, and the solid obtained by recrystallization is centrifuged and dried.Tenofovir was obtained, which was used; wherein the NaOH solution in step C) was a 40% NaOH solution. | |
1.28 kg | Stage #1: (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate With chloro-trimethyl-silane; sodium bromide at 30 - 60℃; for 10h; Large scale; Stage #2: With sodium hydroxide In dichloromethane Large scale; | 4-6 Preparation of compound VII Add 5L DMF to the reactor, add 1.25kg (6.47mol) of compound IV and 6.47mol of magnesium tert-butoxide under stirring and react at 50 for 1h, then add 7.76mol of compound V, and react at 60 for 4h after dripping.TLC monitors the reaction. After finishing, add 25.88mol of sodium bromide and dropwise add 32.35mol of trimethylchlorosilane when the temperature is lower than 30. After the dripping is completed, the temperature is controlled at 60 and react for 10h.TLC monitors the completion of the reaction.Then it is hydrolyzed and extracted with dichloromethane to collect the aqueous phase, then adjust the pH to 2.5-3.5 with sodium hydroxide solution, and stir for 1-2h after the solid is precipitated, filter, add water and acetone to rinse in sequence,The obtained crude product was refined with water and dried in vacuum to obtain 1.28 kg of compound VII, with a yield of 65.0%, a purity of greater than 99%, and a maximum single impurity of less than 0.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; thionyl chloride In dichloromethane at 20℃; for 0.5h; | ||
6.7 g | With thionyl chloride for 1.5h; Reflux; | 2.1 PMPA (5 g, 17.8 mmol) was added to 20 ml of thionyl chloride, After stirring and heating to reflux for 1.5 hours, the solid dissolved in the system, Samples were added to anhydrous methanol to monitor the conversion of the starting material. The reaction solution was concentrated under reduced pressure to dryness, To give a foamy solid PMPA-2Cl, weighing 6.7 g; |
With thionyl chloride In acetonitrile for 4h; Reflux; Large scale; | 1.1 first step:6-amino-9 - [(2R) -2- (dichlorophosphorylmethoxy)Propyl] purine(1B) A solution of [[(1R) -2- (6-aminopurine-9-yl) -1-methylethoxy] methyl](PMPA, Tenofovir) (1 kg, 3.48 mol) was dissolved in acetonitrile (5.0 L)Dropping at room temperatureDichloro(1.65 kg, 13.92 mol),The temperature was raised to reflux for 4 hours. The reaction solution was cooled to room temperature,And concentrated under reduced pressure to give the title product as a yellow solid6-amino-9 - [(2R) -2- (dichlorophosphorylmethoxy) propyl] purine(1B), the crude product weight of 1.60kg, directly to the next step. |
110 g | With thionyl chloride at 70℃; Inert atmosphere; | 1 Preparation of III IV (100 g, 0.348 mol) was placed in a 2 L three-necked flask,Under the addition of dichlorosulfoxide (1 L), heated to the outside temperature of 70 degrees reflux reaction overnight,TLC showed the reaction was complete and the solvent was evaporated to dryness to give 110 g (0.341 mol, yield 97.9%) of crude III as a pale yellow solid. |
With thionyl chloride In acetonitrile for 3h; Reflux; | 1.1 first step:6-amino-9 - [(2R) -2- (diphenoxyphosphorylmethoxy) propyl] purine (1C) 9 - [(2R) -2- (diphenoxyphosphorylmethoxy) propyl] purin-6-amineA solution of [[(1R) -2- (6-aminopurine-9-yl) -1-Methyl ethoxy] methyl] phosphoric acid(PMPA, Tenofovir) (400 g, 1.4 mol) was dissolved in acetonitrile (2.5 L)Dropping at room temperatureDichloroacid (666 g, 5.6 mol),The temperature was raised to reflux for 3 hours. The reaction solution was cooled to room temperature,Concentrated to give the compound6-amino-9 - [(2R) -2-(Dichlorophosphorylmethoxy) propyl] purine(1B). | |
With thionyl chloride In N,N-dimethyl-formamide for 1h; Reflux; | 1 Tenofovir(4.31 g, 15mmol) is placed into the reaction flask, add 50mL thionyl chloride, and then added a catalytic amount of N, N-dimethylformamide (1-2 drops), reflux for 1 hour, the reaction solution turned from white suspension into yellow solution after that, rotary evaporator vacuum distillation to remove thionyl chloride, and then washed twice with dichloromethane, and then obtained tenofovir phosphoryl chloride. | |
With thionyl chloride; N,N-dimethyl-formamide In acetonitrile for 0.5h; Reflux; | 2 Example 2: Preparation of (R)-9-[2-(dichlorophosphonomethoxy)propyl]adenine (6) (R)-9-[2-(phosphomethoxy)propyl]adenine (5) 2.87 g (10 mmol, 1 eq),Dry acetonitrile 30ml,Thionyl chloride 2.38g (20mmol, 2eq),DMF 1d, heated at reflux for 30 min.After the reaction is completed, cool the reaction solution to 50°C.Concentrate under pressure and keep it for use. | |
With thionyl chloride at 70℃; Inert atmosphere; | 1 Example 1Preparation of Compound III Place IV (100 g, 0.348 mol) in a 2 L three-necked flask.Add thionyl chloride (1 L) under nitrogen and heat to an external temperature of 70 ° reflux overnight., TLC shows that the reaction is complete,Evaporate the solvent directlyThe crude pale yellow solid of V was 110 g (0.341 mol, yield 97.9%). | |
With thionyl chloride In acetonitrile at 80℃; for 3h; | 1-5 Example 3 At room temperature, place acetonitrile (1.5L) and dichlorosulfoxide (165g, 1.392mol) in a 2L three-necked flask, stir well, and add [[(1R)-2-(6-aminopurine-9-yl)-1-methylethoxy]methyl] phosphonic acid (PMPA, 100g, 0.348mol), slowly heated to 80 ° C and refluxed for 3h, the reaction was completed by HPLC (HPLC purity 93.58%), and the solvent was directly evaporated to dryness to obtain Crude II (light yellow solid). | |
With thionyl chloride In acetonitrile at 70 - 80℃; for 3h; | 1-5 Example 1 Preparation of Compound 1 1 In a 500mL three-neck flask, add PMPA (25g, 0.082mol, containing one molecule of water), acetonitrile (170ml), stir at room temperature, add thionyl chloride (48.8, 0.41mol), and heat to 70-80 degrees. The reaction was stirred for 3 hours, and samples were taken and dissolved in methanol. HPLC detected that the conversion of the raw material PMPA was complete, cooled to ambient temperature, and evaporated the solvent under reduced pressure to obtain a pale yellow solid, which was directly used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.63% | With pyridine; dicyclohexyl-carbodiimide at 70℃; for 4h; | 1 Preparation method 2 of (R)-9-[2-(phosphoryl phenol methoxy) propyl] adenine the compound represented by formula (I) (R)-9-[2-(phosphoryl methoxy) propyl] adenine (100.01g, 0.35mOl, 1.0eq, Zhejiang Supor Pharmaceutical Co., Ltd.) and phenol (65.50g, 0.70mol, 2.0eq, Xiqiao Chemical) dissolved into 1000ml of pyridine (Shanghai Titan Chemical Co., Ltd.), warm up at 70 ° C, added the drops of N,N’-dicyclohexylcarbodiimide (287.42g, 1.39mOl, 4.0eq, Suzhou Qifan Biotechnology Co., Ltd.) pyridine solution (500ml, Shanghai Titan Chemical Co., Ltd.), after the addition is completed, the reaction is carried out at 70 ° C for 4 hours, HPLC monitoring of the raw material reaction completely, cooling at room temperature, add 1500ml of ethyl acetate (Hangzhou Jiachen Chemical Co., Ltd.), filter, the filtrate is directly concentrated, added 1M sodium hydroxide (Zhejiang Sanying Chemical Reagent Co., Ltd.) solution to adjust the pH at 11~12, extracted three times with ethyl acetate (Hangzhou Jiachen Chemical Co., Ltd.) (100ml*3), and then by using 2M hydrochloric acid solution adjust the pH at 3 (Zhejiang Sanying Chemical Reagent Co., Ltd.), liquid was directly concentrated and then obtained the target product (118.42 g, yield 93.63%, containing a small amount of sodium chloride salt), HPLC purity was 68.54%. |
85% | Stage #1: (R)-9-[2-(phosphonomethoxy)propyl]adenine; phenol In acetic acid butyl ester at 20℃; for 1h; Stage #2: With 4-dimethylaminopyridine; triethylamine; dicyclohexyl-carbodiimide In acetic acid butyl ester at 90℃; for 24h; | 1 [[(1R)-2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]monophenyl phosphate (STW3) The starting material STWA (10g, 34.8mmol) was added to 40ml of n-butyl acetate, and phenol (9.8g, 104.1mmol) was added at room temperature, After stirring for 1h, add triethylamine (7.0g, 69.6mmol), 4-dimethylaminopyridine (6.4g, 52.2mmol), Dicyclohexylcarbodiimide (DCC) (14.4 g, 69.6 mmol). React at 90°C for 24h. Filter, extract the filtrate with 30ml purified water, The pH of the aqueous phase was adjusted to 1.5-3.5 with concentrated HCl, and a solid was precipitated. Incubate at 05 for 2h, filter, beat the filter cake with 100ml methanol, Filter and dry the filter cake to obtain 10.1g of solid, The yield was 85%. |
83% | With triphenyl phosphite; 4-dimethylaminopyridine; triethylamine In toluene; acetonitrile at 100℃; for 28h; | 1.S1-4.S2 Example 2 A method for preparing propofol tenofovir key intermediate, phenyl PMPA, includes the following steps: S1. Weigh 100 g of tenofovir, 33 g of phenol, 43 g of 4-dimethylaminopyridine,35 g of triethylamine and 108 g of triphenyl phosphite were added to the reaction flask, and 200 mL of acetonitrile was measured.200mL of toluene was added to the reaction flask, and the temperature was raised to 100 ° C under reflux for 28 hours with stirring. S2. After the reaction is completed, most of the solvent is distilled off under reduced pressure.200 g of water was added and washed with 200 mL of ethyl acetate.Wash three times, add hydrochloric acid to adjust the pH to 2.5, lower the temperature to 0-10 ° C, and keep crystallization for 2 hours.The filter cake was washed with 100 mL of water with pH 2.5, and dried to obtain 105 g of a monophenyl PMPA product.The yield was 83%, the purity by HPLC was 99.9%, and the content of tenofovir was 0.01%. |
83% | With triphenyl phosphite; triethylamine In toluene at 105 - 115℃; for 24h; | 1-2 Example 1 In a 1L round bottom flask, add 100mL toluene, 80g PMPA, 53g phenol,56g of triethylamine and 95g of triphenyl phosphite were heated to 105°C with stirring, and the temperature was controlled at 105-115°C,The reaction was carried out for 24h, most of the solvent was removed by distillation under reduced pressure, 160g of water was added,Wash with ethyl acetate (200mL*3), add hydrochloric acid to adjust pH to 3.0,Filter and wash the filter cake with 100mL pH2.0 water,dryto 9-[(R)-2-[[(phenoxy)-hydroxyphosphinyl]methoxy]propyl]adenineProduct 84g (HPLC purity 99.6%,Maximum single impurity≤0.1%, content 100.3%, yield 83%). |
81.01% | Stage #1: (R)-9-[2-(phosphonomethoxy)propyl]adenine; phenol With sodium hydroxide In toluene at 20℃; for 4h; Reflux; Stage #2: With thionyl chloride; potassium carbonate In toluene at 40 - 90℃; for 14h; | 1 Example 1 At room temperature,Add 100 g of pre-dried compound (01) to the reaction flask.42.6g of phenol,17.74g sodium hydroxide and 100mL toluene,Heat reflux for 4 hours;Then the internal temperature of the reaction system is lowered to 40°C-45°C.48.12 g of potassium carbonate and 62.13 g of thionyl chloride were added in one go.After the addition, the temperature in the system rises to 80°C-90°C.Stir and stir for 14 hours. The reaction system is brought to room temperature,Add 450g of water to quench the reaction,Slowly add 30% sodium hydroxide (mass fraction) to adjust pH to6.0-9.0;Liquid separation,Keep the water phase,The aqueous phase is adjusted to pH 1.5-3.0 with concentrated hydrochloric acid.Stir at room temperature for 8 hours,Suction filtrationThe filter cake was vacuum dried at 90°C for 24 hours.White solid compound (02) 102.48g,The yield is about 81.01%. |
80.16% | With thionyl chloride; anhydrous sodium carbonate In toluene at 55 - 95℃; | 7 Example 7 Ten grams of pre-dried compound (01) was added to the reaction flask at room temperature.3.6g phenol and 100mL toluene,The system is temperature controlled to 55°C, 8.28g of thionyl chloride is added in one go, and then 11.07g of sodium carbonate is added.After the addition is completed, the system is heated to 95° C. and stirred until the end of the reaction.The system was allowed to come to room temperature and 20 g water was added to quench the reaction.Slowly add 30% sodium hydroxide solution (mass fraction) to adjust the system to pH=2.0-3.0 and stir overnight at room temperature.After suction filtration, the filter cake was vacuum dried at 90° C. for 24 h to obtain compound (02) as a white solid (10.1 g, yield about 80.16%). |
70.3% | With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide at 60 - 100℃; for 16h; Large scale; | 1 Example 1: Method for the preparation of tenofovir alafenamide intermediate III (reference 2 US7803788 Example 2) Tenofovir 3.0 kg and 1.98 kg of phenol was added N- methylpyrrolidone 9L, Heated to 60 ° C to 70 ° C, added with 1.68 kg of N, N-diisopropylethylamine and 3.53 kg of dicyclohexylcarbodiimide, Heated to 90 ~ 100 deg C for 16 hours, After cooling to 10 ~ 20 ° C was added dropwise 7.5L of water and stirred for 2 hours, filter, Wash 3L with water. The filtrate with a mass percentage of 20% aqueous sodium hydroxide solution (the mass percentage refers to the mass percentage of sodium hydroxide aqueous sodium hydroxide mass percentage of the total mass) adjusted to a pH of 11 ~ 12, Extract twice with 7.5 L of ethyl acetate, After the water phase is separated with concentrated hydrochloric acid to adjust the pH to 2.5 ~ 3.5, Cooled to 10 ~ 20 ° C for 2 hours, filter, 40 ~ 50 deg C vacuum (-0.08 ~-1.0MPa) drying 8 ~ 12 hours Tenofovir alafenamide intermediate III was obtained 2.67 Kg, Yield 70.3% HPLC purity 95.85%. |
61.4% | Stage #1: (R)-9-[2-(phosphonomethoxy)propyl]adenine; phenol With triethylamine In 1-methyl-pyrrolidin-2-one at 85℃; for 0.666667h; Inert atmosphere; Stage #2: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 26h; Inert atmosphere; | 1 Intermediate-1: Phenyl((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid The commercially available tenofovir (TFV) (14.6 g, 50.8 mmol) and phenol (9.6 g, 102.0 mmol) were dried in vacuo for half an hour and dissolved in N-methylpyrrolidone (39 g). Under nitrogen protection, the temperature was raised to 85 ° C. After stirring for 30 minutes, triethylamine (6.3 g, 62.3 mmol) was added, the reaction was carried out for 10 minutes, the temperature was raised to 100 ° C. A solution of dicyclohexylcarbodiimide (DCC) (17.1 g, 82.9 mmol) in N-methylpyrrolidone (16 g) was slowly added dropwise. After 6 hours, the reaction was continued for 20 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was stirred with methanol (30 mL) and the precipitated solid was filtered to dryness to give intermediate-1 (11.3 g, yield: 61.4%). |
61.4% | Stage #1: (R)-9-[2-(phosphonomethoxy)propyl]adenine; phenol In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 0.166667h; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one | Tenofovir (14.6 g, 50.8 mmol) and phenol (9.6 g, 102 mmol) were dried under vacuum for half an hour,Was dissolved in N-methylpyrrolidone (39 g) and heated to 85 ° C under nitrogen. After stirring for 30 minutes, triethylamine (6.3 g, 62.3 mmol) was added, followed by reaction for 10 minutes, and the temperature was raised to 100 ° C. A solution of DCC (17.1 g, 82.9 mmol) in N-methylpyrrolidone (16 g) was added dropwise over 6 hours and the reaction was continued for 20 h. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was stirred with methanol (30 mL)The precipitated solid was filtered and dried to give (R) -9- [2 - [(phenyl) phosphoric acid methoxy] propyl] adenine (Intermediate 1)(11.3 g, 61.4%). |
57.4% | With triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 85 - 100℃; for 18h; | 4 Comparative Example 4 (Repeat Example of WO0208241) (R)-9-[2-(phosphorylmethoxy)propyl]adenine (PMAP 146.0 g, 508.0 mmol, 1.0 eq), phenol (96.0 g, 1020.0 mmol, 2.0 eq) was addedN-methylpyrrolidone (300 ml, 2.0 vol) was added triethylamine (63.0 g, 623.0 mmol, 1.2 eq). Heat to 85 ° C, temperature control 85 ~ 100 ° C dropwise addition of dicyclohexylcarbodiimide (DCC; 171.0g, 829.0mmol, 1.6eq) N-methylpyrrolidone (100ml, 0.7vol) solution, 2 hours drop . After the completion of the dropwise addition, the mixture was stirred at 100 ° C for 16 hours. Cool to 15 ~ 25 ° C, add water (290ml) and stir for 30 minutes, filter, water (150ml) rinse the filter cake, the filtrate was concentrated at 60 ° C to constant weight, add water (250ml), with a concentration of 25% oxidized Adjust the pH of the sodium solution to11 (the mass concentration refers to the mass of sodium hydroxide as a percentage of the total mass of the sodium hydroxide aqueous solution), the diatomaceous earth pad is filtered, the water (40 ml) is rinsed, and the combined filtrate is extracted with ethyl acetate (280 ml). The aqueous phase is adjusted to pH 3 with concentrated hydrochloric acid, stirred and cooled to 0-10 ° C, filtered, and washed with methanol (50 ml×2), and dried to obtain 106.0 g of product, HPLC purity 98.12%, yield57.4%. |
47.6% | With 1-methyl-pyrrolidin-2-one; triethylamine; dicyclohexyl-carbodiimide at 100℃; for 16h; | 2.1.1. [(R)-2-(Phenylphosphonomethoxy)propyl]adenine(1) phenol (131g, 1392 mmol) and triethylamine (115 mL,831 mmol) were added to a stirred solution of anhydrousPMPA (200 g, 696 mmol) in NMP (520 mL) at room temperature.The mixture was heated to 100oC. A solution of 1,3-dicyclohexylcarbodiimide (287g, 1.391 mmol) in NMP (20mL) was then added over 6 hours at 100oC. The mixture wasstirred at this temperature for 10 hours more. Water (400mL) was added after the reaction was cooled to 45oC, thenthe reaction was cooled to room temperature and stirred for30 min, the mixture was filtered and solids were rinsed withwater (200 mL) to give the filtrate. The filtrate and rinsewere combined and evaporated under reduced pressure, afterremoving the solvent by reduced pressure distillation, the tanslurry obtained finally. Water (300 mL) was added, and adjustedto pH=11 with 25% sodium hydroxide solution. Thesuspension was removed by filtration through a funnelcharged with celite. The filtrate was extracted with ethylacetate (500 mL*3). Concentrated hydrochloric acid wasadded into the aqueous solution until the mixture was adjustedto pH=3.1, and then cooled to 0oC and stirred for 2h,the precipitation was isolated by filtration under reducedpressure and washed with methanol (500 mL), and dried togive 1 as a white powder (120 g. 47.6% yield). 1H NMR(300 MHz, D2O, δ): 1.16 (d, J = 3.7 Hz, 3H), 3.54 (m, 2H),3.71 (dd, J = 10.5 Hz, 2H), 4.03 - 3.99 (m, 2H), 4.22-4.10(m, 2H), 4.45 (dd, J=11.3, 8.3Hz, 2H), 6.59 (d, J =5.2 Hz,2H), 7.05 (t, J =5.3 Hz, 1H), 7.21 (t, J =5.1 Hz, 2H), 8.05 (s,1H), 8.16 (s, 1H); 13CNMR (100 MHz, DMSO-d6): δ155.8(C-6), 152.7(C-2), 151.3(C-19), 149.2(C-4), 140.7(C-8),130.0 (C-21), 130.0(C-23), 124.9(C-22), 120.6(C-20), 120.6(C-24), 119.8(C-5), 72.4(C-12), 56.3(C-14), 55.6(C-11),19.0 (C-25); 31P NMR (72 MHz, D2O, δ):15.0 (decoupled). |
40.4% | With triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 85 - 120℃; for 16h; | 3.1 Step 1: Synthesis of (R)-9-[2-(phenoxyphosphorylmethoxy)propyl]adenine (Compound 5). Add in the reaction bottleTenofovir (2.4g, 8.36mmol),Phenol (1.62 g, 16.72 mmol)And 6.5ml NMP,Heated to 85 ° C,Add triethylamine (TEA, 1.04 g, 10.3 mmol),Warming up to 100 ° C,Dicyclohexylcarbodiimide (DCC, 2.81 g, 13.63 mmol) was added.The reaction was further stirred at 120 ° C for 16 hours.After TLC detects the disappearance of the raw materials, the temperature is lowered to 45 ° C.Add 4.8ml of water,Down to room temperature,Filter to remove insoluble matter,Wash the filter cake with 2.5 ml of water.The filtrate is concentrated,Add 4ml of water,Adjust the pH to 11 with NaOH,Chloroform extraction 3-4 times,Adjust the pH of the aqueous phase to 3.1 with concentrated hydrochloric acid.Extract 4-5 times with chloroform/isopropanol (3:1).The organic phases are combined and evaporated to dryness.Add a small amount of methanol to purify,After filtration, the |
22.14% | With triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 85 - 100℃; for 16h; | 11 Phenyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate Example 11 Phenyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate To a 100 ml 3 neck flask was charged with Tenofovir (1.25 g, 4.35 mmol), phenol (0.819 g, 8.70 mmol) and NMP (11 mL). The mixture was heated to 85° C. and TEA (0.789 mL, 5.66 mmol) was added. A solution of DCC (1.437 g, 6.96 mmol) in NMP (2.4 mL) was then added slowly at 100° C. Heating is continued for 16 h. The reaction is cooled to 45° C., diluted with water (10 mL) and cooled to 25° C. Solids were removed by filtration and rinsed with water (5 mL). The combined filtrate and rinse was concentrated to a tan slurry under reduced pressure. It was diluted with water. The resulting tan solution was purified by LC-MS (5-65% ACN in Water), yielding 0329531-0138 (350 mg, 0.963 mmol, 22.14% yield) as a white solid. LCMS: for C15H18N5O4P calculated 363.11. found 364.20 [M+H]+. 31P NMR (500 MHz, CD3CN) δ: 15.09. |
With triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 22h; | ||
With triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 85 - 100℃; for 22h; | 51 10971] Tenofovir is commercially available or conveniently prepared using procedures outlined in WO 02/08241. In a typical run, tenofovir (5 mmol) is suspended in i-methyl-2- pyrrolidinone (30 mE) along phenol (10.2 mmol). The reaction mixture is heated to 85° C. and triethylamine (62 mmol) is added. A solution containing i,3-dicyclohexylcarbodiim- ide (83 mmol) in 15 mE of 1 -methyl-2-pyrrolidinone is then added over a 6 h period while stirring at 1000 C. The resulting reaction mixture is stirred at 1000 C. for 16 h. It is then cooledto about 45° C. and water (50 mE) is added. The resulting solids are filtered. The filtrate is concentrated under reduced pressure to remove volatile solvents. The slurry is further diluted with water and basified to pHi 1 with NaOH. The aqueous layer is then washed with EtOAc, and then sufficient HC1 (6N) is added to adjust the pH3. The resulting solids are collected by filtration, washed with MeOH and dried under vacuum to afford phenyl hydrogen ((((R)-i -(6-amino-9H- purin-9-yl)propan-2-yl)oxy)methyl)phosphonate. | |
7.2 g | With triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 85 - 100℃; | 4 14.6 g of 9-[(R)-2-(phosphonylmethoxyl)-propyl]-adenine (PMPA) and 9.6 g of phenol were added to 50 ml of N-methylpyrrolidone and heated to 85° C., and then 6.3 ml of triethylamine was added. 13.4 g of DCC was slowly added under stirring and heated at 100° C. and stirred overnight, and 30 ml of water was added after cooling. After standing, the solid was filtered, and the filtrate was combined and evaporated under reduced pressure to dryness, 30 ml of water was added, and the pH was adjusted to 11 with 25% sodium hydroxide, the solid was filtered, and the filtrate was combined and extracted by 30 ml of ethyl acetate. The pH of the aqueous solution was adjusted to 3.1 by 37% hydrochloric acid, it was left and the solid was precipitated out. The solid was collected by filtration, and then washed by adding 50 ml of methanol under stirring, filtered and dried under vacuum, to obtain 7.2 g of phenol monoester derivatives of PMPA. |
390 g | With cyclopentyl methyl ether; triethylamine; dicyclohexyl-carbodiimide at 100 - 106℃; | 1 Example 1: Preparation of monophenyl PMPA (Form II) To a round bottom flask equipped with reflux condenser, PMPA (400 gms), cyclopentyl methyl ether (3.2 Lit) and triethyl amine (268 gms) were added, heated to 100-106°C and water removed azeotropically. Phenol (248 gms), triethyl amine (240 gms) and DCC (440gms) were added to the reaction mass. The temperature of the reaction mass was raised to100-106°C and maintained for 20-24 hrs at the same temperature. The reaction mass was cooled to 40-50°C, diluted with water (600 mL) and filtered to remove the precipitate. The pH of the filtrate was made alkaline with addition of 25% (w/w) aqueous sodium hydroxide solution and organic layer was separated. The pH of the aqueous layer wasmade acidic with slow addition of dilute HC1. The precipitated white solid was filtered and washed with water (400 mL). The crude material was sluned in mixture of acetone (1600 ml) and water (400 ml) at room temperature for 2-3 hrs and filtered. The resulting wet material was dried at 60-65°C for 12 hrs to afford Form II of monophenyl PMPA (390 gms). |
1 g | Stage #1: (R)-9-[2-(phosphonomethoxy)propyl]adenine; phenol In 1-methyl-pyrrolidin-2-one at 85℃; Stage #2: With triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; | 11.1 Step 1: Preparation of ((1R)-2-(6-amino-9H-purin-9-yl)-1-methyl-ethoxy)methyl) phosphoric acid monophenyl ester [(1R)-2-(6-amino-9H-purin-9-yl)-1-methyl-ethoxy]methylphosphoric acid (PMPA, 3.1 g, 10.8 mmol) and phenol(1.0 g, 10.8 mmol) were dissolved in N-methylpyrrolidone (20 mL) at room temperature, and the temperature was raisedto 85°C. Triethylamine (1.1 g, 10.8 mmol) was added dropwise such that the white turbid reaction mixture become clear.After completion of the dropwise addition, the temperature was further raised to 100°C, and a solution of DCC (4.8 g,23.1 mmol) in N-methylpyrrolidone (10 mL) was added dropwise. After the completion of the dropwise addition, thereaction was kept at 100°C overnight. The temperature of the reaction mixture was lowered to room temperature, andthe mixture was allowed to stand for 2 h. After filtration, the filtrate was concentrated and dissolved in dichloromethane.A small amount of white insoluble material was observed. After further filtration, the filtrate was concentrated, and theresidue was purified by preparative liquid chromatography to afford the title compound (1.0 g).ESI-MS (m/z): 364.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; | Tenofovir (60 g, 0.209 mol) was placed in a 500 ml four-necked flask.250 g of N-methylpyrrolidone, and triethylamine (62.3 g, 0.617 mol) was added with stirring.Additional tetrabutylammonium bromide (40.25 g, 0.125 mol) was added.Warming up to 50 C,At this temperature, <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (63.5 g, 0.418 mol) was added dropwise.Investment,Keep warm for 5 to 10 hours,After the end of the heat preservation, after extracting twice with n-heptane 250 ml×2, the water was separated into 480 g of purified water, and extracted three times with isopropyl acetate 240 g+120 g+120 g, and the isopropyl acetate solution was combined and washed twice with an aqueous solution of 180 g×2. , concentrated to dryness under reduced pressure at 40 C, 60 g of isopropanol, 40 CConcentrated to dryness under reduced pressure, adding 100 g of isopropanol, heating and dissolving, cooling to -10 to -20 C, adding 0.5 g of seed crystals, keeping for 2-8 hours, suction filtration,The wet product was dried at 40 C under reduced pressure to obtain tenofovir (99.28 g).Yield 91.5%The purity is 98.3%. |
90.6% | With triethylamine; N-butylpyridinium tetrafluoroborate; at 40℃; for 1.5h; | Tenofovir 28.7 g (0.1 mol), acid-binding agent50.6 g (triethylamine, 0.5 ml),Chloromethyl isopropyl carbonate45.8 g (0.3 mol) and ionic liquid(1-butylpyridinium tetrafluoroborate) was added to the reaction flask and the temperature was raised to 40 (: Stirred for 1.5 hours, after the reaction was completed, cooled to room temperature, the reaction solution was poured into water, extracted with ethyl acetate,The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure,Concentration of petroleum ether to give Tenofovir disoproxil 47. lg,Yield 90.6%, Book 1 (: 99.47% purity. |
87.6% | To the reaction flask was added 10 g (0.0348 mol) of anhydrous tenofovir,Tetrabutylammonium bromide (8.5 g, 0.0263 mol)20 ml of N-methylpyrrolidone (NMP) and 9.4 g (0.093 mol) of triethylamine,The temperature was raised to 50 C and stirred at this temperature for 0.5 h.To the reaction solution was slowly added dropwise 22.7 g (0.149 mol) of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong>, and after completion of the dropwise addition,The temperature was raised to 60 C and stirred at this temperature for 4 h. After the reaction is complete,The reaction solution was poured into a cooled aqueous solution of supersaturated sodium chloride and stirred at -10 C for 24 hours. Filter,Washed with cold water, and the resulting solid was dried at 25 C using a blast oven,Get 15.7g crude tenofovir dipinate. The crude product was added to 75 ml of isopropyl ether, heated to reflux temperature, refluxed for 1 h,Then slowly down to 10 , stirring 1h, continue to cool to 0-5 , stirring 2h. Filtered, washed with 28 ml of isopropyl ether at 0-5 C,And dried to obtain 14.9 g of powdered tenofovir dipivoxil, the yield was 87.6% and the purity was 99.1%. |
82% | A method for synthesizing tenofovir disoproxil, in a dry and clean 1000 mL three-neck reaction flask with mechanical stirring, after nitrogen substitution, 500 mL of N, N-dimethylacetamide was added at room temperature, and tenofovir (PMPA ) 86.1g (0.3 mol, 1.0 equiv), triethylamine 60.6g (0.6 mol, 2.0 equiv), tetrabutylammonium bromide 9.7g (0.03 mol, 0.1 equiv), urea 18.2g (0.3 mol, 1.0 equiv) After stirring for 30min, the temperature was raised to 50 ~ 60 C, and 137.2g (0.9mol, 3 equiv) of POC was slowly added dropwise. After the dropwise addition was completed, the reaction was continued for about 3 hours. After the temperature was lowered, the reaction solution was flushed into 2000mL of ice brine, and stirred Hours, filtered to obtain crude tenofovir dipyrfurate, then beaten once with 300 ml of isopropyl acetate, filtered, and dried to obtain 127.8 g of tenofovir dipyrfurate, purity 98.5%, yield 82.0%. | |
66% | Tenofovir (25 g) and cyclohexane (100 ml) were stirred at 25 C to 30 C.Triethylamine (25 g) was added slowly and the reaction mixture was stirred at 70 C to 75 C for 2 hours.The reaction was completely concentrated at 40 C to 40 C and 1-methyl 2-pyrrolidone (100 ml) was stirred at 25 C to 30 C.Triethylamine (25 ml) was added slowly and the reaction mixture was heated to 50 & lt; 0 & gt; C to 55 [deg.] C for 30 minutes.Chloromethylisopropyl carbonate (65 g) was slowly added to the reaction mixture over about 15-20 minutes.Thereafter, the reaction mixture was stirred at 50 C to 55 C for 4 hours, and then cooled to 25 C to 30 C.Purified water (200 ml) was added and stirred for 30 minutes.Ethyl acetate (200 ml) was added and stirred for 30 minutes, followed by layer separation.Purified water (200 ml) was added to the obtained ethyl acetate layer and stirred for 30 minutes, followed by layer separation.Purified water (200 ml) was added to the obtained ethyl acetate layer and stirred for 30 minutes, followed by layer separation.Magnesium sulfide (50 g) was added to the obtained ethyl acetate layer and stirred for 30 minutes.After filtration, the ethyl acetate layer was completely concentrated at 25 C to 30 C to obtain the compound of formula (2) in an oil phase.Ethyl acetate (100 ml) was added to the resulting oily phase mixture and crystallized at 0 to 5 for 5 hours.Filtered and then dried under nitrogen for 2 hours to obtain 28 g of clear white colored tenofovir disoproxil (Formula 2).(Purity 98.7%) | |
65.12% | With 1-methyl-pyrrolidin-2-one; triethylamine; In cyclohexane; at 50℃; for 16h; | Preparation of tenofovir disoproxil: PMPA (25 g), dryN-methyl-2-pyrrolidone (NMP, 6.0 equiv, 50 mL) and cyclohexane(120 mL) were charged to a reactor vessel and agitatedwith a magnetic stirrer (500 rpm) at 50 C. PMPA was driedin advance at about 80 C under vacuum for 24 h. Cyclohexanewas removed in advance by distillation twice under reducedpressure at 50 C. When the reaction was cooled to 45 C,triethylamine (35.2 g, 4.0 equiv) and PEG-600 (31.3 g, 0.6equiv, water content < 1 %) were added. Precipitation oftriethylamine salts of PMPA was caused. The reaction mixturewas heated to 50 C and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong>(66.4 g, 5.0 equiv) was added at this temperature. The reactionwas monitored for completion at 16 h and the initially thicksuspension was almost clear. The reaction samples wereanalyzed by HPLC (purity 88.7 %) which was performed on aliquid chromatograph (Shimadzu, Japan, 10 Atvp) withShimadzu DAD detectoran and ACQUITY BEH C18 column(2.1 mm × 150 mm, 1.7 um). The binary mobile phase wascomposed of water and methanol in proportion 40/60 (v/v).The flow rate was 0.6 mL/min. |
Ca. 10% | With triethylamine; In N,N-dimethyl-formamide; at 50℃; for 20h; | To a stirred suspension of PMPA (7.26 g, 0.026 mmol) in DMF (100 mL) was added Et 3 N (10.8 mL, 0.0778 mmol) at 50 C. The reaction mixture became homogeneous and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (12.1 g, 0.0778 mmol) was added to the reaction mixture and stirring was continued at 50 C. (oil bath temperature) for 20 h. The solvent was removed under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 10% isopropanol in CH 2 Cl 2 removed all nonpolar impurities. Further elution with the same solvent mixture yielded 1.3 g (about 10%) of the prodrug. |
Example 1; <n="13"/>Tenofovir (25 kg) and 1 -methyl 2-pyrrolidinone (100 kg) were stirred at 25-30 C. Triethyl amine (25 kg) was added slowly and the reaction mass was heated to 50-550C for 30 minutes. Chloromethyl isopropyl carbonate (65 kg) was added to the reaction mass gradually over about 15 to 20 minutes. The reaction mass was then heated to 65-700C and stirred for 4 hours and then cooled to 25-30 0C.In another reaction vessel, a saturated solution containing 300 kg sodium chloride, 200 kg of water and 300 kg crushed ice was stirred to a temperature below -15C.The reaction mass from the first step was quenched into the chilled saturated solution maintaining temperature below 0 0C and stirred for 12-15 hours. The resulting solid was filtered and washed with chilled water and spin dried for 1 hour. The solid was further dried in vacuum to obtain 25-30 kg of tenofovir disoproxil Form C. | ||
To a clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20C to 35C. Heated to 80C to 85C and stirred for 2 hours and simultaneously removed water liberated. After complete removal of water from the reaction, the solvent was removed completely from the reaction mixture by distillation under vacuum at below 65C and to the obtained residue, charged N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) at 25C to 30C. Heated to 50C to 55C and added <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (125 gms) at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20C to 25C and washed with cyclohexane (200 ml) and separated the product containing organic layer. To the organic layer charged methylene chloride (500 ml) and stirred for 1 hour at 10C to 15C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50C to 55C and stirred for 20 minutes and added above obtained oily product solution at 50C to 55C. Stirred for 30 minutes at this temperature and cooled to 25C to 30C and stirred for 1 hour. Again cooled to 0C to 5C and stirred for 4 hours. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound as crude (80 gms). In another clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10C to 15C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35C to 40C for 6 hours under reduced pressure to provide the title compound. Yield: 55 gms. HPLC purity: 98.9% HPA: Not detected The XRPD is set forth in Figure-2 The DSC is set forth in Figure-3 Residual Solvents: | ||
With triethylamine;tetrabutylammomium bromide; In 1-methyl-pyrrolidin-2-one; at 50 - 60℃; | EXAMPLE 3Preparation of Tenofovir Disoproxil(R)-9-[2-(phosphonomethoxy)propyl]adenine (25 gm), triethyl amine (25 ml) and cyclohexane (200 ml) were combined and heated to remove water and the solvent was distilled off under vacuum. The reaction mass was cooled to room temperature N-methyl pyrrolidinone (55 ml), triethyl amine (25 ml) and tetra butyl ammonium bromide(54 gms) were added to the reaction mixture. The reaction mass was heated to 50-60 C. and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (65 gm) was added and maintained for 4-8 hrs at 50-60 C. and then cooled to 0 C. The reaction mass was diluted with chilled water or ice and precipitated solid product was filtered. The mother liquor was extracted with methylene chloride (150 ml). The methylene chloride layer was washed with water (200 ml). The filtered solid and the methylene chloride layer were combined and washed with water and the solvent was distilled under vacuum. Ethyl acetate was charged to the precipitated solid. The reaction mass was then cooled to 0-5 C. and maintained for 6 hrs. The solid was filtered and dried to produce Tenofovir disoproxil (45 gm). | |
To a clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20C to 35C. Heated to 80C to 85C and stirred for 2 hours and simultaneously removed water liberated. The solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 C and to the obtained residue N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) were charged at 25C to 30C. Heated to 50C to 55C and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (125 gms) was added at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20C to 25C and washed with cyclohexane (200 ml). Methylene chloride (500 ml) was charged into the organic layer and stirred for 1 hour at 10C to 15C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50C to 55C and stirred for 20 minutes and above obtained oily product solution was added at 50C to 55C. Stirred for 30 minutes at this temperature and cooled to 0C to 5C. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound as crude (80 gms). In another clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10C to 15C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35C to 40C for 6 hours under reduced pressure to provide the title compound. Yield: 55 gms. HPLC purity: 98.9%. | ||
To a clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20 C. to 35 C. Heated to 80 C. to 85 C. and stirred for 2 hours and simultaneously removed water liberated. After complete removal of water from the reaction, the solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 C. and to the obtained residue, charged N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) at 25 C. to 30 C. Heated to 50 C. to 55 C. and added <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (125 gms) at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20 C. to 25 C. and washed with cyclohexane (200 ml) and separated the product containing organic layer. To the organic layer charged methylene chloride (500 ml) and stirred for 1 hour at 10 C. to 15 C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35 C. to obtain oily product and then the oily product was diluted with isopropanol (150 ml). | ||
Starting compound 4 (10 g, 34.8 mmol) was dried at 100 C and 0.1 mbar overnight, and cyclohexane (80 mL) was added, followed by azeotropic distillation. The rest of the cyclohexane was removed in vacuo. After cooling the mixture to RT, dry NMP (40 mL) was added and mixture was stirred for 30 min at RT under argon atmosphere. Then Et3N (10.6 g, 14.7 mL, 105 mmol) was added to the reaction mixture and stirring continued at 45 C for 1 h. Subsequently, <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (CMIC, 26.5 g, 174 mmol) was added and the reaction was stirred at 60 C for 5 h. The reaction was cooled to RT and cyclohexane (80 mL) was added and the mixture stirred for 15 min and then let settle down for 30 min. Organic phase was removed and the same procedure was repeated once more. Then, the reaction mixture was diluted with cold EtOAc (100 mL) and organic phase was washed with chilled water (2 x 50 mL, 5 C). Water phase was washed with cold EtOAc (1 x 50 mL) and combined organic fractions (EtOAc) were washed with chilled brine (10 %, 5 C, 2 x 50 mL) and dried (Na2SO4). Solvents were immediately evaporated in vacuo at 30 C and the product was codistilled with dry toluene (50 mL) to afford 14.48 g (80%, 75% purity according to HPLC) as yellowish oil (crude Tenofovir disoproxil). | ||
With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl acetamide; at 55℃; for 8h; | 1000ml 400ml reaction flask in ether, 50ml dimethylacetamide and 40g tenofovir monohydrate, openStirring, controlling the temperature of dropping 85g at 20 C under N, N- diisopropylethylamine, dropwise 71/92 100g <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was added dropwise to the reaction system was heated to 55 C insulation 8 hours of reaction, the reaction detected monoester is less than 10%, the reaction solution was concentrated under reduced pressure below 40 C until no liquid outflow, the concentrated residue was added 500ml of ethyl acetate, 200ml 6% sodium hydrogen carbonate solution, stirred after separation the organic phases were washed twice with 200ml of water continues purified, the resulting organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, the resultant concentrated residue was used directly in the next reaction. | |
With triethylamine; In 1-methyl-pyrrolidin-2-one; acetonitrile; at 20 - 50℃; for 8h; | In 1000 ml reaction flask by adding 400 ml acetonitrile, 50mlNMP and 40g tynofovir a water composition, stirring is opened, to control the temperature to 20 C dropping under 67g triethylamine, drops to continue dropping 100g chloro methyl isopropyl carbonate, the reaction system after the dipping temperature is increased to 50 C insulation reaction 8 hours, the detection reaction monoester less than 10%, in the reaction liquid 40 C the following concentrate under reduced pressure until there is no liquid can flow out, in the concentrated residual liquid by adding 500 ml ethyl acetate, 200ml6% of sodium bicarbonate solution, stir layered after extraction, the organic phase continue to use 200 ml purified water washing two times, the resulting organic phase after drying by anhydrous sodium sulfate concentrated under reduced pressure to dry, the resulting concentrated residual liquid directly used for the next reaction. | |
With N,N-dimethyl acetamide; N-ethyl-N,N-diisopropylamine; In ethanol; at -25 - 60℃; for 10h; | 400 ml of ethanol, 50 ml of dimethylacetamide and 40 g of tenofovir monohydrate were added to a 1000 ml reaction flask,Stirring, control the temperature of 20 C dropwise add 85g of N, N-diisopropylethylamine, drop finished to continue dropping 100g chloromethyl carbonateThe reaction system was heated to 50 C for 8 hours and the monoester was detected to be less than 10%. The reaction solution was concentrated under 40 C under reduced pressure until no liquid flowed out and concentrated to the residue 500 ml of ethyl acetate, 200 ml of a 6% solution of sodium hydrogencarbonate,After stirring, the layers were extracted and the organic phase was washed twice with 200 ml of purified water,The obtained organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure,The resulting concentrated residue was used directly in the next step. | |
With 1-methyl-pyrrolidin-2-one; potassium carbonate; In diethyl ether; at 20 - 50℃; for 8h; | A 1000 ml reaction flask was charged with 400 ml of ether,50 ml of N-methylpyrrolidone and 40 g of tenofovir monohydrate,Turn on agitation,Control temperature: 91 g of potassium carbonate was added dropwise at 20 C,After dropping, 100 g of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was continuously added dropwise,After the completion of the dropping, the reaction system was heated to 50 C for 8 hours,Detection of the reaction less than 10% monoester,The reaction solution was concentrated under reduced pressure at 40 C or lower until no liquid flowed out,To the concentrated residue was added 500 ml of ethyl acetate,The organic phase was washed twice with 200 ml of purified water. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting concentrated residue was used directly in the next step reaction. | |
With potassium carbonate; In N,N-dimethyl acetamide; acetonitrile; at 50℃; for 8h; | 400 ml of acetonitrile, 50 ml of dimethylacetamide and 40 g of tenofovir monohydrate were added to a 1000 ml reaction flask, and stirring was started. 91 g of potassium carbonate was added dropwise at a controlled temperature of 20 C, and 100 g of chloromethyl carbonate Isopropyl ester. After dropping, the reaction system was heated to 50 C for 8 hours. The monoester was detected to be less than 10%. The reaction solution was concentrated under reduced pressure at 40 C until no liquid flowed out. To the concentrated residue was added 500 ml And the organic phase was washed twice with 200 ml of purified water. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting concentrated residue was directly purified by filtration, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. For the next reaction. | |
With triethylamine; In 1-methyl-pyrrolidin-2-one; ethanol; at 20 - 57℃; for 8h; | In a 1000 ml reaction flask was added 400 ml of ethanol,50 ml of N-methylpyrrolidone and 40 g of tenofovir monohydrate,Turn on agitation,Control temperature: 67 g of triethylamine was added dropwise at 20 C,After dropping, 100 g of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was continuously added dropwise,After dropping, the reaction system was heated to 57 for 8 hours,Detection of the reaction less than 10% monoester,The reaction solution was concentrated under reduced pressure at 40 C or lower until no liquid flowed out,To the concentrated residue was added 500 ml of ethyl acetate,200 ml of 6% sodium hydrogencarbonate solution,After stirring, the layers were extracted,The organic phase was washed twice with 200 ml of purified water,The obtained organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure,The resulting concentrated residue was used directly in the next step. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20 - 57℃; for 8h; | 400 ml of acetonitrile, 50 ml of dimethylformamide and 40 g of tenofovir monohydrate were added to a 1000 ml reaction flask,Stirring, control the temperature of 20 C dropwise add 85g of N, N-diisopropylethylamine, drop finished to continue dropping 100g chloromethyl carbonateIsopropyl ester. After the completion of the reaction, the reaction system was heated to 57 C for 8 hours. The reaction was carried out with the monoester content of less than 10%The liquid was concentrated under reduced pressure at 40 C to no liquid. To the concentrated residue was added 500 ml of ethyl acetate, 200 ml of 6% carbonAnd the organic phase is washed twice with 200 ml of purified water twice, and the obtained organic phase is treated with anhydrous sulfurDried over sodium sulfate, concentrated to dryness under reduced pressure, and the resulting concentrated residue was used directly in the next step | |
With potassium carbonate; In ethanol; N,N-dimethyl-formamide; at 20 - 57℃; for 8h;Large scale; | In 1000 ml reaction flask by adding 400 ml of ethanol, 50 ml dimethyl formamide and 40g tenofovir a water composition, stirring is opened, to control the temperature to 20 C dropping under 91g the potassium carbonate, drops to continue dropping 100g chloro methyl isopropyl carbonate, the reaction system after the dipping temperature is increased to 57 C insulation reaction 8 hours, the detection reaction monoester less than 10%, in the reaction liquid 40 C the following concentrate under reduced pressure until there is no liquid can flow out, in the concentrated residual liquid by adding 500 ml ethyl acetate, 200ml6% of sodium bicarbonate solution, stir layered after extraction, the organic phase continue to use 200 ml purified water washing two times, the resulting organic phase after drying by anhydrous sodium sulfate concentrated under reduced pressure to dry, the resulting concentrated residual liquid directly used for the next reaction. | |
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 70℃; for 10h; | 300 g of N-methylpyrrolidone was added to the reaction vessel,Triethylamine 90 g and tenofovir 25 g,Stirring,Heated to 70 C,40 g of chloromethylisopropylcarbonate was added dropwise,The reaction was stirred for 10 hours with heating and the reaction was stopped. Adding appropriate amount of ethyl acetate, filtering, washing with appropriate amount of ethyl acetate filter residue, washing filtrate, add appropriate amount of water washing 3 times, adding anhydrous sodium sulfate dehydration, filtration. Filtrate by 55 C vacuum distillation, evaporated to dry, tenofovir dipivoxil oil. The molar ratio of tenofovir to triethylamine was 1:10. | |
With benzyltriethylammonium bromide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 4h; | Intermediate (IV) (3.67g) in dry DMF and a three-necked flask (16ml) and dissolved with stirring at room temperature, followed Triethylamine (7.1ml) and triethyl benzyl ammonium bromide (5.23g), then heated to 60 C, was added chloromethyl isopropyl Carbonate (8.5ml), the same temperature, the reaction 4h, cooled to room temperature water was added (16ml) and ethyl acetate (38ml), mixed well After co-liquid separation, the aqueous phase was extracted with ethyl acetate (2 × 38ml), the combined organic phase was washed with water (2 × 100ml), saturated chloride Sodium washing solution (100ml), Na 2 SO 4 dried, filtered, and the filtrate was concentrated to obtain a solid intermediate (V) 5.54g, crude product 84%, directly into the next step (Example 9). | |
24.64 kg | With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 46 - 55℃; for 4h;Autoclave; Inert atmosphere; Large scale; | N-methylpyrrolidone 49.25 kg was added to the reaction kettle, and 10 mg of tenofovir was added to the autoclaveAnd then add 17.2kg of triethylamine and 12kg of tetrabutylammonium bromide to stir well and heat the reaction vessel under nitrogen protection to46 , dropping <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> 30.3kg, control the reaction temperature does not exceed 55 , and continue to stir the reaction to 4 small, The temperature of the reactor to be cooled to 40 C, twice were added 50kg of cyclohexane washing, stirring for 30 minutes, staticSet for 15 minutes, discard the cyclohexane phase, keep the liquid after washing;2) To the washed liquid was added 50 kg of water and 110 kg of ethyl acetate for extraction, delamination, retention of ethyl acetatephase. Two times with 55kg ethyl acetate washing water twice, combined with ethyl acetate phase;3) The organic phase liquid obtained in step 2) was washed with 55 kg of 5% by mass of sodium bicarbonateAnd then with 55kg0.02% by mass of ammonia water washing three times, and finally with 55k saturated sodium chloride for washing aThe washed organic phase liquid was dried over 26.25 kg of anhydrous sodium sulfate for 2 hours to obtain a filtrate by filtration; filtrate 40 ~After distillation, tenofovir dipivoxil 21.64kg. |
3.7 kg | 3. 8 L NMP into the reaction flask, Adding 2.0 kg of TNF-2, Heated to 45 C, Stir for 30 minutes, The solution was turbid. Adding triethylamine and tetrabutylammonium bromide, Stir for 30 minutes, Heated to 50 C. Pass nitrogen protection, Dropping isopropyl chloromethyl carbonate, 1-2 hours dripping finished, Stirring reaction. 2 hours after every half hour sampling to send liquid phase monitoring, Monitor the content of TNF-3 and monoester (when the product peak is no longer increasing and the impurity peak is increasing, the reaction is stopped). After completion of the reaction, Stop heating, Cooled to room temperature, To the reaction solution was added 3 L of cyclohexane, Stirring at room temperature, Static stratification. NMP followed by addition of cyclohexane 3L, Stir and wash away. NMP phase was added 8 L of water and 8 L of dichloromethane,30 C, Static separation.The aqueous phase was continuously extracted several times with dichloromethane, To almost no product in the water phase. The combined dichloromethane phase, The organic phase was washed with 3L * 6 saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and decolored with activated charcoal. filter, Concentrated under reduced pressure to dry, A yellow oil was obtained as 3.7 kg. | |
30.0 mL of N-methylpyrrolidone and 11.6 mL of triethylamine were added to 8.0 g of tenofovir (PMPA), and the reaction solution was heated to 60C and stirred for 30 minutes. 20 g of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was added at 60C , stirred at the same temperature for 4 hours, cooled to 5C , and 50 ml of water was slowly added thereto. The mixture was stirred at 15 DEG C for 1 hour, extracted twice with 30 mL of dichloromethane, and the organic layer was separated and washed twice with 20 mL of water. The organic layer was dried over anhydrous magnesium sulfate (5 g) and concentrated under reduced pressure to obtain an oil-form of tenofovir disoproxil. | ||
With dmap; triethylamine; In 1-methyl-pyrrolidin-2-one; at 10 - 50℃; for 3h;Large scale;Catalytic behavior; | The temperature was 10 to 20 C, PMPA (287.2 g, 1.0 mol)Triethylamine (303.6 g, 3.0 mol), 4-dimethylaminopyridine (DMAP, 12.2 g, 0.10 mol) was added to a 1.44 kg solution of N-methylpyrrolidone,Chloromethyl isopropyl carbonate (762.3 g, 5.0 mol) was added dropwise at a temperature not exceeding 30 C under stirring,Followed by stirring at 40 to 50 C for 3 hours.After the reaction was reduced to 15 to 25 C, 4.31 kg of ethyl acetate was added and stirred for 0.5 h.The filtrate was added with 4.31 kg of purified water, and the aqueous phase was added twice with 2.15 kg of ethyl acetate.The organic phase was combined and the organic phase was washed successively with 4.31 kg of saturated sodium bicarbonate solution, 4.31 kg of saturated sodium chloride solution, dried over 215 g of anhydrous sodium sulfate, filtered and concentrated to give the product.Yield 90.6% and monoester impurity control was 2.31%. | |
41.4 g of Tenofovir monohydrate (commercially available or prepared as disclosed in CN1264387A) was added to 164 g of N-methylpyrrolidone at 20~25 C.,Then added under stirring triethylamine 40g, 20 ~ 25 C under stirring for 0.5 hours,Chloromethyl isopropyl carbonate was added 100g, warmed to 55-65 C incubated for 5 hours;Stop heating, cooling to 20 ~ 30 C, adding ethyl acetate 320g, purified water 180g,0 ~ 5 C under stirring after the separation, the lower layer and then 110g of ethyl acetate at 0 ~ 5 C under extraction,Combined ethyl acetate layer, purified water 0 ~ 5 C washed twice, each 320g,30 ~ 35 C concentrated ethyl acetate; cyclohexane was added to the concentrate 150mL,20 ~ 25 C under stirring for 10 hours, filtered, cyclohexane 20mL rinse,Tenofovir disoproxil, white solid. | ||
Tenofovir (PMPA) prepared in Example 1, 100 g and 1-methyl-2-pyrrolidone (420 mL) were stirred at 25 C to 30 C. 2.54 mol equivalent of triethylamine 82.9 g were slowly added, and the reaction mixture was heated at 50 C to 55 C for 30 minutes. 175.0 g of 3.5 molar equivalents of chloromethylisopropyl carbonate (CMIC) was slowly added to the reaction mixture over about 15 to 20minutes. Thereafter, the reaction mixture was stirred at 60 C to 70 C for 3 hours,and it was cooled to 25 to 30 ..1.0 liter of ethyl acetate was added, and the mixture was stirred for 30 minutes and filtered. 1 L of a 20% NaCl aqueous solution was added, followed by stirring, followed by layer separation. 1 L of a 5% aqueous solution of NaHCO3 was added thereto, followed by stirring, followed by layer separation. 50 g of anhydrous sodium sulfate was added to the obtained ethyl acetate layer, followed by stirring for 30 minutes. After filtration, the ethyl acetate layer was completely concentrated at 30 C to 35 C to obtain 167.9g of Tenofovir disoproxil, as an oil phase(Purity 97.1%). 400 mL of the organic solvent shown in Table 3 below was added to the obtained oily phase mixture and crystallization was carried out at 0 C to 5 C for 5 hours. Filtered and dried under reduced pressure to obtain 108 g of Tenofovir disoproxil. | ||
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃;Large scale; | After pretreating the crude tenofovir obtained in step S02,And 16L N-methylpyrrolidone, 4.44kg of triethylamine, after stirring evenly,Start to warm to 50 C, stir, add 11.15 kg of isopropyl chloromethyl carbonate,After stirring, the reaction was completely quenched by cooling, and after cooling, 12 L of cyclohexane was added twice.Stir, centrifuge, layer, discard the upper layer of cyclohexane, and transfer the filtrate from the lower layer to the reaction vessel.Add 30 L of water and 20 L of ethyl acetate, stir for 30 minutes, and let stand for stratification.The aqueous layer was extracted once with 10 L of ethyl acetate.Add 1.0 kg of anhydrous sodium sulfate, stir dry, centrifuge,The filtrate is transferred to the transfer reactor in batches, concentrated under reduced pressure, and the concentrate is transferred to the reaction vessel.Tenofovir disoproxil give crude ester. | |
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; | S03 condensation: After pretreating the crude tenofovir obtained in the step S02, and stirring 16 L of N-methylpyrrolidone and 4.44 kg of triethylamine, the temperature is raised to 50 C and stirred.11.15 kg of isopropyl chloromethyl carbonate was added dropwise, stirred, and the reaction was completely cooled and quenched.After cooling, add 12 L of cyclohexane twice, stir, centrifuge, layer, and discard the upper layer of cyclohexane. The lower layer of the filtrate was transferred to a reaction kettle, and 30 L of water and 20 L of ethyl acetate were added.After stirring for 30 minutes, the layers were allowed to stand, and the aqueous layer was extracted with 10 L of ethyl acetate.Wash with 20L of 10wt% brine, add 1.0kg anhydrous sodium sulfate, stir dry, centrifuge,The filtrate is transferred to the transfer reactor in batches, concentrated under reduced pressure, and the concentrate is transferred to the reaction vessel.Denotefovir dipivoxilCrude. | |
With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 45 - 55℃; for 1h; | Under nitrogen protection,Tenofovir 50g (0.174mol),Chloromethyl isopropyl carbonate132.8g (0.87mol),Tetrabutylammonium bromide 56.1g (0.174mol)Into 150 ml of N-methylpyrrolidone,Warming up to 45 C,Control temperature 45~55 C, start adding dropwise 44.0g (0.435mol) of triethylamineThe esterification reaction is carried out, the addition is completed, and the reaction is kept for 1 hour.Cooling to 10~20 C, to obtain an esterification reaction solution;HPLC detection of the esterification reaction solution, | |
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50 - 70℃;Industrial scale; | 60 kg of N-methylpyrrolidone and 12 kg of intermediate TN03 were placed in a 200 L glass-lined reaction tank.Stirring was started and 12 kg of triethylamine was added.The heating temperature was controlled to an internal temperature of 50 to 70 C, and 33 kg of isopropyl chloromethyl carbonate was added.After the addition, the temperature was raised to an internal temperature of 50 to 70 C, and the mixture was stirred for 6 to 10 hours, and sampled by HPLC.After the reaction was completed, the temperature was lowered to 10 to 30 C, and 24 kg of purified water was added.Add 55.3 kg of cyclohexane to a 500 L reaction tank and start stirring.The reaction solution was transferred from a 200 L reaction tank to a 500 L reaction tank.Stir for 15 min, let stand for stratification,The lower layer was collected; 36 kg of n-hexane was added to a 500 L reaction tank.Turn on the agitation,The lower aqueous layer was transferred to a reaction tank and stirred for 15 min, and the layers were allowed to stand, and the lower aqueous layer was collected. Transfer the collected water layer to a 500L reaction tank,Add 30 kg of purified water and add 96 kg of ethyl acetate.Stir for 15 min, let stand for stratification,The upper layer was collected; 30 kg of ethyl acetate was added to a 500 L reaction tank.Turn on the agitation and transfer the lower aqueous layer to the reaction tank.Stir for 15 min, let stand for stratification, collect the upper layer,The ethyl acetate organic layer was combined in a 500 L reaction tank, and the 500 L reaction tank was stirred.Adding an already prepared aqueous solution of sodium chloride to the reaction tank,After stirring for 15 min, the layer was allowed to stand, and the lower aqueous layer was discarded to obtain an ethyl acetate layer.Transfer the ethyl acetate layer to a clean 300L glass-lined reaction tank.It was dried by adding 12 kg of anhydrous sodium sulfate.After suction filtration, the filter cake was rinsed with 9 kg to 27 kg of ethyl acetate.The filtrate was pumped into a reaction tank, and concentrated under reduced pressure until no fraction was obtained to obtain TN04.The HPLC purity was 80.2%. | |
With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 55℃; for 0.166667h; | step C)The prepared tenofovir is placed in a mixing kettle,And join at the same timeIsopropyl chloromethyl carbonate,N-methylpyrrolidone and tetrabutylammonium bromide were stirred for 20 min.Then add triethylamine and warm to 55 C for 10 min.Then, it was naturally cooled to room temperature, and then washed with cyclohexane, and allowed to stand for stratification.And keep the lower layer of the solution, then add water and ethyl acetate.After stirring well, let stand and layer, and keep several layers, then wash with 10% NaClPolyester, adding anhydrous sodium sulfate, drying and filtering to obtain an intermediate product.At this point, the intermediate product was again placed in the mixing kettle, and isopropanol and fumaric acid were added for stirring.Then heated to 55 C, stirred until clear, and then naturally cooled to room temperature,And stirring at the same time, after reaching room temperature, continue to cool to 8 C, at this time to maintain the temperature,Crystallize and centrifuge, and dry the solid in a vacuum.A tenofovir disoproxil product is obtained; wherein the equivalent weight of isopropyl chloromethyl carbonate in step D) is 4 eq. | |
17.9 g | With tetrabutylammomium bromide; triethylamine; In N,N-dimethyl-formamide; at 55 - 65℃; for 8h; | In step S1, tenofovir and isopropyl chloromethyl carbonate are prepared.Step S2, adding 15.2 g of tenofovir (0.05 mol), 15.1 g of triethylamine (0.15 mol) and 4.0 g of tetrabutylammonium bromide to 100 mL of N,N-dimethylformamide, stirring and dissolving, heating up To 55 C, 38.1 g of isopropyl chloromethyl carbonate (0.25 mol) was added dropwise, and the first reaction temperature was controlled from 55 C to 65 C for 8 hours.Cool to room temperature, add 100 mL of ethyl acetate and 100 mL of water, stir, and separate.The organic phase was washed twice with 50 mL of saturated sodium chloride, washed and dried over anhydrous sodium sulfate, filtered, and then evaporated.Add 100 mL of methyl tert-butyl ether and stir to clarify.-5 C ~ 0 C rapid stirring for 4 hours into a white turbid liquid,Filtration and drying gave 17.9 g of a white solid. |
S1. Esterification reaction: Add 35 kg of tenofovir to the reaction tank and dissolve it in 140 Kg of N-methylpyrrolidone.Add 23.8Kg of molecular sieve and stir for 30 minutes to remove water; then add 35Kg of triethylamine and stir at 30 C for 2 hours to mix well;Then, 91Kg of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was added to carry out the esterification reaction at 30 C, and the reaction was stopped after 25 hours of reaction.The components in the reaction solution were detected by HPLC;S2. Extraction and separation: adding 4.5 times the mass of ethyl acetate equivalent to the reaction system to the reaction system of S1. For extraction,Stir for 30 minutes and filter in a centrifuge. The resulting filtrate is washed with saturated brine and stirred for 20 minutes.The first organic phase and the aqueous phase were separated by standing. The aqueous phase was extracted again with about 4.5 times the mass of ethyl acetate, and the liquid phase was separated to obtain a second organic phase.Combine the first organic phase and the second organic phase, wash them twice with saturated brine, and dry with anhydrous sodium sulfate.Centrifuging to separate anhydrous sodium sulfate from the system to obtain a tenofovir disoproxil solution; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.2% | With bis(isopropoxy) magnesium; In N,N-dimethyl-formamide; at 45 - 65℃; for 11h;Autoclave; Inert atmosphere; Large scale; | Under a nitrogen atmosphere, 1.25 kg of compound XIV, 6.0 kg of DMF and 0.73 kg of magnesium isopropoxide were added to a 50 L autoclave.The temperature was raised to 65 C, and the reaction was stirred for 1 hour.The temperature was lowered to 45-55 C, and DESMP (formula VI) was slowly added dropwise to the reaction kettle in portions, and the mixture was stirred at 45 to 55 C for 10 hours after the addition. The completion of the reaction was confirmed by HPLC, and DMF and isopropyl alcohol were concentrated under reduced pressure.6.25 kg of concentrated hydrochloric acid was added to the concentrate, the temperature was raised to 90 C, and the reaction was stirred for 10 hours.After the reaction is completed, the temperature is lowered to 10-15 C and stirred for 20-30 minutes.After filtration, the filter cake was washed with 1.0 kg of dilute hydrochloric acid solution, and the filter cake was discarded. The filtrate was transferred to a reaction vessel, and 2.0 kg of dichloromethane was added thereto, and the mixture was stirred for 15 minutes and allowed to stand for 30 minutes.The liquid was separated, the aqueous phase was collected, and hydrochloric acid was concentrated under reduced pressure. Add to the concentrate7.5 kg of water, warmed to 40 C, stirred until dissolved.The pH was adjusted to 3.0 by slowly adding 40% aqueous NaOH solution. After the dropwise addition was completed, the mixture was stirred at 50 C for 3 hours. Naturally cool to room temperature and stir for 10 to 12 hours. After filtration, the filter cake was washed with 0.8 kg of water to give a crude product.The obtained crude product and 18 kg of water were added to the reaction vessel, and the mixture was heated to 100-105 C, and stirred until the system was dissolved. The temperature was naturally lowered to 10 C and stirred for 2 hours.Filtration, the filter cake was washed with 1.0 kg of ice water, and the filter cake was dried to obtain 1.10 kg of Compound I as a white solid with a purity of 99.12% and a yield of 59.2%. |
Example 2 : Preparation of TenofovirN-methyl-2-pyrrolidone (25 gm) was taken along with toluene (150 gm) into a reaction vessel. l-(6-amino-purin-9-yl)-propan-2-ol (100 gm); toluene-4-sulfonic acid diethoxy phosphoryl methyl ester (200 gm) and magnesium ter-butoxide (71.2 gm) were also taken at' 25-35C. Temperature was raised to 74-75 C and maintained for 5-6hrs. After completion of reaction, acetic acid (60 gm) was added and maintained for 1 hr. Later aq.HBr (332 gm) was taken and heated to 90-95 C. After reaction completion, salts were filtered and filtrate was subjected to washings with water and extracted into methylene dichloride. Later pH was adjusted using CS lye below 10 C. Tenofovir product was isolated using acetone.Yield: 110 gm. | ||
82 g | Example 2 Preparation of Tenofovir Using Dimethyl Formamide-Hydrochloric Acid Complex [0080] To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel dimethyl formamide (200 ml), 9-[2-(R)-(hydroxy)propyl] adenine (HPA) (100 gms) and Magnesium t-butoxide (72 gms)were charged at temperature 20 C. to 35 C. and stirred for 30 minutes at same temperature. Diethyl p-toluene sulfonyloxy methyl phosphonate (225 gms) (DESMP) was added and temperature was raised to 75 C. to 80 C. and stirred for 2 hours at same temperature. Reaction mass was cooled to 0 C. to 5 C. and dry hydrochloric acid gas was passed for 5 hours. Reaction mass was heated to 90 C. to 95 C. and maintained for 4 hours. After completion of the dealkylation and monitored by HPLC, the solvent was removed completely under vacuum below 70 C. and water (400 ml) was added to the resultant residue at temperature 60 C. to 65 C. Adjusted pH of the reaction mass to about 1 with Concentrated HCl. Filtered the salts formed and washed the salts with 10% HCl solution. Filtrate was taken and pH was adjusted to about 2.5 with 50% NaOH solution and the reaction mass was cooled to 0 to 5 C. Filtered the precipitated product and washed with water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product water (800 ml) was charged and heated to 90 C. to 95 C. Temperature was cooled to 25 C. to 30 C. and filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70 C. to 75 C. under reduced pressure to provide the title compound. [0081] Yield: 82 gms. [0082] HPLC purity: 99.2% |
With trimethylsilyl bromide; water; sodium hydroxide; In dichloromethane; at 0 - 5℃; for 3h;pH 2.5 - 3; | (5) adding tenofovir diester and trimethylbromosilane to the reactor for hydrolysis, and evaporating the solvent under reduced pressure. Add water and dichloromethane, stir the liquid, adjust the water layer at 0-5 C with 30% sodium hydroxide solutionpH to 2.5-3.0,Cool down to 0-5 C, keep warm for 3 h, crystallization, filtration, drying at 65 C for 24 h under reduced pressure,Preparing a crude tenofovir; the molar ratio of the tenofovir diester to the acid is 1:8;The hydrolysis reaction temperature is 90 C, and the hydrolysis reaction time is 5 h; the volume ratio of the water to the dichloromethane is2:1; the weight ratio of the tenofovir diester to the water is 1:7;(6)The tenofovir crude product and the fourth organic solvent were added to the reactor, and the temperature was raised to 60 C, and the reaction was kept for 2 hours.Cool down to 40 C, keep warm for 1 h, cool to room temperature, keep warm for 1 h, cool to 2 C, keep warm for 1 h, filter,Drying at 60 C for 20 h under reduced pressure gave a product of tenofovir; the fourth solvent was ethanol and ethyl acetate.The volume ratio of the ethanol to the ethyl acetate is 1:0.4;The weight ratio of the crude tenofovir to the fourth organic solvent is 1:8. | |
57.9 g (0.30 mol) of <strong>[14047-28-0](R)-9-(2-hydroxypropyl)adenine</strong> was dissolved in 450 mL of DMF, and 37.5 g (base content 32%, 0.30 mol) of freshly prepared solid base catalyst was added with good stirring. NaOH/Al2O3 and 25.2 g (base content 40%, 0.18 mol) freshly prepared solid base catalyst KOH/Al2O3, 122.4 g (0.38 mol) of p-toluenesulfonyloxymethylphosphonate diethyl ester was added dropwise at 40 C or lower. The temperature was raised to 125-130 C and the reaction was stirred for 18 h. The solid base catalyst is recovered by filtration, and DMF is recovered by distillation under reduced pressure, which is slightly cold.520 ml of pure water and a strongly acidic cation exchange resin catalyst equivalent to 0.06 mole of acid were added. The reaction was stirred at 100-105 C for 18 h, and the strongly acidic cation exchange resin catalyst was recovered by filtration, cooled, filtered, washed and dried.The crude tenofovir was 80.1 g, the yield was 93.0%, the content was 97.6%, and the HPLC retention time was consistent with the tenofovir standard |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In a tenofovir (PMPA) 4.0g prepared in Example 1 was added to the kettle and N- methylpyrrolidone 15 and triethylamine 5.8. The reaction solution was heated to about 63 and stirred for 30 minutes In the chloromethyl isopropyl carbonate 10gAnd then stirred for 4 hours at this temperature. After cooling the reaction solution to room temperature and again it cooled to 5C ,Below 15C cold water were added to maintain 25ml. At 15C stirred for one hour, And extracted twice with methylene chloride 15ml.After washing twice, the organic layer was then partitioned with water 10ml and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the remaining filtrate tenofovir disoproxil (TD) as an oil.The tenofovir disoproxil (TD) of the oil phase Isopropyl alcohol 35ml And 1.6g of fumaric acid Added and the temperature was raised to about 50C Dong was completely dissolved for 30 minutes.Then slowly cooled to about 25 the reaction solution was cooled, dissolved again in 3 was stirred for 4 hours and kept at this temperature.Crystals were filtered and washed with isopropyl alcohol and then dried in vacuo at about 40 10 desired compound of tenofovir disoproxil fumarate (TDF), 4.7g (yield: 53%) was obtained.The obtained tenofovir disoproxil fumarate (TDF) in 4.7g In the 40ml and isopropyl alcohol and heated to about 50C Open completely dissolved during 30 minutes.Then slowly cooled to about 25C the reaction solution was cooled, dissolved again in 3C kept at said temperature and stirred for 4 hours.Crystals were filtered, washed with isopropyl alcohol 100 mland vacuum-dried at about 40C tenofovir disoproxil fumarate (TDF), 4.3g (Yield: 90%) of the crystal form was obtained. | |
78.8% | In a 500 mL three-necked flask equipped with a mechanical stirring, reflux condenser, 150 mL of POC, 2.9 g (10% by weight of PMPA) of tetrabutylammonium bromide as a phase transfer catalyst, and triethylamine, an acid binding agent, were sequentially added. 22.2g (0.22 mol, 2.2 equiv), add 28.7g (0.10 mol, 1.0 equiv) of PMPA in three batches while stirring, pay attention to vigorous stirring to avoid agglomeration.After nitrogen replacement, it was heated to 50 C and reacted for 3 hours. The conversion by HPLC was about 89.6% and the monoester was 3.2%. After the reaction was completed, it was poured into 600 mL of ice-water, stirred for 1 hour and filtered, and the filter cake was used with 200 mL. * 2 Rinse with ice water, combine the water layers, separate the POC from the lower layer, wash with 100mL of 1N dilute hydrochloric acid and 100mL of drinking water and dry on the column to obtain pure POC.The filter cake was dissolved in 200 ml of dichloromethane and separated into layers. After adding anhydrous sodium sulfate to dry and dehydrate, it was concentrated to dryness under reduced pressure. After adding 150 ml of isopropanol, the solution was warmed up, and 12.8 g (0.11 mol, 1.1 equiv) of fumaric acid was added and the mixture was heated to reflux. After the solution was dissolved, the temperature was slowly lowered to 0 C for 2 hours to precipitate crystals. 50.0 g of tenofovir disoproxil fumarate was obtained with a purity of 99.2% and a molar yield of 78.8%. | |
63.6% | 25 g of the terpovorin anhydride obtained in the above example was dissolved in 100 ml of N-methyl-2-pyrrolidinone (NMP)Toluene (50 ml) was added and distilled under reduced pressure at 60 C to remove moisture. 50 ml of toluene was further added to distill once more.The reaction solution was cooled to 35 DEG C, and 35.2 g (4 equiv.) Of triethylamine was added thereto to produce crystals. However, homogenization was suspended with stirring, 28 g (1.0 Equiv.) Of tetrabutylammonium bromide was added RTI ID = 0.0 & gt; 45 C. & lt; / RTI & gt;To this was added 66.4 g (5.0 Equiv.) Of chloromethylisopropyl carbonate and stirring was continued at 45 to 55 .After 5 hours, the progress of the reaction was monitored by TLC and HPLC. When the reaction was completed and the viscous liquid turned transparent red, it was cooled to room temperature, 150 ml of cyclohexane was added thereto,The supernatant was removed with a vacuum syringe tube and again washed with 100 ml of cyclohexane to remove.300 ml of ethyl acetate and 100 ml of cold water were added to the reaction layer and the mixture was stirred to remove the aqueous layer. The aqueous layer was washed twice with 50 ml of ethyl acetate and added to the undiluted solution.The organic layer was washed with 50 ml of cold water and 50 ml of a saturated aqueous solution of sodium chloride, dehydrated with magnesium sulfate, and then vacuum-dried to obtain 53 g of crystalline sludge, Tenofovir disoproxil.The product was further cooled at a lower temperature for crystallization, and the content was analyzed by HPLC (purity 85%, actual amount 45 g compared to area, yield 96%).(0.087 mol) of terpovorbidisopropylsilane crystals were dissolved in 120 ml of isopropyl alcohol, 12.5 g (0.107 mol, 1.2 Equiv.) Of fumaric acid was added, and the mixture was stirred at 50 to 55 C for 2 hours .The reaction solution was cooled to 3 to 5 , and the resulting crystals were sufficiently stirred and then filtered.The crystals were suspended in 250 ml of ethyl acetate and stirred for 1 hour. The reaction solution was warmed to 10 DEG C or lower, filtered and washed. The crystals obtained in this way were vacuum-dried at 40 DEG C to obtain 35 g of terpovorbidisoproxyl fumarate (HPLC area Purity 98.5%, yield 63.6%). |
EXAMPLE 1Process for the Preparation of Tenofovir Disoproxil FumarateToluene (500 ml) was added to the Tenofovir (100 gm) and stirred at room temperature. To this triethylamine (66.31 gm) was added, temperature was raised to 90 C. and water was collected by azeotropic distillation at 110 C. Toluene was completely distilled under vacuum at same temperature. The reaction mixture was cooled to room temperature and to this a mixture of N-methyl pyrrolidine (300 gm), triethylamine (66.31 gm), Tetrabutyl ammonium bromide (52.8 gm) and trimethyl silyl chloride (17.8 gm) were added. The above reaction mixture was heated to 50-55 C. and was added slowly chloromethyl isopropyl carbonate (CMIC) and maintained the reaction mixture at 50-55 C. for 5 hrs. (Qualitative HPLC analysis shows about 85% product formation). The above reaction mixture was cooled to room temperature and filtered. The filtrate was added to DM water at 5-10 C. and extract with dichloromethane. The combined dichloromethane layer was concentrated under vacuum and the crude was Co-distilled with cyclohexane and this crude was taken into isopropyl alcohol (1000 ml). To this fumaric acid (38 gm) was added and temperature was raised to 50 C. The reaction mixture was filtered and filtrate was cooled to 5-10 C. The obtained solid was filtered and washed with isopropyl alcohol. The compound was dried under vacuum to yield Tenofovir Disoproxil fumarate (140 gm). | ||
55 g | Example 9 Preparation of Tenofovir Disoproxil Fumarate [0092] To a clean 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20 C. to 35 C. Heated to 80 C. to 85 C. and stirred for 2 hours and simultaneously removed water liberated. The solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 C. and to the obtained residue N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) were charged at 25 C. to 30 C. Heated to 50 C. to 55 C. and chloromethyl isopropyl carbonate (125 gms) was added at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20 C. to 25 C. and washed with cyclohexane (200 ml). Methylene chloride (500 ml) was charged into the organic layer and stirred for 1 hour at 10 C. to 15 C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35 C. to obtain oily product and then the oily product was diluted with isopropanol (150 ml). [0093] In a clean another 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50 C. to 55 C. and stirred for 20 minutes and above obtained oily product solution was added at 50 C. to 55 C. Stirred for 30 minutes at this temperature and cooled to 0 C. to 5 C. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35 C. to 40 C. under reduced pressure to provide the title compound as crude (80 gms). [0094] In another clean 3-necked 1 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10 C. to 15 C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35 C. to 40 C. for 6 hours under reduced pressure to provide the title compound. [0095] Yield: 55 gms. [0096] HPLC purity: 98.9% | |
35 g | 25 g of the anhydrous tenofovir obtained in the Example was added to 100 ml of n-methyl-2-pyrrolidinone (NMP) and 50 ml of toluene, and the resultant solution was distilled under reduced pressure at 60 C. and removed of water. 50 ml of toluene was further added and distillation was performed. The reactant solution was cooled down to 35 C., and 35.2 g (4 eq.) of triethylamine was added to form crystals. Agitation was continued to make a homogeneous suspension. 28 g (1.0 eq.) of tetrabutylammonium bromide was added, and the resultant solution was heated up to 45 C. 66.4 g (5.0 eq.) of chloromethyl isopropyl carbonate was added to the solution, which was continuously stirred at 45-55 C. In 5 hours of the reaction, TLC and HPLC were used to estimate the progress of the reaction, and the reaction was terminated. As the sticky solution became clear and reddish, it was cooled down to the room temperature, mixed with 150 ml of cyclohexane, and vigorously stirred. The solution was removed of the supernatant using a low-pressure pipette and washed with 100 ml of cyclohexane. 300 ml of ethyl acetate and 100 ml of cold water were added to the reactant layer, which was then stirred and removed of the aqueous layer. The aqueous layer thus obtained was washed twice with 50 ml of ethyl acetate and combined with the crude solution. The organic layer was washed with 50 ml of cold water and 50 ml of saturated saline solution, dehydrated with magnesium sulfate and then isolated under reduced pressure to yield 53 g of tenofovir disoproxil in the form of crystalline sludge. The sludge was further cooled down to the lower temperature to form crystals and then subjected to quantitative analysis through HPLC (purity 85%, actual amount per area 45 g, yield 96%).[Synthesis Method for Tenofovir Disoproxil Fumarate (Teno-DF]53 g (actual 45 g) (0.087 mol) of tenofovir disoproxil coarse crystals were dissolved in 120 ml of isopropyl alcohol, and 12.5 g (0.107 mol, 1.2 eq.) of fumaric acid was added. The resultant solution was stirred at 50 to 55 C. for 2 hours and sufficiently cooled down to 3 to 5 C. to form crystals. After sufficient agitation, the crystals were filtered out and suspended with 250 ml of ethyl acetate. After one-hour agitation, the reactant solution was cooled down to 10 C. or below, filtered and washed. The crystals thus obtained were dried under vacuum at 40 C. to yield 35 g of tenofovir disoproxil fumarate (HPLC area purity 98.5%, yield 63.6%). | |
72 g | Diesterification reaction: Under a nitrogen atmosphere, 100 g Tenofovir (PMPA) And 300ml N-methylpyrrolidone (NMP), the control temperature at 25 ~ 30 , shaking 30min, To dissolve, and then add 106g triethylamine (TEA), 20 ~ 30 shaking 30min until uniform; The above mixture was warmed to 60 ~ 65 , and stirred, In 15 ~ 20min rapid dropping 266g chloromethyl isopropyl carbonate (CMIC) Then warmed to 75 ~ 80 , shaking reaction 60 ~ 70min, When TLC real-time monitoring of the basic reaction of the reaction material completely (3% or less), and monoester content of 15% or less, When the area of the main peak of the product is more than 80%, the double esterification reaction is complete; Then the reaction system first use water bath cooling 5min, After using ice-water bath in 10-15 min the reaction system rapidly reduced to 10-15 ;Extraction and Separation: To the reaction system in step (1) was added 600 ml of ethyl acetate (EA) Heated at 10 ~ 15 , stirred for 15min and filtered, each time with 200ml ethyl acetate (EA) washed the filter cake three times, And the filtrate and the resulting filtrate was combined, to which was added 400ml 10 ~ 15 distilled cold water, Full shock, extraction and separation, the separated aqueous phase was extracted with ethyl acetate twice, The resulting organic phase was combined with the EA layer, washed twice with 1000 ml of distilled water, 300g of sodium chloride was added into the obtained water washing solution twice, dissolved with stirring and cooled down to 10 to 15 C, And then extracted with 500ml of ethyl acetate once, the organic phase was extracted and combined, Washed with 900 to 1000 ml of saturated saline (300 g of sodium chloride dissolved in 850 ml of distilled water) Finally, the organic phase was added 400g anhydrous sodium sulfate 60min after drying filtration;Salt-forming reaction: to step (2) dried and filtered about 2000ml filtrate was added to the reaction vessel, Then 32g fumaric acid (FMA) was added and the temperature was raised to 40 C in a nitrogen atmosphere and the reaction was stirred until the solution became clear. (4) Preparation of tenofovir disoproxil fumarate crude product: Step (3) The reaction solution was concentrated under reduced pressure at 40 C, most of the solvent was distilled off until a large amount of crystals were precipitated, Then the concentrate was naturally cooled to room temperature, and then placed in a -5 C freezer was allowed to cool more than 2h, filtered, The resulting filter cake was washed with a small amount of ethyl acetate 2 to 3 times, pumping dry weighed about 130g, 40 under blast drying 2h, weighed to give 85g Tenofovir disoproxil fumarate crude product, The HPLC detector purity of 98% or more;Recrystallization: Under a nitrogen atmosphere, the reaction vessel was charged with step (4) 85 g crude Tenofovir disoproxil fumarate and 500 ml isopropanol (IPA) The nitrogen atmosphere was warmed to 55 C and stirred for 15 min to clarify the solution. If not, the filtrate should be filtered and the filtrate rapidly crystallized. After the resulting solution was left to cool to room temperature, Placed in a freezer at 4 frozen 2h above, so recrystallized, filtered, rinsed with cold isopropyl alcohol cake, Drained, to obtain white wet crystal 108g, at 40 blast drying 2h or 40 under reduced pressure drying 4h, 72 g of tenofovir disoproxil fumarate finished product was obtained. Tenofovir disoproxil fumarate obtained by the above method was tested by HPLC, Its purity is higher than 99.5%, monoester is less than 0.5%, the sum of other impurities is not more than 0.1%, with tenofovir, The total molar yield is about 35-40%. | |
216.1 g | 120 g (0.418 mol) of tenofovir was heated to 80 C and dried under reduced pressure for 2 hours to remove water.After adding 600 g of DMAc (dimethylacetamide) and stirring uniformly, 120 g of triethylamine (1.186 mol) was added and stirred for 10 minutes, and then 280 g (1.835 mol) of CMIC (isopropylchloromethyl carbonate) was added.The reaction was incubated at 55 C for 7 hours.Sampling HPLC control,The reaction purity is 84.3%,2.2% of raw materials,Monoester 7.5%.The reaction was cooled to 5 C and filtered.The filter cake was washed with 850 g of dichloromethane.Combine the filtrate,Add 1200g of purified water cooled to 5 C with stirring.Let stand, dispense,Collect the lower organic layer,The upper aqueous layer was extracted once with 400 g of dichloromethane.The combined organic layer solutions were washed twice with purified water.The methylene chloride solution was concentrated to a pale yellow oil and then was stirred at 30 C for 30 min with 200 g of isopropanol and 240 g of n-hexane.Then cool down to 0 C for 2 h,filter,Decofolvir dipivoxil wet product 231.2g (about 185.4g dry),The molar yield was 85.3% and the purity was ?99.8%.231.2 g (0.445 mol) of tenofovir disoproxil wet product (about 185.4 g, 0.357 mol) and 55.4 g(0.477 mol) fumaric acid was added to 950 g of isopropanol and dissolved at 55 C.After being dissolved, it is filtered while hot.The filtrate was slowly cooled to 35-40 C. After crystallization for 2 h, the temperature was lowered to 0 C for 2 h.Filtered, pre-cooled isopropyl alcohol wash filter cake,About 120.6g of tenofovir disoproxil fumarateThe temperature was controlled to dry at 50 C for 10 hours under reduced pressure;Tenofovir disoproxil fumarate 216.1g,Molar yield 95.2%,Purity ? 99.8%. | |
A mixture of 1-methyl-2-pyrrolidinone (4.12 kg), PMPA monohydrate (1.00 kg), triethylamine (0.996 kg) in a reactor with an inert atmosphere, Stir for about 15 to 45 minutes (typically about 30 minutes). Chloromethyl-2-propyl carbonate (2.50 kg) is then added and the mixture is heated to about 55-65 C. (typically about 60 C.) and allowed to react for about 3-6 hours, Stir in such a way that the contents will not splash until the reaction is complete, as indicated in HPLC as necessary (only 15% of the mono (POC) PMPA present is present) for 4 hours. The mixture is diluted with isopropyl acetate (10.72 kg), cooled as rapidly as possible to about 15 to 30 C. (typically about 25 C.) and the reactor contents are heated to about 15 to 30 C. (typically About 25 C.), the mixture is stirred for about 20 to 60 minutes (typically about 30 minutes). The solid is removed by filtration and washed with isopropyl acetate (4.44 kg). The combined organic phases are washed with water (3.28 kg) at moderate stirring for about 1 to 10 minutes to avoid the formation of emulsion at about 15 to 30 C. (typically about 25 C.) Extract twice. Thereafter, the phases are separated. The combined aqueous phases are back-extracted twice with isopropyl acetate (3.56 kg) (about 15-30 C., typically about 25 C.). All organic phases are combined and water (2.20 kg) (about 15-30 C., typically about 25 C.) is added with moderate stirring for about 1-10 minutes to avoid the formation of emulsion, . The combined organic phase (which is about 25-43 C., but only 45 C.) is concentrated in vacuo (about 26.5-28 in. Hg) to about 30% of the initial volume (about 10 to 121 / kg PMPA monohydrate). After polishing filtration with an in-line 1 mum filter, concentration of the organic phase is carried out under vacuum (about 28 inches Hg) at a temperature of about 20 to 38 C., but not more than 40 C., as a pale yellow oil Keeps remaining. To a solution of fumaric acid (0.38 kg) in 2-propanol (6.24 kg) warmed oil (about 45-55 C., typically about 50 C.) is added to the solution for about 0.5-2.0 hours Dissolve with vigorous stirring. The warm solution is then filtered, using an in-line 1mu filter, as necessary, while minimizing cooling of the solution. The filtrate at about 34-50 C., typically about 40 C., is stirred to the minimum degree of agitation necessary to obtain a homogeneous solution. The resulting solution is seeded with a small amount of bis (POC) PMPA fumarate (ca. 100 mg), optionally with minimal agitation, in about 30 minutes to give a solution at about 30-33 C. , Typically to about 32 C., and is cooled to about 12-18 C., typically about 15 C., over about 1-2 hours, typically about 1 hour. In the case where crystal formation begins before adding seed crystals, seed crystals may not be necessary in some cases. Crystals can form over a range of about 12 to 33 C. as the solution cools. When the solution is further cooled, crystallization occurs at lower temperatures (eg, about -10 to about 11 C.). When crystal formation begins, stirring is interrupted. The mixture is allowed to stand at about 15 C. for at least about 12 hours (typically about 12 to 30 hours). The resulting slurry is filtered (Tyvek) and the filter cake is washed with a premix solution (1: 4 v / v) in isopropyl acetate (0.70 kg) in butyl ether (2.44 kg). The filter cake, which is only at 40 C., is dried in vacuum for about 1 to 3 days and the dried product is optionally ground (Fitzmill M5A with 0.050 inch screen)Bis (POC) PMPA fumarate is obtained as white, fine, powdery crystals (purity about 97.0 to 99.5%). |
Yield | Reaction Conditions | Operation in experiment |
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98% | With pyridine at 50 - 115℃; for 6h; | 1; 2; 3 Preparation of the compound tenofovir monophenyl ester General procedure: anhydrous tenofovir (50.0g, 0.18 mol) was stirred with pyridine (500 ml) at room temperature to form a turbid solution, and triphenyl phosphite (162.0 g, 0.52 mol) was added. The reaction temperature is 50-115 °C; the temperature is raised by a gradient, the temperature rise time is 5-10 °C / hour, and the reaction time is 6 hours.It was cooled to room temperature, filtered, and the filter cake was washed with acetone (50 ml), and the filter cake was dried at 60-70 °C for 4 hours to obtain 50.7 g of tenofovir monophenyl ester as a white solid in a yield of 82.5%. |
91% | With dmap; triethylamine at 100 - 110℃; | 1.A; 2.A-2.B A. Preparation of TAF Intermediate III Put 1.0eq of II into a 50L clean and dry reaction kettle, and add 4 to 5 times the volume of toluene.Turn on slow stirring. Add 0.7 0.8eqDMAP in order,1.0eq triphenyl phosphite, 2.0eq triethylamine,The temperature was raised to 100-110 ° C, and the reaction was stirred for 20-24 hours. The sum of the II and the acid anhydride monitored by HPLC was less than 0.5%. The reaction was completed.Cool to room temperature 20-25 ° C; add 3 times the volume of purified water, stir well for 30 minutes, and separate the layers to collect the lower aqueous phase (upper toluene recovery treatment);To the obtained aqueous phase, add 0.5 times the volume of absolute ethanol, and slowly add concentrated hydrochloric acid dropwise to pH = 3.8 ~ 4.0; add a few seeds, stir for 0.5h, and gradually solids precipitate; continue to slowly add concentrated hydrochloric acid pH = 2.0 2.1, stir for 3 4h to grow crystals, and centrifuge;The filter cake was beaten with 1 volume of 50% ethanol solution at room temperature for 1 hour and centrifuged; the solid was dried at 90 ° C for 12 hours after centrifugation to obtain white powder intermediate III, yield 91%, purity ≥98%, and bisphenol impurity <0.1% |
89.03% | With dmap; triethylamine In N,N-dimethyl acetamide at 105 - 110℃; for 20h; | 1; 1; 2; 2; 3; 3; 4 Example 2 (R)-9-[2-(phosphorylmethoxy)propyl]adenine(PMPA, 100.0g, 348.2mmol, 1.0eq),4-dimethylaminopyridine (DMAP, 21.3 g, 174.4 mmol, 0.5 eq),Triphenyl phosphite (129.6g, 417.7mmol,1.2eq),Triethylamine (TEA, 70.5 g, 696.7 mmol, 2.0 eq)Adding to N,N-dimethylacetamide (DMA, 200 ml), stirring was started, and the temperature was raised to 105-110 ° C for 20 hours.HPLC monitoring of (R)-9-[2-(phosphorylmethoxy)propyl]The adenine (PMPA) content was less than 0.1% and the reaction was stopped.Cool to room temperature (15 ~ 25 ° C), add water (400ml), dichloromethane (400ml × 3) extraction, the aqueous phase with concentrated hydrochloric acid (12M, 32ml) to adjust the pH to 2 ~ 3 precipitated solid, cooled to 0 ~ 10 °C,Filtration and drying gave (R)-9-[2-(phosphorylphenol methoxy)propyl]adenine 112.9 g,The yield is 89.03%.HPLC purity was 99.24%. |
89.3% | With dmap; N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 135 - 140℃; for 3h; | 1-3; 1-3 Example 1 (R)-9-[2-(phosphorylmethoxy)propyl]adenine (PMPA, 10.0 g, 34.82 mmol, 1.0 eq), 4-dimethylaminopyridine (DMAP, 0.4 g, 3.27 mmol, 0.1eq),Triphenyl phosphite (11.9 g, 38.35 mmol, 1.1 eq), N,N-diisopropylethylamine (DIPEA, 9.0 g, 69.63 mmol, 2.0 eq) was added to N-methylpyrrolidone (NMP) (20ml) In the middle, the stirring is turned on, and the temperature is raised to 135 to 140 ° C for 3 hours.The (R)-9-[2-(phosphorylmethoxy)propyl]adenine (PMPA) content was monitored by HPLC to be less than 0.1%, and the reaction was stopped. Cool to room temperature (15 ~ 25 ° C), add water (40ml),Extracted with dichloromethane (40 ml × 3), concentrated aqueous hydrochloric acid (12M, 3.2 ml)Adjust the pH to 2~3 to precipitate the solid, cool to 0~10 °C, filter and dry to get(R)-9-[2-(phosphorylphenol methoxy)propyl]adenine 11.3 g, yield 89.3%,The HPLC purity was 99.91%. |
88.75% | With pyridine; dicyclohexyl-carbodiimide at 20 - 115℃; for 8h; | 1-3 Preparation method 1 of (R)-9-[2-(phosphoryl phenol methoxy) propyl] adenine the compound (R)-9-[2-(phosphoryl methoxy) propyl] adenine (100.01g, 0.35mOl, 1.0eq, Zhejiang Supor Pharmaceutical Co., Ltd.) which is represented by the formula (1) is dissolved into 1400ml of pyridine (Shanghai Titan Chemical Co., Ltd.) at room temperature, start stirring, turn into a milky solution, at room temperature Triphenyl phosphite (324.04g, 1.05mol, 3. 0eq, Xiqiao Chemical) was added into the reaction solution, heating to reflux temperature at 115 ° C and carry on reaction for 8 hours, first of all solution became clear, and then a large amount of white solid precipitated again, cool down at about -5 ° C ~ 5 ° C, add 1400ml acetone (Hangzhou Jiachen Chemical Co., Ltd.), stir for 1.5 hours, filter, the filter cake is washed with 100ml acetone (Hangzhou Jiachen Chemical Co., Ltd.), the filter residue (white solid) is dried at 60 ° C~70 ° C for 5 hours, the obtained white solid as target product, a total of 112.26g of white solid was obtained, yield 88.75%, HPLC purity 96.90% |
88.1% | With pyridine at 110 - 120℃; for 8h; | 1 Comparative example 1 At room temperature, 16 mL of pyridine was added to the reaction flask, and 2.0 g of tenofovir was added.8.6 g of triphenyl phosphite, the system was heated to 110~120 °C, and the reaction was carried out for 8 hours at this temperature. The TLC detected that the starting material tenofovir disappeared substantially, the reaction system was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of ethyl acetate and dried to obtain 2.23 g of the compound of the formula I, the yield was 88.1%, and the purity was 96.0%. |
84% | With triethylamine In acetonitrile at 120℃; for 6h; | 1-7 Preparation method of PMPA monophenyl ester: Add PMPA (100g, 0.348mol) to a 500ml four-neck bottle.Triphenyl phosphite (162g, 0.523mol),Triethylamine (70.4 g, 0.697) and acetonitrile 150 ml,After stirring and stirring, the oil bath was heated to reflux and reacted for 1 h.The acetonitrile was continuously distilled off, the internal temperature was maintained at 120 ± 3 ° C, and the mixture was stirred for 5 hours, and the reaction was completed.Stir and cool to room temperature, add 300 ml of water,Ethyl acetate (200 ml) was stirred and extracted, and the aqueous layer was washed twice with ethyl acetate (200 ml).The obtained aqueous layer is adjusted to pH 2~2.5 with concentrated hydrochloric acid at room temperature.A large amount of solid was precipitated, and the internal temperature was cooled to 0 to 5 ° C in an ice water bath, and stirred for 3 hours.After suction filtration, the filter cake is washed twice with 0~5 ° C hydrochloric acid water (200 ml, pH 1.5~2).Drying at 60 ° C for 5 hours gave a white solid of 106.3 g, a yield of 84.0%.The HPLC purity was 98.76%. |
82.3% | With dmap; triethylamine In acetonitrile at 81℃; for 22h; | 1-4; 1-4 Specific embodiment 3 General procedure: 1) Take 1Kg GS-SM-101 (3.35mol) into a 1L three-necked flask, add 1000ml acetonitrile, add TEA (triethylamine, 6.5mol), GS-SM-102 (5.2mol), add DMAP (4 -Dimethylaminopyridine, 2.65mol) 2) Heat to 82°C and stir to react; 3) HPLC showed that the starting material GS-SM-101 remained below 0.5% to stop the reaction, about 23h; 4) Stop the reaction and cool to 70°C under reduced pressure and spin dry the solvent (vacuum degree -0.1, 70°C) until there is no solvent dripping, the product becomes viscous, and cool to 20-25°C. 5) Add 2.5L of water and 3L of ethyl acetate to the spin-dried viscous product, stir well to completely dissolve the viscous material, stand still for layering, separate the ethyl acetate, and then add 3L of ethyl acetate to the water phase The ester is fully stirred and the water phase is separated. 6) The water phase is adjusted to pH=2-3 with 350ml of 12mol/L hydrochloric acid (temperature maintained at 20°C±2°C) and stirred for about 1h. A large amount of solids will precipitate out. Continue stirring for 16.2h, then add acetonitrile and stir for 3h, filter out the solids. The solid was washed with 1L acetonitrile, washed twice, dried at 60°C for 16h, 7) Weighing, yield: 81.4%, purity of GS-101 is over 97%. |
81% | With dmap; triethylamine In acetonitrile at 80℃; for 48h; | 5 EXAMPLE 5Preparation of Compound 12 PMPA (100.0 g, 0.35 mol, 1 equiv) was charged to a vessel equipped with an overhead stirrer, reflux condenser, and nitrogen inlet, followed by acetonitrile (800 mL). To the vessel was added triethylamine (71.0 g, 0.70 mol, 2 equiv) followed by DMAP (42.6 g, 0.35 mol, 1 equiv) and triphenylphosphite (162.1 g, 0.52 mol, 1.5 equiv). The mixture was heated to 80° C. and agitated for >48 hours at 80° C. or until the reaction was complete by 31P NMR. (A sample directly from the reaction is taken and an insert containing 10% H3PO2 in D2O is added. The intermediate formed is the PMPA anhydride and is at 7 to 8 ppm; the product is at 12.3 to 12.6 ppm. The reaction is deemed complete when less than 5% anhydride is present). The reaction mixture was distilled to approximately 1.5 volumes of acetonitrile and diluted with ethyl acetate (200 mL) and water (300 mL). The aqueous layer was separated and washed with ethyl acetate (200 mL) twice. The aqueous layer was recharged to the vessel and pH adjusted to pH 3 using 12.1 M HCl (21.0 mL). The reaction was then seeded with 0.05% of compound 12 and allowed to stir at 25° C. An additional 12.1 M HCl was added over 20 minutes (7.0 mL) until pH 2 was achieved. The crystallization was allowed to stir at ambient temperature for 30 minutes and then cooled to 10° C. over 2 hours. Once at 10° C., the crystallization was allowed to stir for 2.5 hours at 10° C. The slurry was filtered and washed with pH 1.5 water (200 g). After drying in the vacuum oven, 102.2 g of compound 12 (81% yield) was obtained as a white solid. 1H NMR (400 MHz, D2O): δ1.31 (d, J=6.1 Hz, 3H), 3.59 (dd, J=14.0, 9.0 Hz, 1H), 3.85 (dd, J=14.0, 9.0 Hz, 1H), 4.1 (m, 1H), 4.3 (dd, J=15.0, 9.0 Hz, 1H), 4.5 (dd, J=15.0, 2 Hz, 1H), 6.75 (d, J=7 Hz, 2H), 7.15 (t, J=7 Hz, 1H), 7.25 (t, J=7 Hz, 2H), 8.26 (s, 1H), 8.35 (s, 1H). 31P NMR (162 MHz, D2O): δ14.8. |
81% | Stage #1: triphenyl phosphite; tenofovir With dmap; triethylamine In acetonitrile at 80℃; Reflux; Inert atmosphere; Stage #2: With hydrogenchloride In water at 25℃; | 5 Synthetic Example 5 Preparation of Compound 12 PMPA (100.0 g, 0.35 mol, 1 equiv) was charged to a vessel equipped with an overhead stirrer, reflux condenser and nitrogen inlet followed by acetonitrile (800 mL). To the vessel was added triethylamine (71.0 g, 0.70 mol, 2 equiv) followed by DMAP (42.6 g, 0.35 mol, 1 equiv) and triphenylphosphite (162.1 g, 0.52 mol, 1.5 equiv). The mixture was heated to 80° C. and agitated for ≧48 hours at 80° C. or until the reaction was complete by 31P NMR. (A sample directly from the reaction is taken and an insert containing 10% H3PO2 in D2O is added. The intermediate formed is the PMPA anhydride and is at 6 ppm; the product is at 11 ppm. The reaction is deemed complete when less than 5% anhydride is present). The reaction mixture was distilled to 1.5 volumes of acetonitrile and diluted with ethyl acetate (200 mL) and water (300 mL). The aqueous layer was separated and washed with ethyl acetate (200 mL) twice. The aqueous layer was recharged to the vessel and pH adjusted to pH 3 using 12.1 M HCl (21.0 mL.). The reaction was then seeded with 0.05% of compound 12 seed and allowed to stir at 25° C. Additional 12.1 M HCl was added over 20 minutes (7.0 mL) until pH 2 was achieved. The crystallization was allowed to stir at ambient temperature for 30 minutes and then cooled to 10° C. over 2 hours. Once at 10° C. the crystallization was allowed to stir for 2.5 hours at 10° C. The slurry was filtered and washed with pH 1.5 water (200 g). After drying in the vacuum oven, 102.2 g of compound 12 (81% yield) was obtained as a white solid. 1H NMR (400 MHz, D2O): δ 1.31 (d, J=6.1 Hz, 3H), 3.59 (dd, J=14.0, 9.0 Hz, 1H), 3.85 (dd, J=14.0, 9.0 Hz, 1H), 4.1 (m, 1H), 4.3 (dd, J=15.0, 9.0 Hz, 1H), 4.5 (dd, J=15.0, 2 Hz, 1H), 6.75 (d. J=7 Hz, 2H), 7.15 (t, J=7 Hz, 1H), 7.25 (t, J=7 Hz, 2H), 8.26 (s, 1H), 8.35 (s, 1H). 31P NMR (162 MHz, D2O): δ. 14.8. |
81% | With dmap; triethylamine In acetonitrile at 80℃; for 60h; | 1.1 (1), Preparation of Compound 2 In a three-necked flask, PMPA (20 g, 70 mmol)Anhydrous acetonitrile (180 ml),Triethylamine (19.6 ml, 140 mmol), DMAP (8.52 g, 70 mmol) andTriphenyl phosphite (32.42 g, 104 mmol),The reaction mixture was heated to 80 ° C,Continue stirring at this temperature for 60 hours until the reaction is complete,Most of the distilled off,Ethyl acetate (100 ml)And water (80 ml),The aqueous phase was washed with ethyl acetate (2 × 100 ml)The aqueous solution was poured into a reaction flask, washed with concentrated hydrochloric acid (12M,4.2 ml) was adjusted to pH 3 and 100 mg of seed crystals were added with stirring at room temperature, then concentrated hydrochloric acid (12 M, 1.4 ml)Adjust to pH 2.After stirring at room temperature for 1 hour,Then gradually cooled to about 10 , stirred overnight, the white solid was collected,And washed with 20 ml (pH 1.5) cold hydrochloric acid solution,Drying 20.4g, yield 81%. |
81.57% | With dmap; triethylamine In acetonitrile at 80℃; for 48h; | 1.1 step 1: Tenofovir (70.5 g),Triethylamine, DMAP,After the mixture of triphenyl phosphite and acetonitrile was refluxed at 80°C for 48 hours, the heating was stopped.Acetonitrile was removed by rotary evaporation and the layers were extracted by extraction with water, ethyl acetate and acetonitrile.The aqueous phase is added dropwise with concentrated hydrochloric acid (30%) to a pH of 3 at low temperature (≤25°C).Continue stirring and a solid precipitates.Concentrated hydrochloric acid was added dropwise until the pH was less than 2.It was filtered and dried to obtain 73.1 g of a white powdered solid IIA in a yield of 81.57%. |
80.1% | With pyridine at 115℃; for 4h; | 1.1 Example 1: Preparation of Form I of Compound I (Plant Type) Anhydrous tenofovir (100.0 g, 0.35 mol) was stirred with pyridine (1000 mL) at room temperature to form a cloudy solution. Triphenyl phosphite (324.0 g, 1.05 mol) was heated to reflux at 115° C. for 4 h, during which it first became clear and a large amount of solids precipitated. After cooling to 0° C., acetone (1000 mL) was added and stirred for 1.5 h. The filter cake was filtered. After washing with acetone (100 mL), the filter cake was dried at 60-70° C. for 5 h to give a white solid ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy). Methyl monophenyl phosphate 101.3 g, yield 80.1%. |
75% | With dmap; triethylamine In N,N-dimethyl-formamide at 90 - 100℃; Large scale; | 1-2 Preparation of compound of formula III Add 1.0Kg of PMPA, 2.2L of DMF, 704.3g of TEA, 425.2g of DMAP and 1619.7g of Ph3O3P into a 10L three-necked flask, raise the temperature to 90100, react for 1518h, after the reaction is complete, cool to room temperature, add 5L of purified water , The water phase was washed twice with ethyl acetate (3L×2), the pH of the water phase was adjusted to 23 with concentrated hydrochloric acid between 2030, the temperature was lowered to 010, and the crystallization was carried out for 23h. After centrifugation, the filter cake was rinsed twice with dilute hydrochloric acid with pH=1.5, the wet filter cake was washed with 7L ethyl acetate for 1 to 2 hours, centrifuged, and the resulting solid product was vacuum dried at 60 to 65°C for 24 to 26 hours to obtain 948.7 g of white solid Namely Formula III, the molar yield is 75.0%, and the HPLC purity is 99.75% |
71% | With dmap; triethylamine In acetonitrile at 83℃; for 70h; | 1.S1-1.S2 Comparative Example 1 A method for preparing propofol tenofovir key intermediate, phenyl PMPA, includes the following steps: S1. Weigh 20g tenofovir, 8g 4-dimethylaminopyridine,13g of triethylamine,30 g of triphenyl phosphite was added to the reaction flask, and 160 mL of acetonitrile was measured.Add to reaction flask, stir to 83 ° C and reflux for 70h. S2. After the reaction is completed, most of the solvent is distilled off under reduced pressure.60 g of water was added, washed with 40 mL of ethyl acetate, and washed 3 times.Add hydrochloric acid to adjust the pH to 2.0, and reduce the temperature to 0 10 for 2 hours.Filtration, the filter cake was washed with 40 mL of water of pH 1.5, and dried to obtain 18 g of monophenyl PMPA product, yield 71%,The purity by HPLC was 99.7% and the content of tenofovir was 0.02%.The preparation method of Comparative Example 1 refers to the method disclosed in CN103842366B for preparing monophenyl PMPA. |
70.4% | With dmap; triethylamine In acetonitrile at 80℃; for 72h; Industrial scale; | 2 Example 2 Take 2kg of tenofovir, 12.5L of acetonitrile, put into a 20L reaction bottle, start stirring, add 1.5kg of triethylamine,0.9kg of p-dimethylaminopyridine, 3.3kg of triphenyl phosphite, after adding, heating to 80 ° C, reflux reaction for 3 days,The reaction solution was concentrated under reduced pressure at 60 ° C to remove solvent acetonitrile to give a brown oily residue.6 L of water and 3 L of ethyl acetate were added to the residue, and the mixture was stirred until the system was homogeneous, and the layer was allowed to stand, and the organic layer was discarded.The aqueous layer was washed twice with 6 L of ethyl acetate, and then the pH was adjusted to 5-6 with concentrated hydrochloric acid.Stir at 20-25 ° C for 30 min., maintain 20-25 ° C, slowly add about 4 L of concentrated hydrochloric acid, adjust the pH to 2, and cool the system to 0-10 ° C for 2 h.Filtration, filter cake dilute hydrochloric acid (5L ice water + 60ml concentrated hydrochloric acid) for 1h, filter, filter cake and then rinse with 10L of the above dilute acid,It was suction filtered to dryness, dried at 80 ° C, and dried under reduced pressure to constant weight to give 1.96 kg of white solid FAT-1, yield 70.4%, HPLC purity over 98%. |
60% | With dmap In acetonitrile for 48h; Reflux; | [(1R)-2-(6-aminopurin-9-yl) -1-methyl-ethoxy]methyl-phenoxy-phosphinicacid A solution of [[(1R)-2-(6-aminopurine-9-yl)-1-methylethoxy]methyl]phosphonic acid (PMPA) (10 g, 0.035 mol) in acetonitrile (80 mL) 4-dimethylaminopyridine (4.26 g, 0.035 mol) and triphenyl phosphite (16.21 g, 0.052 mol) were added and the temperature was raised to reflux for 48 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, ethyl acetate (20 mL) and water (30 mL) were added, extracted and the aqueous phase was extracted with concentrated ethyl acetate (20 mL x 2)concentrated hydrochloric acid to adjust the water phase pH = 3, the filtrate was washed with methanol and dried under reduced pressure to give the title compound [(1R)-2-(6-aminopurine-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphinicacid (Intermediate 1) as a pale yellow solid (7.5 g, yield 60%). |
56% | With dmap; triethylamine In acetonitrile at 80℃; for 48h; Inert atmosphere; | 1.3 Step 3: [[(1R) -2- (6-Aminopurine-9-yl) -1-methylethoxy] methyl] phenoxyphosphoric acid (1E) Under nitrogen protection[[(1R) -2- (6-aminopurine-9-yl) -1-methylethoxy] methyl]Phosphoric acid(Ie PMPA)(3.5 g, 34.8 mmol), 4-dimethylaminopyridine (i.e., DMAP) (2.1 g, 17.4 mmol) was added to a three-necked flask, And triphenyl phosphite (8.1 g, 26.1 mmol) were added and heated to an internal temperature of 80 ° C for two days. The reaction solution was concentrated under reduced pressure to remove acetonitrile, and ethyl acetate (10 mL) and water (15 mL) were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL x 2). The aqueous layers were combined. Hydrochloric acid to adjust the pH to 3, room temperature stirring 10 minutes, with concentrated hydrochloric acid to adjust the pH to 2, ice water cooled to 10 ° C after stirring for two hours after standing overnight, filtered, filter cake (10mL) washing, (1E), [(3.5 g, 56% yield). |
56% | With dmap; triethylamine In acetonitrile at 80℃; for 48h; | 1.3 The third step: [[(1R) -2- (6-aminopurin-9-yl) -1-methylethoxy] methyl] phenoxy hypophosphorous acid (1E) Under nitrogen protection, add [[(1R) -2- (6-aminopurin-9-yl) -1-methylethoxy] methyl] phosphoric acid (ie PMPA) (1D) (5g, 17.4mmol) to In a three-necked flask, add acetonitrile (40mL), triethylamine (3.5g, 34.8mmol), 4-dimethylaminopyridine (ie DMAP) (2.1g, 17.4mmol) and triphenyl phosphite (8.1g, 26.1 After the addition of mmol), the reaction was heated to an internal temperature of 80 ° C for two days. The reaction liquid was concentrated under reduced pressure to remove acetonitrile, ethyl acetate (10 mL) and water (15 mL) were added to the residue, the liquid was separated, and the aqueous layer was extracted with ethyl acetate (10 mL × 2), the aqueous layer was combined, and the aqueous layer was concentrated Adjust the pH to 3 with hydrochloric acid, stir for 10 minutes at room temperature, adjust the pH to 2 with concentrated hydrochloric acid, cool to 10 ° C with ice water and stir for two hours, then let stand overnight, filter, wash the filter cake with water (10 mL), collect the filter cake, and dry the title The compound [[(1R) -2- (6-aminopurin-9-yl) -1-methylethoxy] methyl] phenoxy hypophosphorous acid (1E), (3.5 g, 56% yield). |
55% | With dmap; triethylamine In acetonitrile at 60℃; Inert atmosphere; | 19 Example 19: ((((R)-1-(6-Amino-9H-indol-9-yl)propane)-2-phenyl)oxy)methyl)phosphoric acid monophenyl ester (TAF-1) Under nitrogen protection, 950 g of acetonitrile was added to a 5 L reaction flask, and stirring was started, and 150 g of tenofovir (SM1) was sequentially added.106 g of triethylamine, 96 g of 4-dimethylaminopyridine and 90 g of triphenyl phosphite (SM3). After the feeding is completed,Warming up to 60 ° C,The mixture was stirred and stirred until TLC was used to detect the basic reaction of the raw material SM1. The mixture was distilled under reduced pressure with stirring, and 400 g of methanol was added to the residue. The temperature is controlled at 20 to 25 ° C, 150 g of concentrated hydrochloric acid is added dropwise under stirring, and the dropwise addition time is 0.5 to 1 hour. After the dropwise addition is completed, the mixture is stirred for 0.5 hour to precipitate a large amount of solid, 2.0 Kg of ethyl acetate is added, and the mixture is stirred for 12 to 16 hours. Filtration and drying at 60 ° C for 4 to 6 hours gave a crude intermediate of TAF-1 of about 125 g.Add 750g of water to the 1L reaction bottle, start stirring, add 125g of crude TAF-1, control temperature 10~20 °C, stir for 0.5~1 hour, filter, rinse with 237g ethanol, drum at 55~65°C The air was dried for 6 to 8 hours to obtain 102 g of an off-white powder. Yield: 55.0%. |
With dmap; triethylamine In 1-methyl-pyrrolidin-2-one; cyclohexane at 80℃; for 40h; | 2 process for the preparation of monophenyl PMPA hydrate Cyclohexane (800 ml), triethylamine (66 g), and PMPA hydrate (100 g) were combined in a clean flask and the temperature was raised to reflux. The reaction mass was maintained at reflux temperature under atmospheric pressure, distilling out cyclohexane, until an azeotrope was formed. N-methyl-2-pyrrolidinone (100 ml), dimethylaminopyridine (44 g), and triethylamine (66 g) were then added. Next, triphenylphosphite (163 g) was slowly added and the temperature was raised to 80 ± 3 °C. The reaction conditions were maintained for 40 hours and monitored for completion by HPLC. The reaction mass was then cooled to room temperature. Methylene dichloride (200 ml) was then added and stirred for 30 minutes before cooling to 8 ± 2 °C. Water was added (400 ml) and stirred for 10 min. The temperature was slowly raised to 25 ± 30C, stirred for 30 minutes, then the mixture was allowed to settle. The bottom organic layer was then separated. Methylene dichloride (200 ml) was added to the aqueous layer, stirred for 30 minutes, and the mixture was allowed to settle again before separating the bottom organic layer. This process was repeated once again, adding methylene dichloride (200 ml), allowing the reaction to settle, and then separating the organic layer. The pH of the aqueous layer was then adjusted to 2.25 ± 0.25 with chemically pure HCl. The product was filtered, washed with chilled water followed by acetone and dried to yield monophenyl PMPA hydrate. | |
1.12 g | In pyridine at 118℃; for 8h; | 2 Embodiment 2:9 - [(R)-2 - (triphenylphosphine acyl methoxy) propyl] adenine preparation The 1.01g tenofovir (PMPA) at room temperature by adding 14 ml in pyridine, at room temperature 3.24g triphenyl phosphite is added to the reaction solution, heating to reflow temperature 115 °C reaction 8 hours, first variable to clarify the solution, then separate out a large amount of white solid, cooling to the -5 °C -5 °C left, adding 14 ml acetone, stirring 1.5 hours, filtering, cake 1 ml acetone washing after 60 °C -70 °C drying 5 hours, the resulting white solid is obtained target product, to obtain a total 1.12g white solid 9 - [(R)-2 - (triphenylphosphine acyl methoxy) propyl] adenine. |
474 g | With dmap In acetonitrile at 70 - 80℃; | 1 Preparation of Compounds of Formula TAF-M1 Add 4L acetonitrile to a 10L reaction flask,Then add TAF-SM1 (500g) in order.DMAP (213g), Et3N (352g),Triphenyl Phosphite (810g),After completion of heating to 70-80 ° C reflux reaction 65-72 hours;After completion of the reaction, acetonitrile was concentrated under reduced pressure at about 50°C, and the residue was cooled to room temperature (20-30°C). Water (2000 g) and EA (1500 ml) were added. The mixture was stirred and dissolved. The layers were separated and the aqueous phase was filled with 1500 ml*3 EA. Extract three times, the aqueous phase at 20-30 ° C with concentrated hydrochloric acid to adjust the PH value of 1-2 (about 160-170ml), stirring for 30 minutes, precipitation of solids after cooling down to 0-10 crystallization for 1-2 hours, filtered, 1% thin Rinse with hydrochloric acid (0-10° C.) and filter dry. The wet cake is beaten with 1.5 L of DCM for 2-3 hours, filtered, and air-dried at normal pressure for 24-30 hours to receive 474 g of white solid, namely TAF-M1 compound. HPLC purity is above 98%. |
With dmap; triethylamine In acetonitrile for 72h; Reflux; Large scale; | 1.1 Step 1 (Reaction flowchart shown in Figure 5): Acetonitrile 120kg was pumped into a 500L reactor.Tenofovir 20 kg (69.6 mol) was added,Triphenyl phosphite 32kg (103mol),DMAP 8kg (65.5mol),Triethylamine 14kg (138mol),The temperature is slowly returned to reflux for 72 hours.Cool down to 50°C and concentrate acetonitrile under reduced pressure to dryness.Add purified water 100kg,Extract three times with ethyl acetate,Each use of 60kg,Keep the water layer.Hydrochloric acid is acidified to a pH of 2.0-3.0.Plate centrifuge rejection filter,Rinse the solid with 0.1M hydrochloric acid,Dichloromethane rinses solids,Rejection filter to dry,Reserve TAF-I M solid. | |
With dmap; triethylamine In acetonitrile for 70h; Reflux; | 1.1 (1) Esterification: An acid binding agent, (R)-tenofovir, triphenyl phosphite, a first organic solvent are added to the reactor, and the reaction is refluxed for 70 hours, and the reaction is completed.The organic solvent was concentrated under reduced pressure. The residue was evaporated to room temperature.The aqueous phase was adjusted to pH 2-3 with concentrated hydrochloric acid having a mass fraction of 36%, cooled and crystallized, filtered, rinsed with dilute hydrochloric acid of 1% by mass, and then stirred at room temperature with dichloromethane (the (R) - tenofovir with the first organic solvent,The weight ratio of the water, the ethyl acetate and the dichloromethane is 1:9:3:8:7), filtered, rinsed with methylene chloride, and dried under atmospheric pressure to obtain TAF-1;The acid binding agent in the step (1) is DMAP, triethylamine,The molar ratio of DMAP to the triethylamine is 1:2.05; the (R)-tenofovir and the acid binding agent,The molar ratio of the triphenyl phosphite is 1:3: 1.45; the first organic solvent is selected from the group consisting of acetonitrile; | |
120.5 g | With dmap In acetonitrile at 90 - 100℃; for 8h; | 1.S1 Example 1 S1. Add 100g tenofovir, 162.1g triphenyl phosphite, 42.6g DMAP, 0ml acetonitrile and 71.0g triethylamine to a 2L reaction flask, start heating, increase the temperature to 90-100C, keep the temperature for 8h; end of reaction After cooling down to 40-50C, evaporate acetonitrile under reduced pressure, then add 750ml acetone and 250ml acetonitrile, control the temperature at 30-40C, slowly add concentrated hydrochloric acid until the pH is 2.5-3.5, keep stirring for 1h, cool to 20-30C, keep warm Crystallize for 4h, filter, and rinse the filter cake with 200ml of acetonitrile; put the filter cake into a 2L reaction flask, add 1000ml of acetonitrile, heat to 50-60C, stir for 2h, and cool to 20-30C, keep the crystallization for 4h, filter, use Rinse the filter cake with 200ml of acetonitrile; put the filter cake into a 2L reaction flask, add 150ml of methanol and 650ml of acetonitrile, warm up to 50-60C, stir for 2h, cool to 20-30C, keep and crystallize for 4h, filter, and rinse with 200ml acetonitrile Filter cake; The filter cake was dried under reduced pressure at 40-50C for 12h, and weighed 120.5g of monophenyl tenofovir; |
With dmap; triethylamine | ||
With dmap; triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.4% | In ethyl acetate at 0 - 10℃; for 2h; Cooling with ice; | 1.2 The esterification reaction solution obtained in the step (1) is slowly added dropwise to a mixture of 90 ml of ethyl acetate and 910 ml of ice water.The crystals were mixed and the addition was completed. The mixture was stirred and crystallized at 0 to 10 ° C for 2 h, filtered, suction filtered, and the filter cake was dried to obtain 77.2 g of tenofovir.The yield is 85.4%, and the purity is ≥97.0%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | With dmap; triethylamine; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | Under the protection of nitrogen, into the reaction bottle tenofovir (14.42g, 50mmol), (R)-1-(6-amino-9H-purin-9-yl)propyl-2-ol (11.64g, 60mmol) and DCC (30.95g, 150mmol), Et3N (10.12g, 100mmol), DMAP (0.61g, 5mol) and 150mL DMF, to 90 C stirring reaction sleepovers, cooling to 20-25C, is filtered to remove solid, remove the solvent under vacuum state, slabs obtained is reacted with silica gel column chromatography (dichloromethane/methanol = 1:1) to obtain a target compound 7 (18.00g), the yield is 77.8%. |
55% | With dmap; triethylamine; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | To the mixture of (R)-([1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid (1, 14.42 g, 50 mmol), (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol (5, 11.64 g, 60 mmol) and DCC (41.25 g, 200 mmol) suspended in 150 mL DMF under N2 atmosphere, was added Et3N (10.12 g,100 mmol) and DMAP (0.61 g, 5.0 mmol). The resulting mixture was heated to 90 C and kept at the same temperature overnight. The mixture was cooled to 20?25 C and filtered. The solid was removed and the liquor was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 1:1) to afford the title compound (12.70 g, 55%). 1H NMR (DMSO-d6) (ppm) = 8.27 (s, 1H), 8.17 (s, 1H), 8.15 (s, 2H), 7.56 (br, 1H), 7.36 (br, 2H), 7.32 (br, 2H), 4.58-4.64 (m, 1H), 4.10-4.22 (m, 4H), 3.77-3.81 (m, 1H), 3.28-3.44 (m, 2H), 1.01 (d, J = 6.0 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H). 13C NMR (DMSO-d6) (ppm) = 155.73, 155.68, 152.1, 152.0, 149.81, 149.76, 141.9, 141.8, 118.3, 118.2, 74.8, 74.7, 68.32, 68.26, 65.8, 64.3, 48.6, 46.5, 19.59, 19.57, 16.8. 31P NMR (DMSO-d6) (ppm) = 12.77.HRMS (+ESI): m/z 232.0897 [M + 2H]2+/2 (100%), Calculated: 232.0899 for [C17H23N10O4P + 2H]2+/2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.7 g | Step 2:[0022] DMF (0.1mL) and dichlorosulfoxide (0.73g) were added to a suspension of tenofovir (1g, purchased from Suzhou Henderson Pharmaceutical Co., Ltd.) in sulfolane (2.5mL) at 70 C, and then the temperature was raised to 100 C. The reaction mixture was stirred at 100 C for 1.5 hours until a clear solution was obtained. Then, <strong>[1529-17-5]phenoxy trimethylsilane</strong> (0.70g) was added rapidly and the mixture was continued to stir at 100 C for another 1.5 hour. Then the solvent was evaporated to give a viscous yellow oil. The oil was dissolved in methanol and adjusted to pH 3 with 45% aqueous potassium hydroxide. The precipitate was filtered and dried to give a white powder solid IIa (0.7g). MS (m/z) 363.96 (MH+). | |
0.7 g | At 70C,In a sulfolane (2.5 mL) turbid solution of tenofovir (1g, purchased from Suzhou Henderson Pharmaceutical Technology Co., Ltd.),DMF (0.1 mL) was added dropwiseAnd thionyl chloride (0.73g),Warm up to 100C,The mixture was reacted at 100C for 1.5 hours until the mixture was completely clear.Fast addition of phenoxytrimethylsilane (0.70g),After the mixture has reacted at 100C for 1.5 hours,The solvent is distilled off under reduced pressureA viscous yellow oily liquid is obtained,After the methanol dissolves,Adjust the pH to 3 with a 45% aqueous solution of potassium hydroxide.It was filtered and dried to give 0.7 g of a white powdery solid IIa. | |
0.7 g | In a sulfolane (2.5 mL) turbid solution of tenofovir (1 g, purchased from Suzhou Handerson Medical Technology Co., Ltd.) at 70 C,DMF (0.1 mL) and thionyl chloride (0.73 g) were added dropwise, the temperature was raised to 100 C, and the mixture was further reacted at 100 C for 1.5 hours until the mixture was completely clarified.Quickly add phenoxytrimethylsilane (0.70g),After the mixture was reacted at 100 C for 1.5 hours,Evaporate the solvent under reduced pressure.Obtaining a viscous yellow oily liquid,After the methanol is dissolved,Adjust the pH to 3 with 45% aqueous potassium hydroxide solution.filter,Drying gave 0.7 g of a white powdery solid IIa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.42 g | Example: 11 Preparation of 9-[2-(R)-(phosphonomethoxy)propyl] <strong>[73-24-5]adenine</strong> (II). Method-A Magnesium di-tert-butoxide (51 mg) was added to a stirred suspension of <strong>[73-24-5]adenine</strong> (2 g) in methanol (12 ml) at 10C. After 4 h at this temperature, sodium hydroxide (12 mg) and (R)-(+)-propylene oxide (1 .25 g) were added in succession to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred at this temperature until the reaction was complete, as indicated by TLC. Methanol was evaporated under vacuum. N, N-Dimethylformamide (16 ml) was added to the crude reaction mixture thus obtained and the mixture was heated to 60-70C. Magnesium di-tert-butoxide (7 g) was added to the reaction mixture in four divided batches over a period of 15 minutes at this temperature. The mixture was heated to 80-90C, and stirred at this temperature for 30 minutes. Diethyl p-toluenesulfonyloxymethylphosphonate (13.2 g) was added drop by drop to the reaction mixture over a period of 4 h, and the mixture was stirred at this temperature until the reaction was complete, as indicated by TLC. N, N-Dimethylformamide was distilled out under vacuum at 90-100C. Aqueous hydrobromic acid (48% w/w, 30 ml) was then added to the residue and the reaction mixture was heated to gentle reflux. After approximately 20 h at this condition, the reaction mixture was allowed to cool down to room temperature and filtered. The filtered solid was washed with dichloromethane (10 ml). The washing was concentrated to furnish a residue. The residue was combined with the filtrate and the combined filtrate was washed with dichloromethane (2 X 10 ml). To the aqueous layer, an aqueous solution of sodium hydroxide (50 %) was added until the pH attained 2.1 -3. After several hours at room temperature, the aqueous layer was cooled to 0- 5C and stirred at this temperature for further hours to maximize precipitation of the desired product from the solution. The precipitated solid was filtered, washed with cold water (1 X 5 ml), acetone (2X 5 ml) and dried to obtain 9-[2-(R)-(phosphonomethoxy)propyl]<strong>[73-24-5]adenine</strong>; yield: 1 .42 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.7 g | Example: 12 Preparation of 9-[2-(R)-(phosphonomethoxy)propyl] adenine (II) Method-B Magnesium di-tert-butoxide (1 .76 g) was added in four divided batches to a stirred suspension of 9-[2-(R)-(hydroxyl)propyl)adenine] (1 g) in N, N- dimethylformamide (3 ml) at 60-70C over a period of 1 h. The reaction mixture was heated to 90C and <strong>[3167-63-3]diethyl chloromethylphosphonate</strong> (1 .93 g) was added drop by drop to the reaction mixture over a period of 4 h. The reaction mixture was maintained at this temperature until the reaction was complete, as indicated by TLC. Nu, Nu-Dimethylformamide was distilled out under vacuum at 90-100C. To the residue thus obtained, aqueous hydrobromic acid (48% w/w, 10 ml) was added and the reaction mixture was heated to gentle reflux. After approximately 20 h at this condition, the reaction mixture was allowed to cool down to room temperature and filtered. The filtered solid was washed with dichloromethane (10 ml). The washing was concentrated to furnish a residue. The residue was combined with the filtrate and the combined filtrate was washed with dichloromethane (2 X 10 ml). To the aqueous layer, an aqueous solution of sodium hydroxide (50%) was added until the pH attained 2.1 -3. After several hours at room temperature, the aqueous layer was cooled to 0-5 C and stirred at this temperature for further hours to maximize precipitation of the desired product from the solution. The precipitated solid was filtered, washed with cold water (1 X 5 ml), acetone (2 X 5 ml) and dried to obtain 9-[2-(R)-(phosphonomethoxy)propyl]adenine; yield: 0.7 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.1% | 1g of 9-[(R)-2-(phosphonomethoxy)propyl]adenine placed in a 50 ml of three necked flask, under room temperature added 15ml of acetonitrile and 0.64 g of thionyl chloride, then the mixture was heated to 70 C and stirred for 2 to 3 hours. After the completion of the reaction, the reaction mixture was concentrated and cooled to -5 C. then 15 mL of acetonitrile and 1.45 g of L-Alanine Isopropyl Ester and the mixture was stirred for 1 hour. Then concentrated and by column chromatography separation obtained 0.85 g of a white solid. Yield 60.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.95g | Add to the reaction flask1-methyl-2-pyrrolidone (NMP)(R) -9- [2- (Hydroxy) propyl] adenine (4.0 g, 21.0 mmol, 1.0 eq.) Was added with stirring,Heated to 65 C.To the mixture was added magnesium tert-butoxide (3.0 g, 17.3 mmol, 0.8 eq.) Over 1 hour,Maintaining the temperature at 78 C,A solution of diethyl p-fluorobenzenesulfonyloxymethylphosphonate (10.14 g, about 31.1 mmol, 1.5 eq.) Was slowly added over 2 hours.The reaction was stirred at 75-80 & lt; 0 & gt; C for 7 hours,Cooled to room temperature,Cooled to 0 to 5 C in an ice bath,Trimethylbromosilane (12.9 g, 84.3 mmol, 4.0 eq.) Was added dropwise,The reaction mixture was then heated at 77 & lt; 0 & gt; C for 8 hours.The reaction was stopped,To the reaction solution was added 20 ml of water,50 mol ethyl acetate.The aqueous layer was stirred under ice-cooling and the pH was adjusted to 2.5 to 3.1 with 50% NaOH solution. The off-white solid precipitated and stirred for at least 3 hours. Filtration, drying, tenofovir was 5.95g, yield 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.7% | With hydrogenchloride In water at 90 - 110℃; | 1 Adenine (17.4 g, 0.13 mol),Potassium carbonate (21.5 g, 0.15 mol),R-propylene carbonate (15.8 g, 0.15 mol)Was dissolved in 50 mL of N, N-dimethylformamide,Heated to 90 ~ 125 ° C,Insulation at 90 ~ 125 ° CReaction 3 ~ 6 hours;Down to room temperature,Under argon, magnesium isopropoxide (15.7 g, 0.14 mol) was added,Heating up to 30 ~ 45,Insulation reaction 0.5 ~ 1 hour;Dimethyl p-toluenesulfonyloxymethylphosphonate (44.1 g, 0.15 mol) was added dropwise,Insulation at 30 ~ 45 ° C continue to react 4 ~ 6 hours; the system down to room temperature,The reaction system was concentrated under reduced pressure to give a viscous oily substance intermediate 2;To the resulting intermediate 2 was added 124 g of concentrated hydrochloric acid,Heating up to 90 ~ 110 ° C,Insulation reaction 3 ~ 6 hours;Down to room temperature,The reaction was continued at room temperature for 1 to 2 hours,Filter,The filter cake was washed twice with 150 mL of 5 wt% dilute aqueous hydrochloric acid,The filtrate was adjusted with sodium hydroxide solution ρH- = 2 ~ 3,Crystallization overnight,Cooling to 0 ~ 3 ° C,So that the crystallization for 3 hours;Filter,The filter cake was washed once with 30 mL of water,50 mL of water and acetone (V / V = 1: 1) was washed twice,50mL acetone washed once;Vacuum drying,Tylenolide28g,The total molar yield was 75.7%HPLC purity was 98.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: tenofovir With thionyl chloride In toluene at 80 - 90℃; for 20h; Stage #2: alanine isopropyl ester hydrochloride With sodium sulfate In dichloromethane; toluene at -15℃; for 4h; Inert atmosphere; | 3 Example 3: Synthesis of TAF-impurity C 500 ml of toluene was added to the 1 L reaction flask.Add 50gTenofovirWarm up to90°CRecirculate and divert water until no more water emerges.Slowly add 30g thionyl chloride,After the addition of 80 ° C, the reaction was continued for 20 hours.Concentrate under reduced pressure until no significant distillate appears.The nitrogen protection is lowered to room temperature and 200ml of dichloromethane is added.Stir and disperse for use. Add 500 ml of dichloromethane to the 3 L reaction flask.Add 32 g of L-alanine isopropyl ester hydrochloride and 40 g of potassium hydrogencarbonate.Add 50 g of anhydrous sodium sulfate to room temperature for 4 hours.Filter and drain, and cool to -15 °C under nitrogen protection.Triethylamine and the above-mentioned chlorinated compound are added slowly,After completion of the incubation reaction, TLC monitored the completion of the reaction.Add 10% aqueous sodium dihydrogen phosphate solution,The saturated sodium chloride solution was allowed to stand for separation, and the organic phase was dried over 200 g of anhydrous sodium sulfate.Filter and concentrate the mother liquor at 35°C under reduced pressure to obtain an oily product.Column chromatography of V dichloromethane:V methanol=2:1 gave a pale yellow solid TAF-impurity C,56.1 g, 80% yield, purity greater than 98%. |
80% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In water at 40℃; | |
With 1,2-dichloro-ethane; triethylamine In water at 20 - 40℃; for 16h; | P- { [(1R)-2-(6-amino-9H-purin-9 -yl)- 1 -methylethoxylmethyl } -N- [(18)-i -methyl-2-( 1-methylethoxy)-2-oxoethyljphosphonamidic acid: To a solution of (R)-((( 1 -(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid (referred to herein as TFV, 3.0 g, 10.5 mmol) in water (50 mL) were added EDC (10.0 g, 52.2 mmol) and (5)-isopropyl 2- aminopropanoate hydrochloride (8.8 g, 52.2 mmol) at ambient temperature. The pH value of the resulting solution was adjusted to 7.27.6 with TEA (5.3 g, 52.2 mmol). The resulting mixture was stirred at 40 °C for 16 h. The reaction was monitored by LC-MS. Upon reactioncompletion, the reaction was cooled down to ambient temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (Column: C18, 330 g,20-35 um, 100 A; Mobile Phase A: Water plus 5 mM NH4HCO3, Mobile Phase B: ACN; Gradient: 520% B in 25 mm; Flow rate: 50 mL/min; Detector 254 nm, retention time: 18 mm) to afford the title compound as a colorless solid: LC/MS: [(M+i)j = 401.2. |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In water at 80 - 90℃; for 48h; | 5 TAF-01 (200 g, 0.70 mol), TAF-02 (140 g, 0.84 mol) and EDCI (200 g, 1.00 mol) were added to a 5 L three-necked flask containing 3 L of water.Triethylamine (282 g, 2.79 mol) was added dropwise with stirring, and the system was dissolved after completion of dropwise addition.The temperature was raised to 80-90 ° C for 48 hours.The organic layer was concentrated under reduced pressure, and the mixture was dissolved in 2L methanol and filtered to remove insolubles.The filtrate was dried over anhydrous sodium sulfate and filtered and evaporated.A white solid was obtained as 723 g of crude TAF-03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.8% | Stage #1: tenofovir With thionyl chloride In acetonitrile at 50 - 80℃; for 2h; Inert atmosphere; Stage #2: (R)-1-isopropoxy-1-oxopropan-2-aminium chloride With triethylamine In dichloromethane at -30 - -10℃; for 1h; | 7 The preparation of compound 31 is described in the preparation of compound 12 in patent CN 102786549. TFV (3.6 g, 12.5 mmol) was dried in an oven overnight, cooled, acetonitrile (100 mL) was added, heated to 50 ° C under nitrogen. A solution of dichlorosulfoxide (0.9 mL, 12.5 mmol) was added dropwise, and the temperature was raised to 80 ° C after completion of the dropwise addition. The reaction mixture was stirred for 2 hours. Under reduced pressure, acetonitrile and thionyl chloride were distilled off, dichloromethane (100 mL) was added and solid D-alanine isopropyl ester hydrochloride 17 (2.08 g, 12.5 mmol) was added at -30 ° C. A solution of triethylamine (8.3 mL, 60 mmol) in dichloromethane (50 mL) was slowly added dropwise to a temperature of -10 ° C. The reaction was carried out for 1 hour, the organic phase was washed with 10% sodium dihydrogen phosphate, the organic phase was dried, concentrated, column chromatography gave compound 30 (2 g, 39.8%). Compound 30 (2 g, 5.0 mmol) was dissolved in N, N-dimethylformamide (25 mL) followed by 1-(3-bromopropoxy)hexadecane (1.8 g, 5.0 mmol) and triethylamine (0.85 mL, 6.0 mmol) was added and the reaction was stirred at 80 ° C for 6 hours. N, N-dimethylformamide was distilled off under reduced pressure. A mixture of ethyl acetate and ethanol was added in a volume ratio of 1: 1 (100 mL). The solid was filtered off and the filtrate was concentrated. Column chromatography gave compound 31 (2.1 g, yield: 61%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | TFV (1.09 g, 3.8 mmol) was dissolved in pyridine (16 mL). <strong>[10292-61-2]4-<strong>[10292-61-2]cyclopropylphenol</strong></strong> (2.56 g, 19.08 mmol), D-alanine isopropyl ester hydrochloride 17 (1.15 g, 6.8 mmol) and triethylamine (6.4 mL, 45.76 mmol) were added. The reaction solution was reacted at 60 C for 6 minutes. A solution of dithiopyridine (5.88 g, 26.6 mmol) and triphenylphosphine (7.01 g, 26.7 mmol) dissolved in pyridine (24 mL) was added and reacted at 80 C overnight under N2. The resulting residue was dissolved in dichloromethane. Silica gel column chromatography eluting with petroleum ether: ethyl acetate (100: 20) followed by dichloromethane: ethanol = 100: 5-7 to give compound 8 (1.08 g, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20 - 100℃; for 24.5h; | 4 Example 4 In 80 mL of N,N-dimethylformamide in a solvent,Join(R) -9- [2- (phosphonomethoxy) propyl] -adenine 16 (3.5 g, 8.9 mmol)1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.9 g, 10 mmol)Triethylamine (3.8 mL, 27 mmol)4- (N, N-dimethylamino) pyridine (320 mg, 2.6 mmol) and2-methylbenzyl alcohol (1.8 g, 14.7 mmol),After stirring at room temperature for 30 minutes,The reaction was heated at 100 ° C for 24 hours,After completion of the reaction, the solvent was removed under reduced pressure and the residue was dissolved in water,Purification by reverse phase C-18 column chromatography (methanol: water = 1: 9) gave the product (17,69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium bromide In water; acetonitrile at 25℃; for 0.5h; Electrolysis; | (R)-(((1-(6-amino-8-bromo-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid (3) Tenofovir (22 mg, 0.077 mmol) was dissolved in 30 mL of acetonitrile and 30 mL of 1M NaBr (aq.). The current was controlled at 0.8 amp and the reaction was terminated after 30 min. The reaction mixture was washed with ethyl acetate (30 mL x 2), the aqueous layer was separated, collected and concentrated down by Genevac evaporator. The residue was purified by reverse phase chromatography (Column: Phenomenex C18 100Å, 250 x10 mm, 5 µm; mobile phase A: 0.1% H3PO4 in water, mobile phase B: ACN, Flow = 5.0 mL/min, Gradient: starting with 5% B to 23% B in 3.5 min, then to 80% B in 1 min and hold for 5.5 min.) to give the title compound as a pink solid (32.0 mg with 31 wt%, 0.027 mmol) in 35% yield. Current efficiency is 1.03%. ; MS: 366.32, 368.43 (M+1); 1H NMR (D2O, 500 MHz): δ 7.94 (s, 1H), 4.13 (dd, J = 14.6, 5.9 Hz, 1H), 3.98 (dd, J = 14.5, 6.4 Hz, 1H), 3.83 (m, 1H), 3.24 (d, J = 8.9 Hz, 2H), 0.94 (d, J = 6.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: 4-(trimethylsilyl)phenol; tenofovir In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one for 0.166667h; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one for 20h; | 4.2 Step 2: 4- (Trimethylsilyl) phenylhydrogen ((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl)methyl) phosphonic acid (22)Synthesis Will be tenofovir(7.3 g, 25.4 mmol) andPhenol (8.4 g, 51 mmol) was dissolved in N-methylpyrrolidone (20 g)Under a nitrogen atmosphere, the temperature was raised to 85 ° C. After stirring for 30 minutes, triethylamine (3.2 g, 31.1 mmol) was added thereto, followed by reaction for 10 minutes, and the temperature was raised to 100 ° C. To a solution of DCC (8.6 g, 41.4 mmol) Methylpyrrolidone (8 g), and the reaction was continued for 20 h after completion of the dropwise addition. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated,The residue was added to methanol (15 mL) and the precipitated solid was filtered and dried to give phenoxicin a single ester of 4.6 g, 42%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: tenofovir With trimethylsilyl bromide In acetonitrile at 20℃; Inert atmosphere; Stage #2: (5-chloro-2-methoxyphenyl)methanol; (R)-1-isopropoxy-1-oxopropan-2-aminium chloride With pyridine; 2,2'-dipyridyldisulphide; triethylamine; triphenylphosphine at 50 - 60℃; for 5h; | 16 Example 15 General procedure: Under nitrogen protection,Compound 22 (287 mg, 1 mmol) was dissolved in 10 mL of acetonitrile,TMSBr (0.66 mL, 5 mmol) was then added and the reaction was allowed to stir at room temperature overnight.The solvent was distilled off under reduced pressure,The residue was dissolved in a mixed solvent of anhydrous triethylamine (2 mL) and pyridine (8 mL)Subsequently, D-alanine isopropyl ester hydrochloride (250 mg, 1.5 mmol) and p-acetoxybenzyl alcohol (250 mg, 1.5 mmol) were added and dissolved with stirring.Compound 26 (1.1 g, 5 mmol) and triphenylphosphine (1.31 g, 5 mmol) were combined in dry pyridine (50 mL) in a separate reaction flask,The resulting bright yellow solution was immediately transferred to a reaction flask of Compound 22 using a double-ended needle,The reaction was heated at 50-60 ° C for 5 hours.After the reaction was concentrated under reduced pressure,The residue is partitioned between ethyl acetate and aqueous sodium bicarbonate,The organic phase is dried over anhydrous sodium sulphate,filter,concentrate,The residue was separated by chiral preparative chromatography (Diacel's Chiralpak AS) eluting with 25% methanol in acetonitrile to give the products (27a) and(27b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: tenofovir With trimethylsilyl bromide In acetonitrile at 20℃; Inert atmosphere; Stage #2: (R)-1-isopropoxy-1-oxopropan-2-aminium chloride; 4-Methoxybenzyl alcohol With pyridine; 2,2'-dipyridyldisulphide; triethylamine; triphenylphosphine at 50 - 60℃; for 5h; | 20 Example 15 General procedure: Under nitrogen protection,Compound 22 (287 mg, 1 mmol) was dissolved in 10 mL of acetonitrile,TMSBr (0.66 mL, 5 mmol) was then added and the reaction was allowed to stir at room temperature overnight.The solvent was distilled off under reduced pressure,The residue was dissolved in a mixed solvent of anhydrous triethylamine (2 mL) and pyridine (8 mL)Subsequently, D-alanine isopropyl ester hydrochloride (250 mg, 1.5 mmol) and p-acetoxybenzyl alcohol (250 mg, 1.5 mmol) were added and dissolved with stirring.Compound 26 (1.1 g, 5 mmol) and triphenylphosphine (1.31 g, 5 mmol) were combined in dry pyridine (50 mL) in a separate reaction flask,The resulting bright yellow solution was immediately transferred to a reaction flask of Compound 22 using a double-ended needle,The reaction was heated at 50-60 ° C for 5 hours.After the reaction was concentrated under reduced pressure,The residue is partitioned between ethyl acetate and aqueous sodium bicarbonate,The organic phase is dried over anhydrous sodium sulphate,filter,concentrate,The residue was separated by chiral preparative chromatography (Diacel's Chiralpak AS) eluting with 25% methanol in acetonitrile to give the products (27a) and(27b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | PMPA (202 mg, 0.76 mmol) was added to the dried reaction flask,D-alanine isopropyl ester hydrochloride (230 mg, 1.38 mmol),Hexadecyloxypropanol (685 mg, 2.28 mmol) andAnhydrous pyridine (2 ml),Under nitrogen protection,Triethylamine (1.3 ml, 9.2 mmol) was added dropwise to the reaction solution,The mixture was reacted at 50 C for 10 minutes,Triphenylphosphine (1.4 g, 5.35 mmol) was added,Dithiopyridine (1.18 g, 5.35 mmol)In pyridine (3 ml)The reaction mixture was reacted overnight at 80 C.The residue was concentrated by column chromatography on silica gel (eluted with 0-20% ethyl acetate / petroleum ether followed by 0-8% methanol in dichloromethaneElution),The target compound V-17-a (161 mg, yield 31%) was obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine In N,N-dimethyl-formamide at 80℃; for 6h; | 4.1 Step 1 PMPA (2.88 g, 10 mmol) was added to the reaction flask,1-bromo-3-hexadecanedioxypropane (3.64 g, 10 mmol),Triethylamine (1.67 ml, 12 mmol) andAnhydrous DMF (30 ml),The reaction mixture was reacted at 80 ° C for 6 hours,After completion of the reaction, the solvent was distilled off under reduced pressure,The residue was added to 200 ml of a mixed solvent of methylene chloride / methanol (1: 1), stirred at room temperature for 10 minutes and sufficiently dissolved,Filtration, the filtrate was evaporated to dryness under reduced pressure,The residue was subjected to silica gel column chromatography to obtain 4.0 g (yield 71%) of (R) -9- (2 - ((hexadecyloxy propyl) phosphoryl) propyl) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | With sodium hydroxide In water for 5h; Reflux; | 30 Preparation of Tenofovir General procedure: 135 g of adenine (1 mol), mixed with 1000 ml of 5N sodium hydroxide aqueous solution, stirred and dissolved,226.2 g (1.2 mol, prepared as in Example 9) of (R) - [1 -chloro- (2-propoxy)] - methylphosphonic acid were then added in 4 portions.Plus Canada, heated to reflux, the reaction 5 hours.TLC detection of adenine reaction was complete, cooled to room temperature, add concentrated hydrochloric acid to adjust PH2 ~ 3.Extracted twice with 500 mL of ethyl acetate and twice with 500 mL of methylene chloride.Keep the water phase, ice-water bath with stirring cooling 0 ~ 5 ; heat for 24 hours crystallization.Filter, washed with ice water filter cake, dried to give a white crude 268.9 grams. Crude with 10 times the water recrystallization,236.9 g of a white solid was obtained with a yield of 82.5%. HPLC detection and analysis, chemical purity: 99.2%. 1.2mol of (R) - [1-iodo- (2-propoxy)] - methylphosphinic acid was replaced by 1.2mol of R) - [1-Chloro- (2-propoxy)] - methylphosphinic acid in example 13, the final tenofovir 261.4 g, 91.8% yield dPLC detection and analysis, chemical purity: 99.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | With potassium hydroxide In water for 5h; Reflux; | 28 Preparation of Tenofovir General procedure: 135 g of adenine (1 mol), mixed with 1000 ml of 5N sodium hydroxide aqueous solution, stirred and dissolved,226.2 g (1.2 mol, prepared as in Example 9) of (R) - [1 -chloro- (2-propoxy)] - methylphosphonic acid were then added in 4 portions.Plus Canada, heated to reflux, the reaction 5 hours.TLC detection of adenine reaction was complete, cooled to room temperature, add concentrated hydrochloric acid to adjust PH2 ~ 3.Extracted twice with 500 mL of ethyl acetate and twice with 500 mL of methylene chloride.Keep the water phase, ice-water bath with stirring cooling 0 ~ 5 ; heat for 24 hours crystallization.Filter, washed with ice water filter cake, dried to give a white crude 268.9 grams. Crude with 10 times the water recrystallization,236.9 g of a white solid was obtained with a yield of 82.5%. HPLC detection and analysis, chemical purity: 99.2%.135 g of adenine (1 mol), mixed with 1000 ml of 5N potassium hydroxide aqueous solution, stirred and dissolved, then 278.5 g (1.2 mol, prepared as in Example 10) of (R) - [1-bromo- (2-propoxy)] methylphosphinic acid were added in 4 portions. The procedure of Example 13 was followed by finally obtaining 254.7 g Tenofovir with a yield of 88.7% APLC detection and chemical purity: 99.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.1% | With hydrogenchloride In water at 90 - 110℃; | 3 Example 3 To intermediate II was added 96 g of concentrated hydrochloric acid,Heated to 90 ~ 110 °C incubated for 3 to 6 hours;Then down to room temperature, the reaction was continued at room temperature for 1 to 2 hours,Suction filtration, the filter cake was washed with 150mL 5wt% aqueous dilute hydrochloric acid twice,The filtrate was adjusted with sodium hydroxide solution pH = 2 ~ 3, allowed to stand at room temperature crystallization overnight,Then cooled to 0 ~ 3°C ,So continue crystallization 3 hours; suction filtration,The filter cake was washed once with 30 mL of water,50 mL of a mixed solvent of water and acetone (V / V = 1: 1) twice,50mL acetone washed 1 time;Dried at 45 ° C in vacuo to give compound I:Tenofovir 22.3 g, total molar yield 78.1%, HPLC purity 98.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.8% | With hydrogenchloride In water at 90 - 110℃; | 4 Example 4 To intermediate II was added 96 g of concentrated hydrochloric acid,Heated to 90 ~ 110°C incubated for 3 to 6 hours; Then down to room temperature, the reaction was continued at room temperature for 1 to 2 hours,Suction filtration, the filter cake was washed with 150mL 5wt% aqueous dilute hydrochloric acid twice,The filtrate was adjusted with sodium hydroxide solution pH = 2 ~ 3,Let stand crystallization at room temperature overnight,Then cooled to 0 ~ 3°C ,So continue crystallization 3 hours; suction filtration,The filter cake was washed once with 30 mL of water,50 mL of a mixed solvent of water and acetone (V / V = 1: 1) twice,50mL acetone washed 1 time;Dried at 45 ° C in vacuo to give compound I:Tenofovir 21.9g, the total molar yield of 76.8%HPLC purity 98.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With hydrogenchloride In water at 90 - 110℃; | 1 Example 1 To intermediate II was added 124 g of concentrated hydrochloric acid,Heated to 90 ~ 110°C incubated for 3 to 6 hours;Then down to room temperature, the reaction was continued at room temperature for 1 to 2 hours,Suction filtration, the filter cake was washed with 150mL 5wt% aqueous dilute hydrochloric acid twice,The filtrate was adjusted with sodium hydroxide solution pH = 2 ~ 3,Let stand crystallization at room temperature overnight,Then cooled to 0 ~ 3°C ,So continue crystallization 3 hours; suction filtration,The filter cake was washed once with 30 mL of water,50 mL of a mixed solvent of water and acetone (V / V = 1: 1) twice,50mL acetone washed 1 time;Dried at 45 ° C in vacuo to give compound I: Tenofovir 40.3 g, total molar yield 74.0%, HPLC purity 98.2%. |
74.5% | Stage #1: C15H24N5O5P With lithium hydroxide for 2h; Cooling with ice; Stage #2: With hydrogenchloride; sodium hydroxide In water at 5℃; for 10h; | 2.3 Step (3): Slowly add a solution of inorganic strong base lithium hydroxide (36g) to Intermediate III, react for 2h in an ice bath, filter, and adjust the pH of the filtrate with hydrochloric acid and sodium hydroxide aqueous solution with a solution concentration of 0.5mol/L To 3, stand at 5°C for 10 hours, filter with suction, wash the filter cake, and dry under reduced pressure to obtain 213.8 g of Tenofovir with a purity of 99.4% and a yield of 74.5%. The hydrogen spectrum data of Tenofovir is the same as in Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With hydrogenchloride In water at 90 - 110℃; | 2 Example 2 To intermediate II was added 96 g of concentrated hydrochloric acid,Heated to 90 ~ 110°C , incubated for 3 to 6 hours;Then down to room temperature, the reaction was continued at room temperature for 1 to 2 hours, Filtered, the filter cake was washed with 150mL 5wt% aqueous dilute hydrochloric acid twice, the filtrate With sodium hydroxide solution to adjust the pH = 2 ~ 3,Let stand crystallization at room temperature overnight,Then cooled to 0 ~ 3 ° C, to continue crystallization 3 hours; suction filtration,The filter cake was washed once with 30 mL of water,50mL water and acetone mixed solvent (V / V = 1: 1) twice, 50mL acetone washed once;Dried at 45 ° C in vacuo to give compound I:Tenofovir 21.9g, the total molar yield of 76.5%HPLC purity 98.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: benzyl bromide; tenofovir With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 16h; Stage #2: (L)-phenylalanine isopropyl ester hydrochloride With pyridine; triethylamine at 50℃; for 0.5h; Stage #3: With 2,2'-dipyridyldisulphide; triphenylphosphine at 50℃; for 3h; | 4 Embodiment 4: Preparation of compound 4 DIPEA (10 mmol) and benzyl bromide (5 mmol) were added into the suspension of Tenofovir (5 mmol) in acetonitrile (20 mL) sequentially, the mixture was heated to 80°C and stirred for 16 hours and then evaporated to dryness under reduced pressure. The residue was dissolved with pyridine (20 mL), then triethylamine (5 mL) and L-Phenylalanine isopropyl ester hydrochloride (10 mmol) were added to the solution sequentially. The mixture was heated to 50°C and stirred for 30 minutes, then after triphenyl phosphine (15 mmol) and 2,2'-dithiodipyridine (15 mmol) were added, stirred for 3 hours under the same temperature, and evaporated to dryness under reduced pressure thereafter. The residues were subjected to a silica gel column (eluted by methanol/methylene chloride) to afford a white solid. The yield was 61%. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1 H), 7.90 (s, 1 H), 7.30-7.09 (m, 10 H), 6.23 (s, 2 H), 5.03-4.88 (m, 2 H), 4.33-4.29 (m, 1 H), 4.15-3.90 (m, 3 H), 3.81-3.71 (m, 1 H), 3.48-3.43 (m, 1 H), 3.21-3.02 (m, 3 H), 2.94-2.76 (m, 2 H), 1.47-1.42(m, 3 H), 1.26-1.07 (m, 9 H); 31P NMR (400 MHz, CDCl3)δ 20.78; MS (m/z) 567.32 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With pyridine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 80℃; for 16h; | 1 Example 1 preparation of (2R)-9-{2-[(4S)-4-(3-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphinan-2- yl]methoxypropyl}adenine (R)-9-[2-(phosphonomethoxy)propyl]adenine (84 mg, 0.294 mmol)Soluble in N,N-Dimethylformamide (15mL)And pyridine (3mL),Dicyclohexylcarbodiimide (182 mg, 0.882 mmol) was added separatelyAnd (S)-3-(3-chloro-2-fluorophenyl)-1,3-propanediol (60 mg, 0.294 mmol),The reaction mixture is heated to about 80 degrees,Reaction 16h,After the reaction is completed,The reaction solution was evaporated under reduced pressure.Remove organic solvents,The crude product is soluble in ethyl acetate,Wash with saturated saline,Drying with anhydrous sodium sulfateThe solvent is distilled off under reduced pressureColumn chromatography on silica gel (dichloromethane:methanol = 20:1 to 10:1),Get a white solid,Yield: 41%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.1 g | 144g (0.50mol) [[(R)-2-(6-amino-fluoren-9-yl)-1-methyl-ethoxy-]methyl]phosphonic acid, 276 g (2.00 mmol) of o-ethoxyphenol and 390 g of 1-methyl-2-pyrrolidone were added and heated to 85 C. Then 63 g of triethylamine and 309 g (1.50 mmol) of DCC were added and the mixture was stirred under heating at 100 C for 16 hours. The resulting mixture was cooled, and solids were filtered. The filtrate was concentrated under reduced pressure, separated by silica gel (200-300 mesh) column, eluted with a mixed solvent of dichloromethane : methanol (20:1), the required components were collected and evaporated under reduced pressure to obtain [[(R)-2-(6-aminopurin-9-yl)-1-methylethoxy]methyl]phosphonic acid-bis(2-ethoxy-phenol)-ester (tenofovir bis-ethoxyphenol ester, TDP) 62g. 13 g (25.3 mmol) of TDP was dissolved in 50 ml of acetone (water content <0.2%), hydrogen chloride in ether solution was added and the addition rate was controlled for about 5 minutes to a pH of 2-3. The volume of ether and acetone is controlled at (1:5 to 1:30). The resulting mixture was refluxed for 10 min, cooled, a solid was precipitated, filtered, washed with cold crystallization solvent, dried naturally at room temperature for 6 hours, and then vacuum dried at 60 C for 8 hours to obtain I2 13.1g. Melting point 185-186 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.97% | With dmap; triethylamine; In 5,5-dimethyl-1,3-cyclohexadiene; at 100 - 110℃; for 12h; | 1) Reaction: will be 12.0 kg of xylene is added to the reactor, then under stirring state are sequentially added into a 1.0 KgPMPA, 3.0 kg of <strong>[115-86-6]triphenyl phosphate</strong>, 720 g of triethylamine and 430 g of DMAP (4 - dimethylamino pyridine), with the temperature rising to 100 - 110 C, maintain the temperature reaction 12 h after, cooling to 10 - 15 C, stop stirring natural layered;2) After treatment: congeals the pale yellow oily matter, slowly dropping 20 wt % NaOH aqueous solution 3 kg, adding the ethyl acetate gathers mixed (5 L * 3), extraction temperature 40 - 45 C, collecting the lower aqueous phase, slow drop of concentrated hydrochloric acid, stirring to crystallize overnight.3) After filtering, 70 - 80 C drying 6 h, the water is less than 1.0%, yield 91.97%, purity 99.58%, Figure 2 is the HPLC chart of the report, wherein the report of the results of the HPLC peak data refer to diagram of this embodiment. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 35 - 50℃; | R = Et. (5g, 16mmol) and DIEA PMPA anhyride (Hunig ' s base) (11. 5 ml, 66mmol)In an anhydrous DMF (50 ml). Furthermore, by adding bischloromethylbiphenyl carbonate (49mmol), Then rapidly while mechanically stirring the suspension, is heated up to 50 C under argon. 1 after time, reaction product is transparent, 35 C until the temperature is lowered. The reaction product is stirred for 48 hours. DMF on the evaporator is removed, the reaction product is CH2Cl2between and waterA distributor. CH2Cl2layer is dried with magnesium sulfate, filtered, then condensed in the evaporator. The residue is taken, then the glycopeptide (150g, SiO2) in methylene chloride. This is, respectively, 0, 3, 6, 9, 12, 15, 18%(v/v) methylene chloride in isopropanol 500 ml, then 21%, the elution 2000 ml. An appropriate fractionPool a, then evaporate and the desired product is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72.0h; | Anhydrous PMPA (0.3 g, 1 mmol) and DIEA (1 mL, 6 mmol) were placed in anhydrous DMF (2 mL). Chloromethyl morpholinocarbamate (3 mmol) was then added and then the suspension was stirred at room temperature for 3 days. The reaction was partitioned between CH 2 Cl 2 / isopropanol and 0.1 M citrate buffer (pH 6). The CH 2 Cl 2 layer was washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was taken up in methylene chloride and applied to a silica gel column (5 g, SiO 2). This was eluted with 25 mL of isopropanol in 0, 3, 6, 9, 12, 15, 18% (v / v) methylene chloride and then 21%, 100 mL of isopropanol in methylene chloride. Appropriate fractions were pooled and evaporated to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: tenofovir With thionyl chloride In acetonitrile at 70℃; for 2h; Inert atmosphere; Large scale; Stage #2: phenol In acetonitrile at 80℃; for 13h; Large scale; | 1.1 (1) Preparation of intermediate 1-1: Add 25 L of acetonitrile to a 100 L glass-lined reactor at room temperature and start stirring.Then add tenofovir (5kg, 17.4mol), dichlorosulfoxide (6.2kg, 52.1mol),Replacement of nitrogen protection (nitrogen replacement 3 times, reactor vacuum ≤ -0.080MPa, stirring for 3 to 5min,The nitrogen gas is backfilled to a constant pressure for 3 to 5 minutes for a nitrogen substitution. After the addition, the temperature was raised to 70 ° C, and the reaction was kept at this temperature for 2 h, and concentrated under reduced pressure.After concentration and drying, 25 L of acetonitrile and phenol (6.6 kg, 69.6 mol) were added to the glass-lined reactor.The stirring was started, the temperature was raised to about 80 ° C, the reaction was carried out for 13 h, and concentrated under reduced pressure.25 L of ethyl acetate was added to a 100 L glass-lined reactor containing a concentrated residue, and the mixture was heated to 50 ° C to dissolve.In the system, slowly add n-heptane 25L, cool down to room temperature, crystallize, and filter.Drying gave 6.5 kg of an off-white solid, intermediate 1-1, yield 85%, liquid phase purity 99.17%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | With pyridine; dmap; phosphoric acid triphenyl ester In toluene; acetonitrile for 24h; Reflux; | 1-4 S1. In a 500mL round bottom flask, add 60mL acetonitrile, 60mL toluene,30g tenofovir, 24.8g pyridine,2.5g 4-dimethylaminopyridine and48.6g triphenyl phosphite,Stir and heat to reflux for 24h;S2. After the reaction is completed, the organic solvent is removed by distillation under reduced pressure,Add 300mL N,N-dimethylformamide, add methanesulfonic acid to adjust the pH to 23, and filter quickly;Add 300mL N,N-dimethylaminoformamide to the filter cake to make a slurry,Quickly filter, repeat 4 times;Add 300mL ethyl acetate to the filter cake to make a slurry, quickly filter,Repeat 4 times; vacuum drying at 40°C to obtain 27 g of PMPA phosphoric anhydride with a yield of 92.9% and an HPLC purity of 98.2%. |
88.7% | With pyridine; triethylamine; dicyclohexyl-carbodiimide at 70℃; for 3h; | 1-4 A preparation method of tenofovir dimer, including the following steps: Add -9-(2-phosphate methoxypropyl)-adenine 10.0g (34.82mmo1) and pyridine to the reaction flask80ml, add 14.09g (139.24mmo1) of triethylamine and 7.90g of dicyclohexylcarbodiimide under stirring.(38.29mmo1), heated to 70°C and stirred for 3h, detected by TLC (silica gel GF254, developing solvent is methanol: water = 20:1v/v),After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product.Take the crude product and add 80ml of water, stir to dissolve, filter, adjust the pH of the filtrate to about 2 with hydrochloric acid, cool to 20°C, add acetonitrile80ml was stirred and crystallized for 1 hour, filtered, and the filter cake was dried under reduced pressure at 60°C for 8 hours to obtain an off-white solid, which is the tenofovir dimer copolymer.8.59g, the yield was 88.7%. |
45.5% | With triethylamine; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 90 - 100℃; for 22h; | 2 Example 2 Process Description: Add 5.0g of 9-[(R)-2-(phosphorylmethoxy)propyl]adenine to 50mL DMF and stir.8.1 g of triethylamine and 3.3 g of DIC were sequentially added to the system, and reacted at 90 to 100 ° C for 22 hours. After completion of the reaction, the reaction solution was concentrated to dryness to give a crude material.The crude product was purified by a preparative column, and the preparation conditions were the same as in Example 1, and the obtained preparation liquid was freeze-dried.PMPA dimer impurities were obtained. The yield was 45.5% and the purity was 94.61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In N,N-dimethyl-formamide; at 20 - 40℃; for 12h; | To the dry three-necked flask, 12.04 g (0.044 mol) of anhydrous tenofovir (IV) and DMF (55 ml) were added and stirred to dissolve.17.81 g (0.176 mol) of triethylamine and 26.86 g (0.176 mol) of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> were sequentially added at room temperature.After that, the temperature was raised to 40 C, and the reaction was carried out at the same temperature for 12 h, cooled to room temperature, filtered, and the filtrate was concentrated, water (50 ml) and ethyl acetate (50 ml).After thorough mixing, the layers were separated, and the aqueous phase was washed twice with ethyl acetate (50ml×2), and the aqueous phase was concentrated to a viscous liquid.Add 100 ml of isopropyl alcohol, stir at 0 C for 1 h, and filter.The filtrate is concentrated(R)-((((1-(6-amino-9H-indol-9-yl)propyl-2-yl)oxy)methyl)phosphine)oxy)methyl isopropyl carbonate (V) 13.56g (0.034mol),The molar yield was 76%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride In dichloromethane at 20℃; for 3h; Inert atmosphere; | 1.2 Step 2:Synthesis of (R)-(1-(6-((Dimethylamino)methylenamino)-9H-fluoren-9-yl)propan-2-yloxy)methyldichlorophosphonate (Compound 2) Add to the reaction bottle(R)-(1-(6-((Dimethylamino)methylallyl)-9H-indol-9-yl)propan-2-yloxy)methylphosphoric acid ( tenofovir, 500 mg, 1.74 mmol And anhydrous DMF (153 mg, 2.1 mmol), dissolved in 10 ml of anhydrous dichloromethane.2M oxalyl chloride (4.35 ml, 8.7 mmol) was added dropwise at room temperature under nitrogen.Plus,The reaction was stirred for 3 hours until the reaction solution became clear.Concentration to remove solvent and excess oxalyl chloride to give the product 658mg, yield: 100%,No purification required,Directly invest in the next step. |
100% | With oxalyl dichloride In dichloromethane at 20℃; for 3h; Inert atmosphere; | 1.2 Step 2:(R)-(1-(6-((dimethylamino)methyl olefin)-9H- purine-9-yl)propane-2-oxy)methylphosphonium oxychlorideSynthesis of (Compound 2). Add to the reaction bottle(R) - (1- (6 - ((dimethylamino) methyl enamine)-9H- purin-9-yl) propan-2-oxy) methylphosphonic acid(tenofovir, 500 mg, 1.74 mmol)And anhydrous DMF (153 mg, 2.1 mmol),Add 10 ml of anhydrous dichloromethane to dissolve.2M oxalyl chloride (4.35 ml, 8.7 mmol) was added dropwise at room temperature under nitrogen.After the addition, the reaction was stirred for 3 hours until the reaction solution became clear.The solvent and excess oxalyl chloride were concentrated to give a product 658 mg, yield: 100%.No need to purify, go directly to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
628 g | L-alanine isopropyl ester hydrochloride 500gAnd potassium bicarbonate 730gIt was stirred at room temperature for 12 hours in DCM (2 kg).The mixture was then filtered and further rinsed with DCM (1 kg). The filtrate was dried on a molecular sieve bed until the water content of the solution was < 0.03%.The obtained L-alanine isopropyl ester was cooled to a pot temperature of -20 C for use.Weigh 500g of tenofovir (dried at 105 C in an oven for 3 hours before feeding) into a 2000ml flask, then add 1500g of thionyl chloride, heat to 55 C, after 10 minutes, continue to warm to 70 C and stir After 3 hours, pour into a 20 L rotary flask and distill the thionyl chloride under reduced pressure.After the end of the distillation, 7 kg of acetonitrile was added and refluxed at 85 C for 0.5 h.Add 630 g of <strong>[23377-40-4]3-hexadecyloxy-1-propanol</strong> in 10 portions (add once every 10 minutes).After the addition, the stirring was continued for 0.5 h under reflux.After slowly cooling to 35 C, then add 3 kg of dichloromethane,After further stirring for 0.5 h, 458 g of L-alanine isopropyl ester was added dropwise within 0.5 h.After stirring for 0.5 h, 350 g of triethylamine was added dropwise.After stirring for 0.5 h, the system was cooled to room temperature, suction filtered, and the filtrate was evaporated to dryness to ethyl acetate.The filter cake was stirred with 1 kg of ethyl acetate for 1 hour, and then filtered with suction. The filtrate was combined with the above steps. The combined ethyl acetate solution was washed twice with 6 kg of 5% aqueous potassium hydrogencarbonate solution and twice with 6 kg of 20% aqueous sodium chloride solution. The ethyl acetate solution was cooled to -7 C. After 2 h, suction filtration was started and the filtrate was evaporated to dryness. After evaporation to dryness, the filtrate was crystallized from 2 kg of a mixed solvent of dichloromethane: acetonitrile = 1:20 at -10 C, crystallized, filtered, and the filter cake was recrystallized from 2 kg of acetonitrile, crystallized, and filtered to give a filter cake. Under the truthAfter drying, C0P130 is about 628g.(Yield 52.1%, purity 98.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 1-(4-hydroxy-phenyl)-1H-pyridin-2-one; tenofovir In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one for 0.166667h; Inert atmosphere; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 22h; Inert atmosphere; | 12 Example 12. Preparation of Intermediates 7a to 7d After drying TFV (50.8 mmol) and the corresponding compound 2 (102 mmol) in vacuo for half an hour, it was dissolved in N-methylpyrrolidone (39 g).After heating to 85 ° C for 30 minutes under nitrogen protection,Adding triethylamine(62.3 mmol), after reacting for 10 minutes, the temperature was raised to 100 ° C.Then slowly add 1,3-dicyclohexylcarbodiimide within 6 hours.(DCC, 82.9 mmol) of N-methylpyrrolidone (16 g) solution,The reaction was continued to heat for 16 hours. The reaction solution was cooled to 45 ° C, and water (30 mL) was added.The reaction was then cooled to room temperature, the solid was filtered, and then filtered and washed with water (15mL).The combined filtrate and washings were concentrated under reduced pressure, and then 30 mL of water was added.The pH was adjusted to 11 with a 25% aqueous sodium hydroxide solution and filtered over Celite.The filtrate was extracted with ethyl acetate, and the aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid.After filtration, the crude product was washed with methanol.Beating,After filtration, a white solid was obtained.Intermediate 7a (R2=H): white solid, yield 63% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: tenofovir; 3-(4-hydroxy-phenyl)-2,6-dimethyl-3<i>H</i>-pyrimidin-4-one In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one for 0.166667h; Inert atmosphere; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 22h; Inert atmosphere; | 13 Example 13. Preparation of Intermediates 8a-8c After drying TFV (50.8 mmol) and the corresponding compound 3 (102 mmol) in vacuo for half an hour, it was dissolved in N-methylpyrrolidone (39 g).After heating to 85 ° C under nitrogen for 30 minutes, add triethylamine(62.3 mmol), after reacting for 10 minutes, the temperature was raised to 100 ° C.Then slowly add 1,3-dicyclohexylcarbodiimide within 6 hours.(DCC, 82.9 mmol) of N-methylpyrrolidone (16 g) solution,The reaction was continued to heat for 16 hours. The reaction solution was cooled to 45 ° C.Water (30 mL) was added, then the reaction was cooled to room temperature and filtered to remove solids.The filter cake was washed with water (15 mL). The combined filtrate and washings were concentrated under reduced pressure, and then 30 mL of water was added.The pH was adjusted to 11 with a 25% aqueous sodium hydroxide solution and filtered over Celite.The filtrate was extracted with ethyl acetate, and the aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid.After filtration, the crude product is washed with methanol and beaten.After filtration, it was isolated to give a white solid.Intermediate 8a (R1 = H): White solid, yield 55% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: C11H10N2O2; tenofovir In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one for 0.166667h; Inert atmosphere; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 22h; Inert atmosphere; | 14 Example 14. Preparation of Intermediates 9a-9b After TFV (50.8 mmol) and the corresponding compound 4 (102 mmol) were dried in vacuo for half an hour, they were dissolved in N-methylpyrrolidone (39 g), and the mixture was heated to 85 ° C under nitrogen for 30 minutes, and then triethylamine was added. 62.3 mmol), after 10 minutes of reaction, the temperature was raised to 100 ° C.Then slowly add 1,3-dicyclohexylcarbodiimide within 6 hours.(DCC, 82.9 mmol) of N-methylpyrrolidone (16 g) solution,The reaction was continued to heat for 16 hours. The reaction solution was cooled to 45 ° C.Water (30 mL) was added, then the reaction was cooled to room temperature and filtered to remove solids.The filter cake was washed with water (15 mL). The combined filtrate and washings were concentrated under reduced pressure, and then 30 mL of water was added.The pH was adjusted to 11 with a 25% aqueous sodium hydroxide solution and filtered over Celite.The filtrate was extracted with ethyl acetate, and the aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid. After filtration, the crude product was washed with methanol and then filtered, and then filtered to give white.solid.Intermediate 9a (Y1=N, Y2=H, Y3=H, Y4=H): white solid, yield 35%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: C12H11N3O2; tenofovir In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one for 0.166667h; Inert atmosphere; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 22h; Inert atmosphere; | 15 Example 15. Preparation of Intermediate 10a After drying TFV (50.8 mmol) and compound 5a (102 mmol) in vacuo for half an hour,Dissolved in N-methylpyrrolidone (39 g), heated to 85 ° C under nitrogen for 30 minutes, then added triethylamine (62.3 mmol), reacted for 10 minutes, and then warmed to 100 ° C,Then slowly add 1,3-dicyclohexylcarbodiimide (DCC) within 6 hours.A solution of 82.9 mmol) of N-methylpyrrolidone (16 g) was continued and the reaction was continued for 16 hours.The reaction solution was cooled to 45 ° C and water was added.(30 mL), then cooled to room temperature and filtered to remove solids.The filter cake was washed with water (15 mL). The combined filtrate and washings were concentrated under reduced pressure, and then 30 mL of water was added.Adjust the pH to 11 with 25% aqueous sodium hydroxide, filter with celite, and ethyl acetateExtraction, the aqueous phase is adjusted to pH 3 with concentrated hydrochloric acid, and the crude product is washed and beaten with methanol after filtration.After filtration, a white solid was obtained.Yield 52% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: C13H9N3O2; tenofovir In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one for 0.166667h; Inert atmosphere; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 22h; Inert atmosphere; | 16 Example 16. Preparation of Intermediate 10b TFV (50.8 mmol) and compound 5b (102 mmol) were dried in vacuo for half an hour, dissolved in N-methylpyrrolidone (39 g), heated to 85 ° C under nitrogen for 30 minutes, and then added triethylamine. (62.3 mmol), after reacting for 10 minutes, the temperature was raised to 100 ° C.Then slowly add 1,3-dicyclohexylcarbodiimide (DCC) within 6 hours.A solution of 82.9 mmol) of N-methylpyrrolidone (16 g) was continued and the reaction was continued for 16 hours.The reaction solution was cooled to 45 ° C and water was added.(30 mL), then cooled to room temperature and filtered to remove solids.The filter cake was washed with water (15 mL). The combined filtrate and washings were concentrated under reduced pressure, and then 30 mL of water was added.Adjust the pH to 11 with 25% aqueous sodium hydroxide, filter with celite, and ethyl acetateExtraction, the aqueous phase is adjusted to pH 3 with concentrated hydrochloric acid, and the crude product is washed and beaten with methanol after filtration.After filtration, a white solid was obtained.Yield 54%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 1-(4-hydroxyphenyl)-5-methylpyridine-2(1H)-one; tenofovir In 1-methyl-pyrrolidin-2-one at 85℃; for 0.5h; Inert atmosphere; Stage #2: With triethylamine In 1-methyl-pyrrolidin-2-one for 0.166667h; Inert atmosphere; Stage #3: With dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; for 22h; Inert atmosphere; | 11 Example 11. Preparation of Intermediates 6a to 6f After TFV (50.8 mmol) and the corresponding compound 1 (102 mmol) were dried in vacuo for half an hour, dissolved in N-methylpyrrolidone (39 g), heated to 85 ° C under nitrogen for 30 minutes, and then added triethylamine.(62.3 mmol), after reacting for 10 minutes, the temperature was raised to 100 ° C.Then slowly add 1,3-dicyclohexylcarbodiimide within 6 hours.(DCC, 82.9 mmol) of N-methylpyrrolidone (16 g) solution,The reaction was continued to heat for 16 hours. The reaction solution was cooled to 45 ° C.Water (30 mL) was added, then the reaction was cooled to room temperature and filtered to remove solids.The filter cake was washed with water (15 mL).The combined filtrate and washings were concentrated under reduced pressure, and then 30 mL of water was added.The pH was adjusted to 11 with a 25% aqueous sodium hydroxide solution and filtered over Celite.The filtrate was extracted with ethyl acetate, and the aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid.After filtration, the crude product is washed with methanol and beaten.After filtration, it was isolated to give a white solid.Intermediate 6a (R1=H):White solid, yield 62%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
isopropoxv-2-oxoethoxv)phosphorvnamino)-2-methvlpropanoate: To a stirred mixture of TFV (3 g, 10.44 mmol), INTERMEDIATE A (4.22g, 20.89 mmol), isopropylglycolate (6.43g, 52.23 mmol) and triethylamine (12.68g, 125.34 mmol) in pyridine (35mL) heated at 60C for 5 min was added a freshly prepared solution of l,2-di(pyridin-2-yl)disulfane (Aldrithiol, 16.67g, 74.16 mmol) and triphenylphosphine (19.65g, 74.16 mmol) in pyridine (35 mL). The reaction mixture was stirred at 60C overnight, cooled to rt, and concentrated under reduced pressure. The crude residue was partitioned between EtOAc and an aqueous saturated NaHC03 solution. The organic layer was washed with brine, dried and (0298) concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (DCM/MeOH) to afford the title compound as a diastereomeric mixture. (0299) Step 2; Isooroovl 2-(((S)-((((RVl-(6-amino-9H-Durin-9-vnDroDan-2- vl^xv)memvn(2-isopropoxy-2-oxoemoxv)phosphorvnaminoV2-methvlpropanoate and Isopropvl 2-(((K)-((((R)- 1 -(e-amino-9H-purin-Q-vnpropanm-yl)oxy)methvl)(2-isopropoxv- 2-oxoethoxv)phosphorvnamino)-2-methvlpropanoate (3 A and 3BV The two isomers were separated by chiral Preparative HPLC with the following conditions: Column: Chiralpak IC 0.46*25 cm, 5 mum.; Mobile Phase A: C02: 60%, Mobile Phase B: GammaRhoAlpha: 40%; to afford Isomer 3A (faster eluting): 1H MR (400 MHz; CDC13) delta 8.35 (s, lH), 8.12 (s, lH), 5.72 (s, 2H), 5.08 (heptuplet, J= 6.21Hz, 1H), 5.04 (hept, J= 6.21Hz, lH), 4.56 (dd, J= 16.32Hz and 11.88Hz, lH), 4.46 (dd, J= 16.32Hz and 12.06Hz, 1H), 4.40 (dd, J= 14.37Hz and 3.02Hz, 1H), 4.19 (dd, J= 14.37Hz and 7.09Hz, lH), 4.03-3.96 (m, 2H), 3.88 (dd, J= 13.30Hz and 7.45Hz, 1H), 3.72 (dd, J= 13.30Hz and 10.1 lHz, 1H), 1.52 (d, J= 3.87Hz, 6H), 1.27-1.25 (m, 12H), 1.22 (d, J= 6.21Hz, 3H); 31P MR (198 MHz; CDC13) delta 26.06; LC MS: [(M+l)]+ =515.4; and Isomer 3B (slower eluting): 1H NMR (400 MHz; CDC13) delta 8.35 (s, lH), 8.11 (s, lH), 5.71 (s, 2H), 5.12 (heptuplet, J= 6.25Hz, lH), 4.99 (hept, J= 6.25Hz, 1H), 4.67 (dd, J= 16.32Hz and 11.83Hz, 1H), 4.45 (dd, J= 16.32Hz and 12.43Hz, 1H), 4.39 (dd, J= 14.38Hz and 2.38Hz, lH), 4.16 (dd, J= 14.38Hz and 7.49Hz, lH), 3.99- 3.86 (m, 3H), 3.63 (dd, J= 13.29Hz and 9.44Hz, 1H), 1.45 (d, J= 4.56Hz, 6H), 1.29-1.22 (m, 15H); 31P NMR (198 MHz; CDC13) delta 25.90; LC/MS: [(M+l) + =515.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tributyl-amine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In N,N-dimethyl-formamide at 50℃; for 5h; | 2.2 Synthesis of octadecyloxyethyl tenofovir (ODE-TFV) Tributylamine (388mg, 2.1mmol) was added to a stirred solution of anhydrous tenofovir (500mg, 1.74mmol) and octadecyloxyethan-1-ol (659mg, 2.1mmol) in dry DMF (35mL) and the mixture was heated to 50°C. To the mixture was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 1.56g, 3mmol). After stirring 5h, water (5mL) was added and DMF was evaporated under reduced pressure. The residue was purified by silica gel chromatography (gradient 0-30% MeOH/CH2Cl2) and gave ODE-TFV as a white powder (385mg, 38% yield). 1H NMR (CD3OD) δ 8.38(s, 1H), 8.21 (s, 1H), 4.40 (dd, 1H), 4.22 (dd, 1H), 4.02 (m, 3H), 3.75 (dd, 2H), 3.59 (t, 2H), 3.45 (t, 2H), 1.53 (t, 2H), 1.25-1.30 (br s, 30H), 1.15 (d, 3H), 0.89 (t, 3H). 13C NMR (CD3OD) δ 157.27, 153. 55, 151.03, 144.28, 119.70, 77.25, 77.08, 72.42, 71.86, 71.76, 66.77, 65.29, 65.21, 64.65, 33.22, 30.95, 30.92, 30.80, 30.63, 27.36, 23.89, 17.04, 14.66. 31P NMR (CD3OD) δ 17.94, ESI MS: 584.48 (M+H)+, 606.44 (M+Na)+. HRMS calcd for [C29H55N5O5P]+ 584.3935, found 584.3927. HPLC analysis: Rt=11.68min, purity=97.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.7% | With pyridine at 110 - 120℃; for 4h; | 1-4 Example 1 At room temperature, 16 mL of pyridine was added to the reaction flask, and 2.0 g of tenofovir and 6.5 g of diphenyl phosphite were added.Raise the system to 110~120C,The reaction was carried out at this temperature for 4 hours. The TLC detected that the starting material tenofovir disappeared substantially. The reaction system was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of methyl t-butyl ether and dried.The product of formula I was obtained in 2.31 g, the yield was 91.7%, and the purity was 99.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.15 g | Stage #1: tenofovir With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 35℃; for 5h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at -25℃; Inert atmosphere; Stage #3: 5,6,7,8-Tetrahydro-2-naphthol; 2-amino-2-methylpropionic acid methyl ester Further stages; | 11.2-11.3 Example 1 Synthesis of Compound I-1 General procedure: 1) Add 9- [2- (R)-(phosphonomethoxy) propyl] adenine (5.74g) to dichloromethane (200mL),Add N, N-dimethylformamide (2.40mL),Add oxalyl chloride (8.00mL) dropwise,After dropping, react at 35 for 5h,It was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL) and then concentrated under reduced pressure.Repeat 2 times to get residual solid.Add the residue to dichloromethane (100mL) under nitrogen protection,After cooling to -25 ° C, N, N-diisopropylethylamine (6.60 mL) was added to prepare solution A for use. 2) Dissolve 5,6,7,8-tetrahydro-2 naphthol (2.96g) and N, N-diisopropylethylamine (6.60mL) in dichloromethane (20mL) to prepare solution B set aside. 3) Add L-2-aminobutyric acid (1.00g) to isopropanol (5.83g),Thionyl chloride (1.38g) was added dropwise at room temperature,After dripping, it refluxed for 5.5h,Concentrate under reduced pressure, the residue is adjusted to neutral pH with potassium bicarbonate solution,Dichloromethane extraction (50mL) 3 times,The dichloromethane layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.Isopropyl L-2-aminobutyrate (1.20 g) was obtained. 4) Dissolve isopropyl L-2-aminobutyrate (3.48g) and N, N-diisopropylethylamine (13.20mL) in dichloromethane (20mL),Prepare solution C for use. 5) Nitrogen protection and -25 ,Slowly add solution B to solution A,After dripping, stir at -25 for 45min,Add solution C dropwise to the reaction solution,After dropping, stir at -20 for 3h.The reaction solution was washed 3 times with 5% hydrochloric acid (100 mL) aqueous solution,Wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure.The residue was dissolved with methanol (50mL),Add glacial acetic acid (4.80g, 80.0mmol),Reflux for 2h,It was concentrated under reduced pressure, and the residue was dissolved with dichloromethane (100 mL),Wash 3 times with saturated sodium bicarbonate solution (50 mL), wash with saturated brine, dry, and concentrate under reduced pressure.The residue was purified by column chromatography (dichloromethane: methanol = 50: 1 to 10: 1),Compound 1-1 (1.11g) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.11 g | Stage #1: tenofovir With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 35℃; for 5h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at -25℃; Inert atmosphere; Stage #3: 5,6,7,8-Tetrahydro-2-naphthol; isopropyl L-2-aminobutyrate Further stages; | 1.1-1.2; 1.4-1.5 Example 1 Synthesis of Compound I-1 1) Add 9- [2- (R)-(phosphonomethoxy) propyl] adenine (5.74g) to dichloromethane (200mL),Add N, N-dimethylformamide (2.40mL),Add oxalyl chloride (8.00mL) dropwise,After dropping, react at 35 for 5h,It was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL) and then concentrated under reduced pressure.Repeat 2 times to get residual solid.Add the residue to dichloromethane (100mL) under nitrogen protection,After cooling to -25 ° C, N, N-diisopropylethylamine (6.60 mL) was added to prepare solution A for use. 2) Dissolve 5,6,7,8-tetrahydro-2 naphthol (2.96g) and N, N-diisopropylethylamine (6.60mL) in dichloromethane (20mL) to prepare solution B set aside. 3) Add L-2-aminobutyric acid (1.00g) to isopropanol (5.83g),Thionyl chloride (1.38g) was added dropwise at room temperature,After dripping, it refluxed for 5.5h,Concentrate under reduced pressure, the residue is adjusted to neutral pH with potassium bicarbonate solution,Dichloromethane extraction (50mL) 3 times,The dichloromethane layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.Isopropyl L-2-aminobutyrate (1.20 g) was obtained. 4) Dissolve isopropyl L-2-aminobutyrate (3.48g) and N, N-diisopropylethylamine (13.20mL) in dichloromethane (20mL),Prepare solution C for use. 5) Nitrogen protection and -25 ,Slowly add solution B to solution A,After dripping, stir at -25 for 45min,Add solution C dropwise to the reaction solution,After dropping, stir at -20 for 3h.The reaction solution was washed 3 times with 5% hydrochloric acid (100 mL) aqueous solution,Wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure.The residue was dissolved with methanol (50mL),Add glacial acetic acid (4.80g, 80.0mmol),Reflux for 2h,It was concentrated under reduced pressure, and the residue was dissolved with dichloromethane (100 mL),Wash 3 times with saturated sodium bicarbonate solution (50 mL), wash with saturated brine, dry, and concentrate under reduced pressure.The residue was purified by column chromatography (dichloromethane: methanol = 50: 1 to 10: 1),Compound 1-1 (1.11g) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.3% | Stage #1: C12H18N5O5P With sodium hydroxide In water for 2h; Cooling with ice; Stage #2: With hydrogenchloride; sodium hydroxide In water at 5℃; for 10h; | 1.3 Step (2), dissolve intermediate II, dimethyl hydroxymethylphosphonate (700g) and triphenylphosphine (393.5g) in dimethylformamide, stir at room temperature, and slowly add azodicarboxylate Diethyl acid (261g) was reacted for 1.5h to obtain Intermediate III. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.1% | With potassium dihydrogenphosphate In N,N-dimethyl-formamide at 80℃; | 7 Example 7 Add Tenofovir 28.7g (0.10mol, 1.0equiv), diphenyl iodonium fluoride 30.0g (0.10mol, 1.0equiv), and potassium phosphate 21.2g (0.10mol, 1.0equiv), 150ml of N,N-dimethylformamide, heated to 80°C, TLC detection controls the end of the reaction, when the reaction is over, reduce the temperature to 0°C, add dilute hydrochloric acid to adjust the pH to below 1, add 200ml of water, add Extract twice with dichloromethane 250ml*2, separate the organic layer, slowly add sodium carbonate solid to the water layer to adjust the pH to 2~3, stir for half an hour, filter, and dry to obtain 26.9g of white solid tenofovir monophenyl ester. The molar yield is 74.1%, and the HPLC purity is 98.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine In water at 20℃; for 0.5h; Inert atmosphere; | 7 Example 7 Under the protection of nitrogen, add 28.7g (0.10mol, 1.0equiv) of Tenofovir, 15.2g (0.15mol, 1.5equiv) of triethylamine, 200ml of drinking water to the reactor under nitrogen protection, and add diphenyliodide methanesulfonate 56.4g (0.15mol, 1.5equiv), react at room temperature after stirring for half an hour, TLC detection controls the end of the reaction, when the reaction is over, reduce the temperature to 0, add dilute hydrochloric acid to adjust the pH to below 1, add 250ml of dichloromethane*2 After extraction twice, the organic layer was separated, the aqueous layer was slowly added with sodium carbonate solid to adjust the pH to 2~3, stirred for half an hour, filtered, and dried to obtain 22.9 g of white solid tenofovir monophenyl ester with a molar yield of 63.0%. The HPLC purity is 97.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.3% | With toluene In acetic acid butyl ester at 80℃; Inert atmosphere; | 8 Example 8 Under nitrogen protection, add 28.7g (0.10mol, 1.0equiv) of Tenofovir, 36.0g (0.10mol, 1.0equiv) of diphenyliodonium bromide, and 10.6g (0.10mol, 1.0equiv), 150ml of toluene, 150ml of butyl acetate, heated to 80°C, TLC detection controls the end of the reaction, when the reaction is over, reduce the temperature to 0°C, add dilute hydrochloric acid to adjust the pH to below 1, separate the organic layer, and the water layer slowly Adding solid sodium carbonate to adjust the pH to 2 to 3, stirring for half an hour, filtering, and drying to obtain 31.3 g of white solid tenofovir monophenyl ester with a molar yield of 86.3% and an HPLC purity of 97.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.3% | With triethylamine In toluene Inert atmosphere; Heating; | 1 Example 1 Add Tenofovir 28.7g (0.10mol, 1.0equiv), diphenyliodonium trifluoromethanesulfonate 43.0g (0.10mol, 1.0equiv), and 11.1g triethylamine into the reaction kettle under nitrogen protection (0.11mol, 1.1equiv), 500ml of toluene, heated to reflux, TLC detection to control the end of the reaction, when the reaction is over, reduce the temperature to 0, add dilute hydrochloric acid to adjust the pH to below 1, separate the toluene layer, and slowly add carbonic acid to the water layer Adjust the pH of the sodium solid to 2 to 3, stir for half an hour, filter, and dry to obtain 32.1 g of white solid tenofovir monophenyl ester with a molar yield of 88.3% and an HPLC purity of 97.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap In acetic acid butyl ester Inert atmosphere; Heating; | 2 Example 2 Add Tenofovir 28.7g (0.10mol, 1.0equiv), diphenyliodonium tetrafluoroborate 36.8g (0.10mol, 1.0equiv), 4-dimethylaminopyridine to the reaction kettle under nitrogen protection 14.6g (0.12mol, 1.2equiv), 300ml of butyl acetate, heated to reflux, TLC detection to control the end of the reaction, after the reaction is over, reduce the temperature to 0, add dilute hydrochloric acid to adjust the pH to below 1, and separate the organic layer, water The layer was slowly added with sodium carbonate solid to adjust the pH to 2 to 3, stirred for half an hour, filtered, and dried to obtain 31.6 g of white solid tenofovir monophenyl ester with a molar yield of 87.0% and an HPLC purity of 98.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.1% | With pyridine In 1-methyl-pyrrolidin-2-one at 60℃; Inert atmosphere; | 4 Example 4 Add Tenofovir 28.7g (0.10mol, 1.0equiv), diphenyliodonium hexafluoroarsenate 47.0g (0.10mol, 1.0equiv), and pyridine 9.5g (0.12mol) to the reactor under nitrogen protection. ,1.2equiv), 100ml of N-methylpyrrolidone, heated to 60°C, TLC detection controls the end of the reaction, when the reaction is over, reduce the temperature to 0°C, add dilute hydrochloric acid to adjust the pH to below 1, add 200ml of water, add dichloromethane Extract twice with 250ml*2, separate the organic layer, slowly add sodium carbonate solid to the water layer to adjust the pH to 23, stir for half an hour, filter, and dry to obtain 26.2g of white solid tenofovir monophenyl ester, molar yield 72.1%, HPLC purity is 99.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | Stage #1: formaldehyd With hydrogenchloride In N,N-dimethyl-formamide at 35 - 40℃; for 1h; Stage #2: tenofovir at 10 - 15℃; for 48h; | tenofovir disoproxil (20.78g, 40mmol),Potassium carbonate (12.16g, 88mmol) and bromomethyl ethyl carbonate (SM-1, 10.98g, 60mmol) were added to N,N-dimethylformamide (300mL),Control the temperature at 9095 to react for 7h, the reaction is completeThe reaction solution was cooled to room temperature, filtered,Tenofovir disoproxil (23.89g, 46mmol) was continuously added to the obtained filtrate,React at 115120 for 4h,After the reaction is completed, the reaction solution is reduced to room temperature,Add dichloromethane/purified water (V dichloromethane:V purified water = 2:1, 1200mL) extraction and separation,Take the organic layer, use purified water (250mL×2),Wash with saturated brine (250mL) separately,Dry with anhydrous sodium sulfate, filter,The filtrate was concentrated under reduced pressure to obtain tenofovir disoproxil dimer with a yield of 89.5% and a purity of 99.85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 15 g | Add 18.6g of diol and 90mL of dichloromethane to a dry and clean 250mL reaction flask, Stir and lower the temperature to 05 and start adding 19.0g of titanium tetrachloride dropwise to the reaction system. Then 42.0 g of triethylamine was added dropwise to the reaction solution, and the addition was completed, which was recorded as reaction solution A. Add 370 mL of dichloromethane to the 1.0L reaction flask at room temperature, Turn on the stirring and add 28.7g of Tenofovir and 50.8g of DEF. Add 10.9g of oxalyl chloride dropwise at 1025. After the addition is complete, turn on heating to reflux; reflux reaction for 23h, stop heating, Drop the reaction solution A to 1.0L reaction system when the temperature is lowered to 10C; After the addition is complete, the reaction is stirred for 1 hour. Add methanol and water to the reaction system, stir for 5 min, separate the liquids, The aqueous phase was extracted 4 times with dichloromethane, Combine the organic phases and wash with saturated brine, Separate the liquids, dry the organic phase with anhydrous magnesium sulfate; filter, wash the filter cake with dichloromethane, The filtrate was concentrated under reduced pressure to no fraction; Add the concentrated solution to ethanol to dissolve, transfer to a 500mL reaction flask, And add 32mL of acetic acid and heat to reflux for 5-6h. Concentrate under reduced pressure at 60-70C to almost no fraction, Add methanol and succinic acid, stir and react for 1h; Stir and cool to crystallize, filter, filter cake 5565 blast drying material for 5h, 30g succinate is obtained. Add 300L water to the reaction flask, add 30g HTS succinate, 200mL acetone, After the temperature was raised to 30-40C to dissolve, it was extracted with methyl tert-butyl ether. Discard the organic phase and adjust the Ph of the aqueous phase to 8-9 with saturated sodium bicarbonate solution; The aqueous phase was extracted with dichloromethane. Combine the organic phases and wash once with saturated sodium chloride, The organic phase is dried by adding anhydrous magnesium sulfate, Filter and wash the filter cake with dichloromethane. The filtrate was concentrated under reduced pressure at 30-40C to no fraction. Approximately 18 g of oil is obtained, which is added to the reaction flask after being dissolved in methanol, and about 11.6 g of fumaric acid is added under stirring, and the reaction is stirred for 30 minutes below 30C. Stir and cool to crystallize, filter, and bake the filter cake at 5565 for more than 10h. About 15 g of white powder is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.6% | With sodium hydroxide In water; acetone at 30℃; | 1-4 Example 4 Compound II (100.00 g, 348.17 mmol) and acetone (300 ml) were added to the reaction flask and stirred at room temperature to obtain a white slurry. Sodium hydroxide (14.00g, 350.03mmol) was prepared into a 30% aqueous solution, slowly dripped into the white slurry, kept at 30°C and stirred for reaction, the reaction solution gradually dissolved, and the temperature was kept and stirred for 1 to 2 hours. After the reaction, add Acetone (1200ml), reduced to 0°C and stirred for half an hour, filtered with suction, washed with appropriate amount of acetone, and dried under vacuum at 70°C to obtain a white solid compound Ia-1 (monosodium salt), yield 90.6%, HPLC: 99.421%, Na content 7.47%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.5% | With potassium hydrogencarbonate In water at 40℃; | 5 Example 5 Compound II (100.00 g, 348.17 mmol) and drinking water (500 ml) were added to the reaction flask, and stirred at room temperature to obtain a white slurry. Potassium bicarbonate (34.86g, 348.17mmol) was prepared into a saturated aqueous solution and slowly added to the white slurry. The reaction solution gradually dissolved and released a large amount of gas. The reaction was kept at 40°C and stirred until it was completely dissolved and no gas was generated. Continue to heat and stir 1 ~2 hours, after the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a white solid, which was dried under vacuum at 70°C to obtain a white solid compound Ia-2 (monopotassium salt). The yield was 99.5%, HPLC: 99.583%, and K content was 12.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With lithium hydroxide In acetone at 30℃; | 6 Example 6 Compound II (100.00 g, 348.17 mmol) and acetone (300 ml) were added to the reaction flask and stirred at room temperature to obtain a white slurry. Add purified water (50ml), add lithium hydroxide (8.34g, 348.17mmol) to the white slurry in batches, keep at 30°C and stir for reaction, the reaction solution will gradually dissolve, keep holding and stirring for 1 to 2 hours, after the reaction is over , Add acetone (1200ml), reduce to 0°C and stir for half an hour, then suction filter, wash with appropriate amount of acetone, and vacuum dry at 70°C to obtain white solid compound Ia-3 (monolithium salt), yield 96.5%, HPLC: 99.631%, The lithium content is 2.33%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.6% | With caesium carbonate In water; acetone at 30℃; | 7 Example 7 Compound II (100.00 g, 348.17 mmol) and acetone (300 ml) were added to the reaction flask and stirred at room temperature to obtain a white slurry. Cesium carbonate (56.80g, 174.33mmol) was prepared into a saturated aqueous solution and slowly dropped into the white slurry. The reaction was kept at 30°C and stirred. The reaction solution was gradually dissolved. Continue to keep the temperature and stirring for 1 to 2 hours without gas generation. After the reaction is over , Add acetone (1200ml), reduce to 0°C and stir for half an hour, then suction filter, wash with appropriate amount of acetone, and vacuum dry at 70°C to obtain white solid compound Ia-4 (monocesium salt), yield 97.6%, HPLC: 99.461%, The cesium content is 31.52%. |
Yield | Reaction Conditions | Operation in experiment |
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35% | Stage #1: 1-octadecanol; tenofovir With dmap; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 105℃; Stage #2: With ammonium hydroxide In methanol; dichloromethane | 6 Example 6. Synthesis of ammonium octadecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)phosphonate (MD-1-105) To a stirring suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 1-octadecanol (188 mg, 0.696 mmol, 1.00 eq) in anhydrous DMF (2.3 mL) under inert atmosphere was added triethylamine (194 mL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol %). The reaction mixture was stirred at room temperature for 10 min, then heated to 105 °C overnight. After confirming the formation of product by LC-MS, the reaction mixture was quenched with water, stirred for 20 min at room temperature, and immediately purified by normal phase column chromatography (0-70% DCM:DCM/MeOH/NH4OH (80:20:3)). The product fractions were collected, concentrated under reduced pressure, and purified by reverse phase column chromatography (0-85% H2O:MeOH). The product fractions were collected once again, concentrated under reduced pressure, stirred with 7 N ammonia in methanol (10 mL) for 10 min at room temperature, and dried under vacuum, yielding MD-1-105 as a white solid (132 mg, 35% yield). MP = 154-184 °C (Decomp. started at 171 °C). 1H NMR (600 MHz, CD3OD) d 8.33 (s, 1H), 8.21 (s, 1H), 4.39 (dd, J = 14.4, 3.1 Hz, 1H), 4.24 (dd, J = 14.5, 6.7 Hz, 1H), 3.91 (pd, J = 6.3, 2.9 Hz, 1H), 3.81 - 3.68 (m, 3H), 3.48 (dd, J = 12.8, 10.0 Hz, 1H), 1.56 - 1.44 (m, 2H), 1.35 - 1.21 (m, 30H), 1.16 (d, J = 6.3 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H).13C NMR (126 MHz, CD3OD) d 157.2, 153.5, 150.9, 144.2, 119.6, 76.9 (d, J = 12.8 Hz), 65.9 (d, J = 5.9 Hz), 65.6 (d, J = 160.3 Hz), 33.1, 32.1 (d, J = 6.3 Hz), 30.8, 30.7, 30.7, 30.7, 30.5, 26.9, 23.7, 16.8, 14.4. 31P NMR (243 MHz, CD3OD) d 15.4. HRMS (APCI) m/z calculated for C27H51N5O4P+ [M + H]+: 540.36732, found 540.36763. HPLC 95% MeOH in H2O, 10 min, m/z = 540.4 (M + H), t = 2.440 min; 75-95% MeOH in H2O, 10 min, m/z = 540.4 (M + H), t = 8.845 min. |
35% | Stage #1: 1-octadecanol; tenofovir With dmap; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 105℃; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | Stage #1: 3-(hexadec-15-yn-1-yloxy)propan-1-ol; tenofovir With dmap; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 55 - 95℃; for 17h; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane at 20℃; | 5.F F Synthesis of ammonium 3-(hexadec-15-yn-1-yloxy)propyl (R)-(((1-(6-amino-9H-purin-9- yl)propan-2-yl)oxy)methyl)phosphonate (MD-5- 72) Prior to use, commercially available tenofovir was dried under vacuum oven at 55 °Covernight. A 100 mL three neck flask equipped with a condenser was charged with 3 -(hexadec- 15-yn-1-yloxy)propan-1-ol (155.0 mg, 0.522 mmol, 1.0 eq), tenofovir (150.15 mg, 0.522 mmol, 1.0eq), and suspended in anhydrous DMF (2 mL) and added triethylamine (0.15 mL, 1.045 mmol, 2.0eq) dropwise. To the resulting homogeneous solution, N,N’-dicyclohexylcarbodiimide (215.73 mg,1.045 mmol, 2.0 eq) and 4-dimethylaminopyridine (6.3 mg, 0.052 mmol, 0.1 eq) were added andstirred at room temperature for 10 mm and then heated at 95 °C overnight. After 17 h, TLC analysisindicated product (30% MeOH/CH2C12 spiked with 10% NH4OH). The mixture was allowed tocool to room temperature and directly loaded on silica gel chromatography for purification elutingwith 0-30% MeOH (spiked with 10% NH4OH) /DCM to obtain product as a white solid. The solidwas resubjected to second purification on reverse-phase C18 chromatography (CombiFlash)eluting with 5-100% MeOHIH2O to obtain product in 70-90% gradient. Product fractions werepooled and concentrated and co-concentrated with methanol spiked with 10% NH4OH (x 3) andvacuum dried to obtain product as a white solid (73.0 mg, 0.125 mmol, 24% yield). Melting point(MP) 135 °C - 160.9 °C. 1H NMR (399 MHz, CD3OD) 8.31 (s, 1H), 8.20 (s, 1H), 4.37 (dd, J= 14.4, 3.1 Hz, 1H), 4.22 (dd, J= 14.4, 6.7 Hz, 1H), 3.92-3.81 (m, 3H), 3.71 (dd, J 12.7, 9.4Hz, 1H), 3.50 -3.45 (m, 1H), 3.42 (t, J= 6.4 Hz, 2H), 3.33 (t, J 6.6 Hz, 2H), 2.16 -2.10 (m,3H), 1.77 (p, J= 5.5 Hz, 2H), 1.51 - 1.44 (m, 4H), 1.42- 1.33 (m, 2H), 1.33- 1.24 (m, 18H), 1.16(d, J 6.2 Hz, 3H). 13C NMR (151 IVIFIz, CD3OD) 156.2, 152.3, 150.5, 144.1, 119.2, 85.0, 76.6(d, J 12.9 Hz), 71.8, 69.0, 68.2, 65.1 (d, J 159.9 Hz), 62.8 (d, J 5.5 Hz), 48.9, 32.1 (d, J6.1 Hz), 30.5, 30.4, 30.4, 30.4, 30.3, 29.9, 29.5, 29.4, 27.0, 18.9, 16.7. 31P NMR (162 MHz, CD3OD) 15.45. HRMS (APCI) m/z calculated for C28H49N505P [M+H]: 566.34658, found 566.34623. LC-MS (ESI) 85-95% MeOHIH2O (0.1% HCO2H), 5 mm, 1.00 mL/min, rt= 2.56 mm, m/z = 566.4 [M+H] LC-MS (ESI) 80-95% MeOHIH2O (0.1% HCO2H), 5 mm, rt= 3.38 mm, m/z = 566.4 [M+H]t |
24% | Stage #1: 3-(hexadec-15-yn-1-yloxy)propan-1-ol; tenofovir With dmap; triethylamine; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 105℃; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: 3-(hexadec-15-yn-1-ylthio)propan-1-ol; tenofovir With dmap; triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; Stage #2: With ammonium hydroxide In methanol; dichloromethane | 12.E E. Synthesis of ammonium 3-(hexadec-15-yn-1-ylthio)propyl (R)-(((1-(6-amino-9H-purin-9- yl)propan-2-yl)oxy) methyl) phosphonate (MD-1-182) To a stirring suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 3-(hexadec-15-yn-1-ylthio)propan-1-ol (218 mg, 0.696 mmol, 1.00 eq) in anhydrous NMP (2.3 mL) under inert atmosphere was added triethylamine (194 mL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol %). The reaction mixture was stirred at room temperature for 10 min, then heated to 100 °C overnight. After confirming the formation of product by LC-MS, the reaction mixture was quenched with water, stirred for 20 min at room temperature, and immediately purified by normal phase column chromatography (0-80% DCM:DCM/MeOH/NH4OH (80:20:3)). The product fractions were collected and concentrated under reduced pressure to give a pale orange solid. The solid was taken up in a solution of NH4OH in methanol (1:1) and purified by reverse phase column chromatography (0-85% H2O:MeOH). The product fractions were collected and concentrated under reduced pressure, yielding the MD- 1-182 as a white solid (206 mg, 51% yield).1H NMR (600 MHz, CD3OD) d 8.33 (s, 1H), 8.22 (s, 1H), 4.39 (dd, J = 14.4, 3.2 Hz, 1H), 4.24 (dd, J = 14.5, 6.7 Hz, 1H), 3.95 - 3.81 (m, 3H), 3.73 (dd, J = 12.8, 9.4 Hz, 1H), 3.49 (dd, J = 12.8, 10.0 Hz, 1H), 2.51 (t, J = 7.3 Hz, 2H), 2.47 - 2.42 (m, 2H), 2.18 - 2.13 (m, 3H), 1.82 - 1.71 (m, 2H), 1.55 - 1.46 (m, 4H), 1.43 - 1.25 (m, 20H), 1.17 (d, J = 6.3 Hz, 3H).13C NMR (151 MHz, CD3OD) d 157.1, 153.3, 150.9, 144.3, 119.6, 85.1, 76.9 (d, J = 13.1 Hz), 69.3, 65.5 (d, J = 160.0 Hz), 64.6 (d, J = 5.7 Hz), 32.8, 32.2 (d, J = 6.3 Hz), 30.8, 30.7, 30.7, 30.7, 30.7, 30.4, 30.2, 29.9, 29.8, 29.7, 29.2, 19.0, 16.8.31P NMR (243 MHz, CD3OD) d 15.4. HRMS (NSI) m/z calculated for C28H49N5O4PS+ [M + H]+: 582.3237, found 582.3232. HPLC 85-95% MeOH in H2O, 10 min, m/z = 582.2 (M + H), t = 2.057 min; 45-95% MeOH in H2O, 10 min, m/z = 582.3 (M + H), t = 6.502 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propan-1-ol; tenofovir With dmap; triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; Inert atmosphere; Stage #2: With diammonium hydrogenphosphate In methanol; dichloromethane | 17.D D. Synthesis of ammonium 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl (R)-(((1-(6- amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-187) To a stirring suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propan-1-ol (248 mg, 0.696 mmol, 1.00 eq) in anhydrous NMP (2.3 mL) under inert atmosphere was added triethylamine (194 mL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol %). The reaction mixture was stirred at room temperature for 10 min, then heated to 100 °C overnight. After confirming the formation of product by LC-MS, the reaction mixture was quenched with water, stirred for 20 min at room temperature, and immediately purified by normal phase column chromatography (0-80% DCM:MeOH). The product fractions were collected and concentrated under reduced pressure to give a pale orange solid. The solid was taken up in a solution of 80% MeOH in water and diammonium phosphate (460 mg, 3.48 mmol, 5.00 eq) was added. The mixture was stirred for 20 min and immediately purified by reverse phase column chromatography (0-85% H2O:MeOH). The product fractions were collected and concentrated under reduced pressure, yielding the MD-1-187 as a white solid (226 mg, 52% yield).1H NMR (600 MHz, CD3OD) d 8.34 (s, 1H), 8.22 (s, 1H), 4.39 (dd, J = 14.4, 3.1 Hz, 1H), 4.24 (dd, J = 14.5, 6.8 Hz, 1H), 3.94 - 3.80 (m, 3H), 3.73 (dd, J = 12.8, 9.4 Hz, 1H), 3.48 (dd, J = 12.7, 10.0 Hz, 1H), 2.50 (t, J = 7.3 Hz, 2H), 2.46 - 2.42 (m, 2H), 2.20 (t, J = 7.0 Hz, 2H), 1.81 - 1.70 (m, 2H), 1.54 - 1.45 (m, 4H), 1.42 - 1.24 (m, 16H), 1.17 (d, J = 6.2 Hz, 3H), 0.11 (s, 9H). 13C NMR (151 MHz, CD3OD) d 156.5, 152.4, 150.8, 144.6, 119.5, 108.7, 84.8, 76.9 (d, J = 12.8 Hz), 65.4 (d, J = 160.3 Hz), 64.6 (d, J = 5.8 Hz), 32.8, 32.2 (d, J = 6.4 Hz), 30.8, 30.7, 30.7, 30.7, 30.6, 30.4, 30.1, 29.9, 29.8, 29.7, 29.18, 20.4, 16.8, 0.3. 31P NMR (243 MHz, CD3OD) d 15.5. HRMS (APCI) m/z calculated for C29H51N5O4PSSi- [M - H]-: 624.3174, found 624.3178. HPLC 95% MeOH in H2O, 10 min, m/z = 626.3 (M + H), t = 2.716 min; 75-95% MeOH in H2O, 10 min, m/z = 626.3 (M + H), t = 7.843 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 12-(heptylthio)dodecan-1-ol; tenofovir With dmap; triethylamine; dicyclohexyl-carbodiimide In 1-methyl-pyrrolidin-2-one at 100℃; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane | 21.B B. Synthesis of ammonium 12-(heptylthio)dodecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl) phosphonate (MD-1-220) To a stirring suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 12-(heptylthio)dodecan-1-ol (220 mg, 0.696 mmol, 1.00 eq) in anhydrous NMP (2.3 mL) under inert atmosphere was added TEA (194 mL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol %). The reaction mixture was stirred at room temperature for 10 min, then heated to 100 °C overnight. After confirming the formation of product by LC-MS, the reaction mixture was quenched with water, stirred for 20 min at room temperature, and immediately purified by normal phase column chromatography (0-80% DCM:DCM/MeOH/NH4OH (80:20:3)). The product fractions were collected and concentrated under reduced pressure to give a light orange solid. The solid was taken up in a solution of DCM:7N NH3 in MeOH (1:1, 10 mL) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (0-90% H2O:MeOH). The product fractions were collected and concentrated under reduced pressure, yielding the MD-1-220 as a white solid (291 mg, 69% yield). 1H NMR (600 MHz, CD3OD) d 8.31 (s, 1H), 8.20 (s, 1H), 4.37 (dd, J = 14.4, 3.1 Hz, 1H), 4.23 (dd, J = 14.4, 6.7 Hz, 1H), 3.89 (pd, J = 6.3, 3.1 Hz, 1H), 3.79 - 3.67 (m, 3H), 3.46 (dd, J = 12.7, 10.0 Hz, 1H), 2.51 - 2.47 (m, 2H), 2.52 - 2.46 (m, 2H), 1.60 - 1.51 (m, 4H), 1.53 - 1.44 (m, 2H), 1.42 - 1.35 (m, 4H), 1.35 - 1.21 (m, 20H), 1.16 (d, J = 6.2 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H).13C NMR (151 MHz, CD3OD) d 157.2, 153.5, 150.9, 144.2, 119.6, 76.9 (d, J = 12.7 Hz), 65.9 (d, J = 5.8 Hz), 65.6 (d, J = 159.8 Hz), 33.0, 32.9, 32.1 (d, J = 6.4 Hz), 30.8, 30.8, 30.7, 30.7, 30.7, 30.5, 30.3, 30.0, 29.9, 29.9, 26.9, 23.7, 16.8, 14.4. 31P NMR (243 MHz, CD3OD) d 15.2. HRMS (NSI) m/z calculated for C28H53N5O4PS+ [M + H]+: 586.3550, found 586.3542. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: pentadec-14-yn-1-ol; tenofovir With pyridine; 2,4,6-triisopropylphenylsulfonyl chloride at 20℃; for 48h; Inert atmosphere; Stage #2: With ammonium chloride In water | 1.D D. Synthesis of ammonium pentadec-14-yn-1-yl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2- yl)oxy)methyl)phosphonate (EJM-8-006) Tenofovir (100 mg, 0.350 mmol, 1.00 eq) was added to a 25 mL flame-dried flask with a stir bar, diluted with pyridine (2.90 mL), and stirred vigorously at room temperature under Ar. After addition of pentadec-14-yn-1-ol (117 mg, 0.520 mmol, 1.50 eq) and 2,4,6- triisopropylbenzenesulfonyl chloride (316 mg, 1.04 mmol, 3.00 eq), the resulting yellow reaction mixture was stirred vigorously overnight at room temperature under Ar. After 2 days, TLC indicated significant product formation. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the resulting mixture was evaporated under reduced pressure. The resulting white solid was diluted with 50 mL of 4:1 DCM to MeOH, and the resulting slurry was stirred vigorously at room temperature under Ar overnight. In the next morning, the contents were filtered, and the resulting mother liquor was evaporated under reduced pressure to yield a white solid, which was purified via column chromatography eluting with 80:20:3 DCM/MeOH/NH4OH to yield a waxy white solid (0.064 g, 0.130 mmol, 37% yield). 1H NMR (600 MHz, CD3OD) d 8.33 (s, 1H), 8.21 (s, 1H), 4.38 (dd, J = 14.4 Hz, J = 3.0 Hz, 1H), 4.23 (dd, J = 14.4 Hz, J = 6.6 Hz, 1H), 3.90 (sextet, J = 3.4 Hz, 1H), 3.70-3.78 (m, 3H), 3.46 (dd, J = 12.6 Hz, J = 10.2 Hz, 1H), 2.14-2.18 (m, 3H), 1.45-1.52 (m, 4H), 1.40 (p, J = 7.5 Hz, 2H), 1.22-1.28 (m, 16H), 1.16 (d, J = 6.6 Hz, 3H).13C NMR (150 MHz, CD3OD) d 155.1, 150.8, 150.1, 144.3, 123.1, 119.0, 85.0, 76.3 (d, J = 12.2 Hz), 68.8, 65.7 (d, J = 5.9 Hz), 64.9 d (J = 159.9 Hz), 31.7 (d, J = 6.2 Hz), 30.3, 30.3, 30.3, 30.3, 30.2, 30.1, 29.8, 29.4, 29.2, 26.5, 18.8, 16.7. 31P NMR (122 MHz, CD3OD) d 15.6. HRMS (APCI) m/z calculated for C24H41O4N5P [M + H]+: 494.28907, found 494.28924. LC-MS (ESI) 50-95% MeOH in H2O (0.1% HCO2H), 6 min, rt = 5.430, m/z = 494.0 [M + H]+, 491.9 [M - H]-. |
37% | Stage #1: pentadec-14-yn-1-ol; tenofovir With pyridine at 20℃; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | Stage #1: 18-(trimethylsilyl)octadec-17-yn-1-ol; tenofovir With pyridine; 2,4,6-triisopropylphenylsulfonyl chloride In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; Stage #2: With ammonium chloride | 25.E E. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(18- trimethylsilyloctadec-17-ynoxy)phosphinate (NP-PD-042) Tenofovir (100 mg, 0.348 mmol, 1.00 eq) and pyridine (2.00 mL) were added to a 25 mL oven-dried flask equipped with a stir bar under an atmosphere of Ar. This was followed by the addition of 18-trimethylsilyloctadec-17-yn-1-ol (177 mg, 0.522 mmol, 1.50 eq) and 2,4,6- triisopropylbenzenesulfonyl chloride (316 mg, 1.05 mmol, 3.00 eq). The reaction was left to stir vigorously at room temperature for 48 hours under Ar. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride and concentrated once again in vacuo. The resulting salt was then vigorously stirred up in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered and the resulting filtrate was collected, concentrated in vacuo and purified by column chromatography (100% DCM-100% 80:20:3 DCM:MeOH:NH4OH) to yield a white solid (51.0 mg, 0.0816 mmol, 24%).1H NMR (500 MHz, CD3OD) d 8.31 (s, 1H), 8.20 (s, 1H), 4.38 (dd, J = 14.4, 2.8 Hz, 1H), 4.23 (dd, J = 14.4, 6.8 Hz, 1H), 3.93-3.86 (m, 1H), 3.76- 3.68 (m, 3H), 3.46 (dd, J = 12.5, 10.3 Hz, 1H), 2.20 (t, J = 6.9 Hz, 2H), 1.52-1.44 (m, 4H), 1.43- 1.37 (m, 2H), 1.34-1.20 (m, 22H), 1.17 (d, J = 6.2 Hz, 3H), 0.11 (s, 9H). 13C NMR (126 MHz, CD3OD) d 157.0, 153.2, 150.9, 144.2, 119.5, 108.7, 84.8, 76.9 (d, JCP = 13.1 Hz), 65.9 (d, JCP = 6.2 Hz), 65.5 (d, JCP = 160.2 Hz), 32.1 (d, JCP = 6.4 Hz), 30.8 (2C), 30.7 (2C), 30.5, 30.1, 29.7 (2C), 26.9, 20.4, 16.8, 0.3. 31P NMR (121 MHz, CD3OD) d 15.27. HRMS (ESI) m/z calc. for C30H55N5O4PSi [M + H]+, 608.37554 found, 608.37562. LCMS (ESI) 95% ISO MeOH in H2O (0.1 % HCO2H), 9 min, rt = 3.838, m/z = 608.4 [M + H]+, 606.3 [M - H]-; 85-95% MeOH in H2O (0.1 % HCO2H), 10 min, rt = 6.163, m/z = 608.4 [M + H]+, 606.4 [M - H]-. |
23% | Stage #1: 18-(trimethylsilyl)octadec-17-yn-1-ol; tenofovir With pyridine at 20℃; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: 20,20,20-trifluoroicos-18-yn-1-ol; tenofovir With pyridine; 2,4,6-triisopropylphenylsulfonyl chloride In 1-methyl-pyrrolidin-2-one at 20℃; for 48h; Inert atmosphere; Stage #2: With ammonium chloride | 27.F F. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(20,20,20- trifluoroicos-18-ynoxy)phosphinate (NP-PD-102) Tenofovir (100 mg, 0.348 mmol, 1.00 eq) and pyridine (2.00 mL) were added to a 25 mL oven-dried flask equipped with a stir bar under an atmosphere of Ar. This was followed by the addition of 20,20,20-trifluoroicos-18-yn-1-ol (182 mg, 0.522 mmol, 1.50 eq) and 2,4,6,- triisopropylbenzenesulfonyl chloride (316 mg, 1.05 mmol, 3.00 eq). The reaction was left to stir vigorously at room temperature for 48 hours under Ar. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride and concentrated once again in vacuo. The resulting salt was then vigorously stirred up in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered and the resulting filtrate was collected, concentrated in vacuo and purified first by silica gel column chromatography (100% DCM-100% 80:20:3 DCM:MeOH:NH4OH) and then by RP C18 column chromatography (10% MeOH/H2O - 100% MeOH) to yield a white solid (69.0 mg, 0.109 mmol, 31%).1H NMR (500 MHz, CD3OD) d 8.32 (s, 1H), 8.21 (s, 1H), 4.38 (dd, J = 14.4, 3.1 Hz, 1H), 4.23 (dd, J = 14.4, 6.9 Hz, 1H), 3.90 (pd, J = 6.3, 3.0 Hz, 1H), 3.78-3.67 (m, 3H), 3.47 (dd, J = 12.7, 10.0 Hz, 1H), 2.38 (dt, J = 7.3, 3.6 Hz, 1H), 1.62-1.20 (m, 31H), 1.17 (d, J = 6.2 Hz, 3H).13C NMR (151 MHz, CD3OD) d 156.9, 153.0, 150.9, 144.3, 119.5, 115.6 (q, JCF = 254.9 Hz), 94.5, 91.5 (q, JCF = 6.2 Hz), 77.0 (d, JCP = 12.8 Hz), 68.7 (q, JCF = 51.9 Hz), 65.9 (d, JCP = 5.8 Hz), 65.5 (d, JCP = 159.9 Hz), 32.1 (d, JCP = 6.3 Hz), 30.8, 30.7 (2C), 30.6 (2C), 30.5 (2C), 30.1, 30.0, 29.8 (2C), 29.7, 28.3, 26.9, 21.3, 18.6, 16.8. 19F NMR (376 MHz, CD3OD) d -51.45 (t, J = 4.0 Hz, 3F).31P NMR (121 MHz, CD3OD) d 15.27. HRMS (APCI) m/z calc. for C29H46O4N5F3P [M - H]-, 616.32450 found, 616.32505. LCMS (ESI) 95% ISO MeOH in H2O (0.1 % HCO2H), 9 min, rt = 1.260, m/z = 618.4 [M + H]+, 616.2 [M - H]- ; 85-95% MeOH in H2O (0.1 % HCO2H), 10 min, rt = 2.946, m/z = 618.4 [M + H]+, 616.3 [M - H]-. |
31% | Stage #1: 20,20,20-trifluoroicos-18-yn-1-ol; tenofovir With pyridine at 20℃; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: tenofovir; [16,16,16-2H3]-hexadecanol With pyridine; 2,4,6-triisopropylphenylsulfonyl chloride at 20℃; for 48h; Inert atmosphere; Stage #2: With ammonium chloride In water | 3.D D. Synthesis of ammonium hexadecyl-16,16,16-d3 (R)-(((1-(6-amino-9H-purin-9-yl)propan- 2-yl)oxy)methyl)phosphonate (EJM-8-036) Tenofovir (100 mg, 0.350 mmol, 1.00 eq) was added to a 25 mL flame-dried flask with a stir bar and diluted with pyridine (3.48 mL). The resulting slurry was stirred vigorously at room temperature under Ar. After addition of hexadecan-16,16,16-d3-1-ol (120 mg, 0.490 mmol, 1.40 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (316 mg, 1.04 mmol, 3.00 eq), the resulting yellow reaction mixture was stirred vigorously overnight at room temperature under Ar. After 2 days, TLC indicated significant product formation. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the resulting mixture was evaporated under reduced pressure. The resulting white solid was diluted with 60 mL of 5:1 DCM to MeOH, and the resulting slurry was stirred vigorously at room temperature under Ar for 1 hr. After this time, the contents were filtered, the filtrate was washed thoroughly with 5:1 DCM to MeOH, and the resulting mother liquor was evaporated under reduced pressure to yield a white solid. The crude material was further purified via column chromatography (CombiFlash, 12 g column, 30 mL/min) eluting with the following gradient to yield a white solid (98.0 mg, 0.190 mmol, 55% yield): 0-3 min, 25% 80:20:3 DCM/MeOH/NH4OH in DCM; 3-20 min, 25-100% 80:20:3 DCM/MeOH/NH4OH in DCM; 20- 30 min, 100% 80:20:3 DCM/MeOH/NH4OH.1H NMR (600 MHz, CD3OD) d 8.32 (s, 1H), 8.20 (s, 1H), 4.38 (dd, J = 3.3 Hz, J = 14.7 Hz, 1H), 4.22 (dd, J = 6.6 Hz, J = 14.4 Hz, 1H), 3.87-3.90 (m, 1H), 3.70-3.78 (m, 3H), 3.46 (dd, J = 10.2 Hz, J = 12.6 Hz, 1H), 1.47-1.52 (m, 2H), 1.23-1.27 (m, 26H), 1.16 (d, J = 6.6 Hz, 3H).13C NMR (150 MHz, CD3OD) d 155.0, 150.9, 150.0, 144.0, 129.2, 76.2 (d, J = 12.5 Hz), 65.5 (d, J = 5.7 Hz), 64.7 (d, J = 159.2 Hz), 48.7, 32.5-32.3 (m, 3C), 31.5 (d, J = 6.0 Hz), 30.2 (3C), 30.2, 30.2, 29.9, 29.9-29.8 (m), 26.3, 23.2-22.5 (m), 16.7, 14.3, 14.1-13.4 (m). 31P NMR (122 MHz, CD3OD) d 15.6. HRMS (APCI) m/z calculated for C25H41D3O4N5P [M - H]-: 513.34029, found 513.33931. LC-MS (ESI) 50-95% MeOH in H2O (0.1% HCO2H), 8 min, rt = 4.613, m/z = 515.3 [M + H]+, 537.3 [M + Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride In N,N-dimethyl acetamide; water at 25℃; Inert atmosphere; Large scale; | 3 SO42-/ZrO2-Nd2O3 type solid acid hydrolyses (R)-9-[2-(di-tert-butylphosphonomethoxy)propyl]adenine to prepare tenofovir (PMPA): Add 30LDMA and 2.5kg R-hydroxypropyl adenine to a 50L reactor, and stir for 10 minutes. Add 7.2kg magnesium tert-butoxide in three times. The internal temperature was raised to 92±2°C, and the mixture was stirred for 30 minutes. The reaction temperature was controlled to 92±2°C, and 6kg of di-tert-butyl methanesulfonyl methoxyphosphonate was added dropwise to the reaction kettle under the protection of nitrogen. After the addition is complete, control the temperature to 92±2°C and keep stirring for 24 hours. After the reaction is over, the internal temperature drops to 25±5°C. Control the temperature of the reactor at 25±5°C, and add hydrochloric acid dropwise to the reactor to adjust the pH to 7.0. The internal temperature rose to 75±5°C, and the DMA was concentrated under reduced pressure until no liquid flowed out. After the concentration is completed, the internal temperature is reduced to 30°C, 12L of acetone is slowly added, and the mixture is stirred to dissolve. Stir for 1 hour at the internal temperature of 8±2°C, filter, filter to remove insolubles, collect the filtrate, add the filtrate to a 50L reactor, control the internal temperature to 35±5°C, and concentrate under reduced pressure until no liquid flows out. Add 0.8kg of SO42-/ZrO2-Nd2O3 solid acid, stir to raise the temperature of the oil bath in the jacket of the 50L reactor to 72±2, and slowly add 4.5L of deionized water to the reactor within 1 hour. After the feeding is completed, keep the temperature of the oil bath in the jacket of the 50L reactor at 72±2°C and stir for 8 hours. Filter while it is hot to filter out SO42-/ZrO2-Nd2O3 solid acid, wash the filter cake with 7.5L of hot deionized water at 80°C for 5 times, and collect the filtrate. Transfer the filtrate to a 50L reaction kettle while it is hot, keep the temperature in the kettle at 65±5°C, add 0.3kg of activated carbon with stirring, stir and decolorize for 1 hour, filter while hot, filter out the activated carbon, and collect the filtrate. Transfer the filtrate to a 50L reaction kettle while it is hot, keep the temperature inside the kettle at 65±5°C, add sodium hydroxide solution to the reaction kettle dropwise with stirring, adjust the pH to 3.0, after the addition is complete, slowly lower the temperature in the reaction kettle 2°C. Stir for 2 hours. Centrifuge the material in the reaction kettle to dryness, wash the filter cake with 5L of water, and take out the filter cake after centrifugation to dryness to obtain a wet product of tenofovir. Control the temperature at 72±2 and dry under reduced pressure for 20 hours to obtain a white powder. Norfovir (PMPA) 2.8kg. The molar yield is 75%, and the HPLC purity is 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: n-eicosanol; tenofovir With pyridine at 20℃; Inert atmosphere; Stage #2: With ammonium hydroxide In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: benzyl 2-amino-2-methylpropionate hydrochloride; tenofovir With pyridine; triethylamine at 70℃; for 0.0833333h; Inert atmosphere; Stage #2: With pyridine; 2,2'-dipyridyldisulphide; triphenylphosphine at 70℃; for 16h; Inert atmosphere; | 3 PMPA (100 mg, 0.35 mmol), intermediate 3a (239 mg, 1.04 mmol) and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (1 mL) and heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (344 mg, 1.39 mmol), 2,2'-dipyridyldisulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and, and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5μm C18-110Å 100 x 30 mm column, 25%-100% acetonitrile in water gradient over 30min run) to afford the title compound (3).1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.12 (s, 1H), 7.39 - 7.28 (m, 10H), 7.22 (s, 2H), 5.17 - 5.03 (m, 4H), 4.28 - 4.06 (m, 4H), 3.91 - 3.83 (m, 1H), 3.63 - 3.45 (m, 2H), 1.391.44 - 1.34 (m, 12H), 1.00 (d, J = 6.2 Hz, 3H).31P NMR (162 MHz, DMSO-d6) δ 18.71 (t, J = 9.2 Hz). LCMS: MS m/z = 638.13 [M+1], tR = 1.46 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2μl/min. HPLC: tR = 2.91 min; HPLC system: Agilent 1100 series.; Column: Gemini 5μ C18110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN at 2 mL/min. | |
Stage #1: benzyl 2-amino-2-methylpropionate hydrochloride; tenofovir With pyridine; triethylamine at 70℃; for 0.0833333h; Inert atmosphere; Stage #2: With pyridine; 2,2'-dipyridyldisulphide; triphenylphosphine at 70℃; for 16h; Inert atmosphere; | 3 PMPA (100 mg, 0.35 mmol), intermediate 3a (239 mg, 1.04 mmol) and triethylamine (0.38 mL, 2.79 mmol) were combined in pyridine (1 mL) and heated to 70 °C for 5 min under an atmosphere of argon. A solution of triphenylphosphine (344 mg, 1.39 mmol), 2,2'-dipyridyldisulfide (307 mg, 1.39 mmol) in pyridine (1 mL) was added. The reaction was stirred at 70 °C for 16 h. The reaction was cooled to room temperature and diluted with 5 mL of EtOAc. The organics were washed with a saturated aqueous solution of sodium bicarbonate (5 mL x 2), water (5 mL), and, and dried over sodium sulfate. The product was loaded onto silica gel (12 g). EtOAc (100 mL) was eluted and discarded. The product was recovered with 15% MeOH in DCM (50 mL). The organics were concentrated under reduced pressure. The residue was purified by HPLC chromatography (Gemini 5μm C18-110Å 100 x 30 mm column, 25%-100% acetonitrile in water gradient over 30min run) to afford the title compound (3).1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.12 (s, 1H), 7.39 - 7.28 (m, 10H), 7.22 (s, 2H), 5.17 - 5.03 (m, 4H), 4.28 - 4.06 (m, 4H), 3.91 - 3.83 (m, 1H), 3.63 - 3.45 (m, 2H), 1.391.44 - 1.34 (m, 12H), 1.00 (d, J = 6.2 Hz, 3H).31P NMR (162 MHz, DMSO-d6) δ 18.71 (t, J = 9.2 Hz). LCMS: MS m/z = 638.13 [M+1], tR = 1.46 min; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18100A, 50 x 4.6 mm; Solvents: acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid; Gradient: 0 min-2.0 min 2-100% acetonitrile, 2.0 min-3.05 min 100% acetonitrile, 3.05 min-3.2 min 100%-2% acetonitrile, 3.2 min-3.5 min 2% ACN at 2μl/min. HPLC: tR = 2.91 min; HPLC system: Agilent 1100 series.; Column: Gemini 5μ C18110A, 50 x 4.6 mm; Solvents: Acetonitrile with 0.1% TFA, Water with 0.1% TFA; Gradient: 0 min-5.0 min 2-98% ACN, 5.0 min-6.0 min 98% ACN at 2 mL/min. |
Tags: 147127-20-6 synthesis path| 147127-20-6 SDS| 147127-20-6 COA| 147127-20-6 purity| 147127-20-6 application| 147127-20-6 NMR| 147127-20-6 COA| 147127-20-6 structure
A137641[ 206184-49-8 ]
(R)-(((1-(6-Amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonic acid hydrate
Reason: Hydrate
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Health hazards | |
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H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
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H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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