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Chemical Structure| 147127-20-6
Chemical Structure| 147127-20-6
Structure of 147127-20-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 147127-20-6 ]

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

Calculated chemistry of [ 147127-20-6 ]

Physicochemical Properties

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

Pharmacokinetics

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

Lipophilicity

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

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

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

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.39

Safety of [ 147127-20-6 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P264-P270-P301+P310+P330-P405-P501 UN#:2811
Hazard Statements:H301 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 147127-20-6 ]

* 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.

  • Upstream synthesis route of [ 147127-20-6 ]
  • Downstream synthetic route of [ 147127-20-6 ]

[ 147127-20-6 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 147127-20-6 ]
  • [ 379270-37-8 ]
Reference: [1] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 621 - 628
[2] Patent: US2013/90473, 2013, A1,
[3] Patent: US2013/90473, 2013, A1,
[4] Patent: US2016/115186, 2016, A1,
[5] Patent: US2017/56423, 2017, A1,
[6] Patent: WO2017/221189, 2017, A1,
[7] Patent: WO2017/221189, 2017, A1,
[8] Patent: CN108409790, 2018, A,
[9] Patent: CN108409788, 2018, A,
  • 2
  • [ 147127-20-6 ]
  • [ 108-95-2 ]
  • [ 379270-37-8 ]
  • [ 383365-04-6 ]
Reference: [1] Patent: CN106478725, 2017, A,
  • 3
  • [ 35180-01-9 ]
  • [ 110-17-8 ]
  • [ 147127-20-6 ]
  • [ 202138-50-9 ]
YieldReaction ConditionsOperation 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.

Reference: [1] Patent: KR2016/38627, 2016, A, . Location in patent: Paragraph 0121; 0122; 0123; 0124
[2] Patent: KR2016/135112, 2016, A, . Location in patent: Paragraph 0113; 0114; 0115; 0116; 0118; 0119
[3] Patent: US2013/5969, 2013, A1, . Location in patent: Page/Page column 4
[4] Patent: US2014/303368, 2014, A1, . Location in patent: Paragraph 0092; 0093; 0094; 0095; 0096
[5] Patent: US2017/354668, 2017, A1, . Location in patent: Paragraph 0129-0132
[6] Patent: CN107400145, 2017, A, . Location in patent: Paragraph 0018
[7] Patent: CN108329352, 2018, A, . Location in patent: Paragraph 0006; 0019; 0047-0071
[8] Patent: JP2015/164934, 2015, A, . Location in patent: Paragraph 0166; 0167; 0181
  • 4
  • [ 147127-20-6 ]
  • [ 202138-50-9 ]
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 5, p. 1194 - 1201
[2] Patent: WO2011/111074, 2011, A2,
[3] Patent: WO2015/51874, 2015, A1,
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