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Chemical Structure| 863329-66-2
Chemical Structure| 863329-66-2
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Product Details of [ 863329-66-2 ]

CAS No. :863329-66-2 MDL No. :
Formula : C10H13FN2O5 Boiling Point : -
Linear Structure Formula :- InChI Key :ARKKGZQTGXJVKW-VPCXQMTMSA-N
M.W : 260.22 Pubchem ID :11311503
Synonyms :
GS-331007;RO 2433

Calculated chemistry of [ 863329-66-2 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.6
Num. rotatable bonds : 2
Num. H-bond acceptors : 6.0
Num. H-bond donors : 3.0
Molar Refractivity : 58.0
TPSA : 104.55 Ų

Pharmacokinetics

GI absorption : High
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) : -8.66 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.22
Log Po/w (XLOGP3) : -1.09
Log Po/w (WLOGP) : -1.39
Log Po/w (MLOGP) : -0.59
Log Po/w (SILICOS-IT) : -0.05
Consensus Log Po/w : -0.38

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.88
Solubility : 34.2 mg/ml ; 0.131 mol/l
Class : Very soluble
Log S (Ali) : -0.62
Solubility : 63.0 mg/ml ; 0.242 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.71
Solubility : 50.4 mg/ml ; 0.194 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.94

Safety of [ 863329-66-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 863329-66-2 ]

* 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.

  • Downstream synthetic route of [ 863329-66-2 ]

[ 863329-66-2 ] Synthesis Path-Downstream   1~84

  • 1
  • (2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate [ No CAS ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
100% With ammonia In methanol at 20℃;
93% With ammonia In methanol at 20℃; for 17h; 10 Example 10: Preparation of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (10) Take a 500ml reaction flask, add 300ml methanol, and cool to about -5° in an ice bath.Slowly inject ammonia gas for 30 minutes to prepare a methanol saturated solution of ammonia, and then add 47 grams of intermediate 9 to the system.Incubate the reaction for 5 hours, then slowly warm to room temperature and continue the reaction for 12 hours. After the reaction, the solvent is recovered under reduced pressure.Disperse the residue in dichloromethane for beating, filter, and wash the filter cake with absolute ethanol.Vacuum drying to obtain 25 grams of white solid, yield 93%.
93.8% With methanol; triethylamine for 53h; Reflux; 1-5 Add 4g of compound b (8.54mmol), 32g of anhydrous methanol, 4g of triethylamine (39.53mmol) into the reaction flask, stir, and the system becomes white and turbid; the temperature is raised to reflux until the solid disappears, which takes about 28h;After the reaction was carried out for 25 hours, samples were taken every 2 hours for HPLC control until the content of compound b was below 0.2%; After the reaction, the temperature is lowered to 50±5°C, 0.2g activated carbon is added and the temperature is raised to the reflux state and kept for 1h;After the decolorization is completed, control the temperature below 60°C, and adjust the vacuum to below -0.08MPa, carry out reduced pressure desolvation, and stop desolvation when no fraction flows out; Add 10.6g of dichloromethane, raise the temperature to 38±3, stir for 1h, then lower the temperature to 23±5, stir until there is solid precipitation, filter, the filter cake is the crude wet product of compound a;Add 10g of isopropanol to the crude wet product, heat to reflux and maintain this state for 1 hour,Then the temperature is lowered to room temperature, and then the temperature is lowered to 5±2° C., the temperature is kept for 2 hours to crystallize; it is filtered and dried to obtain compound a. The total yield is 93.8%, and the purity of the target product is 99.5%.
90.7% Stage #1: (2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate With N-butylamine at 45 - 50℃; Stage #2: With methanol In tert-butyl methyl ether at 60 - 70℃; 2.5 A method for the synthesis of sofosbuvir, the fifth step: A 250 ml four-necked flask was charged with 20.0 g (43 mmol)Of compound 3 and 80 g of n-butylamine,Heated to 45 ~ 50 stirring 5 ~ 6 h,Concentrated under reduced pressure to essentially no liquid drops,Add 30 mL of methanol and dry once, add 10 mL of methanol, 60 ~ 70 heating and stirring to dissolve, dropping 120 mLOf methyl tertiary ether,20 ~ 30 min addition is completed, a large number of white solid precipitation,Continue stirring heat insulation 30 min, cooled to 20 ~ 25 after filtration,The filter cake was rinsed twice with 20 mL of a mixture of methanol and methyl tertiary ether (methanol: isopropyl ether = 1: 12, V / V)After washing, 70-80 ° C in vacuo to give 10.1 g of compound 4,The molar yield is 90.7%.
82.6% With sodium methylate In methanol Reflux; 1.d As shown in formula IV compound (8.1g, 17 . 2mmol), 100 ml methanol, stirring and dissolving, adding sodium methoxide (1.0g, 18 . 9mmol), stirring, warming to reflux the reaction, TLC monitoring reaction: reaction finishes, cooling to room temperature, adding citric acid and water quenching reaction, stirring, reducing pressure and methanol, ethyl acetate (30 ml × 3) extraction, the combined organic phase, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, shall be 8.5g white solid crude product, the film thickness isopropanol refining, shall be 3.7 white solid product, yield: 82.6%; HPLC purity 97.3%.
78% With ammonia In methanol at 0 - 15℃; for 27h;
78% With ammonia In methanol at 0 - 15℃; for 27h; 1 In a 10 L flask, was added 3', 5l-O-dibenozyl-2'-deoxy-2'-fluoro-2'-C-methyl-N4-benzoylcytidine (500 g, 0.874 mol) and 70% aqueous acetic acid (7.5 L). The solution was heated to reflux (110C) for 20 h. TLC indicated a complete reaction (Rf 0.6 in 5% methanol in dichloromethane (DCM)). The mixture was cooled to ambient temperature and diluted with water (2 L). After stirring for 2 h, the resulting precipitate was collected by filtration and the solid was rinsed with water (5 L) and dried in the atmosphere at ambient temperature for 12 h to afford 360 g (88%). This dibenzoyluridine intermediate was used directly in the next step by adding it all to freshly prepared methanolic ammonia (5.4 L, ca 25%) at 0C. This temperature was maintained for 3 h and then allowed to warm to 15C for 24 h. TLC indicated a complete reaction (Rf 0.4 in 10% methanol in DCM). The reaction mixture was filtered through a Celite bed and concentrated under reduced pressure to give the crude product (216 g). The crude product was stirred with ethyl acetate (325 mL) for 3 h at ambient temperature. The resulting solid was collected by filtration and washed with ethyl acetate (216 mL). The solid was dried under vacuum at ambient temperature for 4h to afford 160 g (78%) of the desired product in 98.7% HPLC purity. 1H-NMR (DMSO-c/6) δ 11.44 (br s, IH, NH), 7.95 (d, IH, C-6H), 5.97 (d, IH, C-I1H), 5.64 (d, IH, C-5H), 3.84-3.77 (m, 3H, C-5'-Ha, C-3Η. C-4'H), 3.63-3.60 (m, IH, C5'-Hb), 1.23 (d, 3H, C-2'-CH3). ES-MS M-I 259.
78% With ammonia In methanol at 0 - 15℃; for 27h; 9 Preparation of 2'-deoxy-2'-fluoro-2,-C-methyluridine (from US2010/0298257 Example 1) Preparation of 2'-deoxy-2'-fluoro-2,-C-methyluridine (from US2010/0298257 Example 1) In a 10 L flask, was added 3', 5'-0-dibenozyl-2'deoxy-2'-fluoro-2'-C-methyl-N4-benzoylcytidine (500 g, 0.874 mol) and 70% aqueous acetic acid (7.5 L). The solution was heated to reflux (110° C.) for 20 h. TLC indicated a complete reaction (RfO.6 in 5% methanol in dichloromethane (HCL)). The mixture was cooled to ambient temperature and diluted with water (2 L). After stirring for 2 h, the resulting precipitate was collected by filtration and the solid was rinsed with water (5 L) and dried in the atmosphere at ambient temperature for 12 h to afford 360 g (88%). This dibenzoyluridine intermediate was used directly in the next step by adding it all to freshly prepared methanolic ammonia (5.4 L, ca 25%) at 0° C. This temperature was maintained for 3 h and then allowed to warm to 15° C. for 24 h. TLC indicated a complete reaction (Rf 0.4 in 10% methanol in HCL). The reaction mixture was filtered through a Celite bed and concentrated under reduced pressure to give the crude product (216 g). The crude product was stirred with ethyl acetate (325 mL) for 3 h at ambient temperature. The resulting solid was collected by filtration and washed with ethyl acetate (216 mL). The solid was dried under vacuum at ambient temperature for 4 h to afford 160 g (78%) of the desired product in 98.7% HPLC purity. 1 H-NMR (DMSO-d6 ) 011.44 (br s, 1H, NH), 7.95 (d, 1 H, C-6H), 5.97 (d, 1 H, C-1'H), 5.64 (d, 1 H, C-5H), 3.84-3.77 (m, 3H, C-5'-Ha, C-3'H. C-4'H), 3.63-3.60 (m, 1 H, C5'-Hb), 1.23 (d, 3H, C-2'-CH3). ES-MS M-l 259
62% With methanol; ammonia at 20℃; for 30h;
60% With ammonia In methanol at 0 - 20℃; for 18.5h; 2; b Preparation of 2'-deoxy-2'-fluoro-2'-C-methyluridine To a solution of 3',5'-dibenzoyl-2'-Deoxy-2'-fluoro-2'-C-methyluridine (10 gm) in MeOH (120 mL) was added to a solution of saturated ammonia in MeOH (60 mL). The reaction mixture was stirred at 0°C for 30 min, warmed to room temperature slowly and then allow to stir for another 18 hours at same temperature. The solvent in the resultant mixture was evaporated under reduced pressure to give the residue, further it was recrystallized with methanol and water to afford pure compound of title product. (Yield: 50-60 %)
60% With methanol; ammonia at 0 - 20℃; 4 To a solution of 3',5'-dibenzoyl-2'-Deoxy-2'-fluoro-2'-C-methyluridine (1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammonia in MeOH (20 mL). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature slowly. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give the residue, which was purified by column chromatography to afford pure compound 2'-deoxy-2'-fluoro-2'-C-methyluridine (500 mg, Yield: 60 %).
59.15% Stage #1: (2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate With sodium methylate In methanol at -10 - 20℃; for 2h; Inert atmosphere; Large scale; Stage #2: With sulfuric acid In methanol at -10℃; Large scale; 1.2 Step 2 Synthesis of 1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl]pyrimidine-2,4(1H,3H)-dione (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate (5.60 kg, 11.95 mol) prepared in the step 1 and Anhydrous methanol (28.0L) was added to the 50L reaction vessel, and under nitrogen protection, the temperature was lowered, and the temperature of the system was lowered to below -10 °C.A methanol solution of sodium methoxide (3.66 L, 30% by weight, 17.93 mol) was added dropwise to the reaction vessel, and after completion of the dropwise addition, the mixture was warmed to room temperature, and after 2 h, the mixture was cooled.After the temperature of the system was lowered to below -10 ° C, a concentrated solution of sulfuric acid (5.60 L, 10.03 mol) in methanol (volume ratio 1:9) was added dropwise to the reaction vessel. After the reaction was completed,The diatomaceous earth was aided by filtration, the filter cake was washed with methanol, and the filtrate was combined. The filtrate was concentrated under reduced pressure, a large amount of white precipitate was precipitated, and dichloromethane (8.0 L) was added to the rotary flask.Filtration and drying of the filter cake gave the title compound 1.84 kg, yield 59.15%.
59.15% Stage #1: (2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate With sodium methylate In methanol at -10 - 20℃; for 2h; Inert atmosphere; Large scale; Stage #2: With sulfuric acid In methanol at -10℃; Large scale; 1.2 Step 2 1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl]pyrimidine-2,4-(1H,3H)-dioneSynthesis Prepared in step 1(2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate(5.60kg, 11.95mol) and anhydrous methanol (28.0L) were added to the 50L reactor, cooled under nitrogen, and the temperature of the system was lowered to below -10 °C. A methanol solution of sodium methoxide was added dropwise to the reaction kettle ( 3.66L, 30%wt, 17.93mol), after the addition was completed, the temperature was raised to room temperature, and after 2 hours, the temperature was lowered. After the temperature of the system was lowered to below -10 °C, a concentrated solution of sulfuric acid (5.60 L, 10.03 mol) in methanol (volume ratio 1:9) was added dropwise to the reaction vessel. After the reaction was completed, the diatomaceous earth was filtered, and the methanol was washed. , the filtrate was combined. The filtrate was concentrated under reduced pressure, and a large white solid precipitated, and dichloromethane (8.0L) was added to the rotary flask, and the filter cake was dried to give the title compound 1.84 kg.The yield was 59.15%.
With sodium methylate In methanol Reflux; 1; 2 preparation of Intermediate type 2-5 In the reaction bottle, by adding 30g intermediate type 2-4,300 ml methanol, stirring is dissolved, add 3g sodium methoxide, stirring, then heating to reflux the reaction, TLC monitoring reaction; after the reaction, cooling to room temperature, add citric acid and material reaction, stirring, reducing pressure and evaporating methanol, then with ethyl acetate (100 ml × 3) extraction, combined organic phase, dried anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to obtain 24.5g kind of white solid product. For crude product 120 ml isopropanol refining, shall be 12.8g white solid product. Yield: 78%
35 g With methanol; ammonia at 0 - 15℃; for 27h; 3 Weigh obtained in Comparative Example 2 3 ', 5'- O - dibenzoyl-2'-deoxy-2'-fluoro uridine -2'-C- methyl 70g, put it into 1L 25% ammonia methanol solution, at 0 ° C conditions, after stirring for 3h, then stirring was continued at 15 ° C under 24h, TLC until the reaction was complete after detection, filtration under reduced pressure through celite, and the filtrate was evaporated under reduced pressure to remove the solvent and spin volatiles after , in the distillation residue was added 60ml of ethyl acetate, stirred at room temperature for 3h, vacuum filtration, the filter cake washed with ethyl acetate, dried to give 2'-deoxy-2'-fluoro -2'-C- methyl uridine 35g, was an off-white solid.
3 g With monomethanolamine at 25 - 30℃; for 24h; 7 Example 7 Synthesis of Compound I 6.8 g of compound II'b was added to the flask, 20 mL of a methanolamine solution was added, and the reaction was carried out at 25 to 30C for 24 h. Add 0.7 g of activated carbon decolorization, filtration, concentrated white solid, add 20mL ethyl acetate slurry, filter and dry to get the white solid 3.0g
With sodium methylate In methanol Reflux; 2 Preparation of (2'R) -2'-deoxy-2'-fluoro-2'-methylurea (SF-1) 400 g of the (2'R) -2'-deoxy-2'-fluoro-2'-methyluridine-3 ', 5'-dibenzoate was dissolved in 15 times the volume of anhydrous MeOH, 1eq MeONa, the reaction solution heated to reflux, reaction 2-4 hours, the raw material reaction is complete. The reaction solution was cooled to about 50 ° C, and 3 times the amount of the strong acid cationic resin (type H) was added to the reaction solution, and the mixture was stirred for about 15 minutes to about 6 to 6.5 ° C of the reaction solution. The reaction solution was filtered, the filter cake was washed with MeOH, and the filtrate was combined and concentrated under reduced pressure. The residue was added to 10 volumes of MTBE, refluxed for 2 hours, cooled to room temperature, filtered, rinsed, and dried in vacuo to the desired product (2'R) -2'-deoxy-2'-fluoro-2'-methylurea , Purity 99.7%.
55 g With ammonia at 0 - 15℃; for 20h; Connect the device to check the airtightness of the device.b. 1000 g of ammonia was added to a 2000 mL three-necked flask V1,Slow down the temperature,Control V1 internal temperature at 0~5°C .Then, 100 g of compound 6 was added to V1, Maintain the internal temperature of V1°C~15°C , stirring 20h.c. sampling control: (compound 6 / compound 7 ≤ 0.5%) to adjust the V1 temperature to 40°C~45°C ,Vacuum distillation to 100 ~ 200mL, 200 g of methanol was added to V1 to maintain the internal temperature of V1 at 40 to 45 ° C,And distilled to 100 to 200 mL under reduced pressure.The inner temperature of V1 was maintained at 45 to 50 ° C, 2000 mL of toluene was added to R1,Distilled to 1500 to 1600 mL under reduced pressure, and 500 mL of toluene was added to V1,Maintain V1 internal temperature of 45 ~ 50 ,Vacuum distillation to 1600 ~ 1700mL.Slowly increase the internal temperature of V1 80°C, to maintain the inner temperature of V1 80°C , stirring 6h.Samples were tested by hot filtration. Purity: 99%.The material in V1 was transferred to the filter F1 at 80 ° C under vacuum,The filtrate was transferred to V2.100 g of toluene at 80 ° C was added to F1 for vacuum filtration.The filtered solids were placed in oven Dl,While keeping the inner temperature of D1 at 50 ° C, it can be kept under a nitrogen stream,Vacuum drying 20h. To give 55 g of a white solid,The white solid is compound 7, Its purity is 99%Yield 98%.
With ammonia In methanol

Reference: [1]Clark, Jeremy L.; Hollecker, Laurent; Mason, J. Christian; Stuyver, Lieven J.; Tharnish, Phillip M.; Lostia, Stefania; McBrayer, Tamara R.; Schinazi, Raymond F.; Watanabe, Kyoichi A.; Otto, Michael J.; Furman, Phillip A.; Stec, Wojciech J.; Patterson, Steven E.; Pankiewicz, Krzysztof W. [Journal of Medicinal Chemistry, 2005, vol. 48, # 17, p. 5504 - 5508]
[2]Current Patent Assignee: JIANGSU COLLEGE OF ENGINEERING AND TECHNOLOGY - CN111253454, 2020, A Location in patent: Paragraph 0052; 0071-0072
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[4]Current Patent Assignee: ZHEJIANG A & F UNIVERSITY - CN106905398, 2017, A Location in patent: Paragraph 0039; 0047
[5]Current Patent Assignee: JIANGSU FURUI BIO PHARMACEUTICAL - CN106432388, 2017, A Location in patent: Paragraph 0048-0050
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  • 2
  • [ 817204-32-3 ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 87 percent / aq. HOAc / 12 h / Heating 2: 100 percent / NH3 / methanol / 20 °C
Multi-step reaction with 2 steps 1: acetic acid / water / 5 h / 110 °C 2: ammonia; methanol / 30 h / 20 °C
Multi-step reaction with 2 steps 1: acetic acid / water / 90 - 105 °C 2: sodium methylate / methanol / Reflux
Multi-step reaction with 2 steps 1: acetic acid / water / 20 h / Reflux 2: ammonia; methanol / 27 h / 0 - 15 °C
Multi-step reaction with 2 steps 1.1: acetic acid / water / Reflux 2.1: N-butylamine / 45 - 50 °C 2.2: 60 - 70 °C
Multi-step reaction with 2 steps 1: water; acetic acid / Reflux 2: ammonia / methanol / 18.5 h / 0 - 20 °C
Multi-step reaction with 2 steps 1.1: acetic acid / water / 120 - 140 °C / Large scale 2.1: sodium methylate / methanol / 2 h / -10 - 20 °C / Inert atmosphere; Large scale 2.2: -10 °C / Large scale
Multi-step reaction with 2 steps 1: acetic acid / water / Reflux 2: methanol; ammonia / 0 - 20 °C

  • 3
  • [ 863329-66-2 ]
  • [ 142629-80-9 ]
  • [ 1015255-46-5 ]
YieldReaction ConditionsOperation in experiment
15.6% With N-methylimidiazole In tetrahydrofuran at 20℃;
15.6% With 1-methyl-1H-imidazole In tetrahydrofuran at 20℃; 14 Example 14: Preparation Example 5) 4 Preparation of 2,-Deoxy-2'-fluoro-2'-C-methyluridine-5'-phenyl methoxy-alanyl phosphate) Example 14: Preparation Example 5) 4 Preparation of 2,-Deoxy-2'-fluoro-2'-C-methyluridine-5'-phenyl methoxy-alanyl phosphate) Phenyl methoxyalaninyl phosphorochloridate (1 g, 6.5 eq) dissolved in 3 mL of THF was added to a mixture of 2,-Deoxy-2,-fluoro-2'-C-methyluridine (0.15 g, 1 eq) and N-methylimidazole (0.3 g, 8 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25x30x2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduce pressure to give the desired product (50.1 mg, 15.6%). 1H NMR (DMSO-d6 ) δ 1.20-1.27 (m, 6H), 3.58 (d, J=16.0 Hz, 3H), 3.75-3.92 (m, 2H), 4.015-4.379 (m, 2H), 5.54 (t, J=10.2 Hz, 1 H), 5.83-5.91 (m, 1H), 6.00-616 (m, 1 H), 7.18 (d, J=8.0 Hz, 2H), 7.22 (s, 1 H), 7.35 (t, J=4.4 Hz, 2H), 7.55 (s, 1H), 11.52 (s, 1 H); MS, m/e 502 (M+1)+.
15.6% With 1-methyl-1H-imidazole In tetrahydrofuran at 20℃; 5 Example 5 Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-phenyl methoxy-alanyl phosphate) Phenyl methoxyalaninyl phosphorochloridate (1 g, 6.5 eq) dissolved in 3 mL of THF was added to a mixture of 2'-Deoxy-2'-fluoro-2'-C-methyluridine (0.15 g, 1 eq) and N-methylimidazole (0.3 g, 8 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduce pressure to give the desired product (50.1 mg, 15.6%). 1H NMR (DMSO-d6) δ 1.20-1.27 (m, 6H), 3.58 (d, J=16.0 Hz, 3H), 3.75-3.92 (m, 2H), 4.015-4.379 (m, 2H), 5.54 (t, J=10.2 Hz, 1H), 5.83-5.91 (m, 1H), 6.00-616 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.22 (s, 1H), 7.35 (t, J=4.4 Hz, 2H), 7.55 (s, 1H), 11.52 (s, 1H); MS, m/e 502 (M+1)+.
  • 4
  • [ 863329-66-2 ]
  • [ 261910-17-2 ]
  • [ 1064684-23-6 ]
YieldReaction ConditionsOperation in experiment
With 1-methyl-1H-imidazole In tetrahydrofuran at 20℃; 6 Example 6 Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(phenyl methoxy-valyl phosphate) Phenyl methoxy-valyl phosphorochloridate (0.6 g, 3.6 eq) dissolved in 3 mL of THF was added to a mixture of 2'-Deoxy-2'-fluoro-2'-C-methyluridine (0.15 g, 1 eq) and N-methylimidazole (0.44 g, 9 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25*30*2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product (60 mg, 2096). 1H NMR (DMSO-d6) δ 0.74-0.947 (m, 6H), 1.20-1.28 (m, 3H), 1.89-1.92 (m, 1H), 3.50-3.54 (m, 1H), 3.58 (d, J=10.4 Hz, 3H), 3.72-3.95 (m, 1H), 4.03-4.05 (m, 1H), 4.23-4.43 (m, 2H), 5.56 (t, J=16.0 Hz 1H), 5.85-5.92 (m, 1H), 6.01-6.07 (m, 1H), 7.16-7.21 (m, 3H), 7.37 (t, J=8 Hz, 2H), 7.55-7.60 (m, 1H), 11.52 (s, 1H); MS, m/e 530 (M+1)+.
  • 5
  • [ 863329-66-2 ]
  • [ 1064685-41-1 ]
  • [ 1064684-24-7 ]
YieldReaction ConditionsOperation in experiment
26% With 1-methyl-1H-imidazole In tetrahydrofuran at 20℃; 7 Example 7 Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(4-bromophenyl methoxy-valyl phosphate) 4-Bromophenyl methoxy-valyl phosphorochloridate (1 g, 3.4 eq) dissolved in 3 mL of THF was added to a mixture of 2'-deoxy-2'-fluoro-2'-C-methyluridine (0.2 g, 1 eq) and N-methylimidazole (0.35 g, 6 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed reduced pressure to give the desired product (120 mg, 26%). 1H NMR (DMSO-d6) δ 0.72-0.82 (m, 6H), 1.19-1.26 (m, 3H), 1.86-1.92 (m, 1H), 3.48-3.50 (m, 1H), 3.56 (d, J=12.0 Hz, 3H), 3.72-3.89 (m, 1H), 3.96-4.03 (m, 1H), 4.22-4.37 (m, 2H), 5.54-5.60 (m, 1H), 5.85-5.91 (m, 1H), 5.98-6.13 (m, 1H), 7.15 (d, J=8.0 Hz, 2H), 7.49-7.56 (m, 3H), 11.53 (s, 1H); MS, m/e 608 (M+1)30 .
  • 6
  • [ 863329-66-2 ]
  • [ 217090-42-1 ]
  • [ 1064684-25-8 ]
YieldReaction ConditionsOperation in experiment
12% With 1-methyl-1H-imidazole In tetrahydrofuran at 20℃; 8 Example 8 Preparation of 2'-Deoxy-2'-fluoro-2'-C-methyluridine 5'-(4-bromophenyl methoxy-alanyl phosphate) 4-Bromophenyl methoxy-alanyl phosphorochloridate (0.6 g, 5 eq) dissolved in 3 mL of THF was added to a mixture of 2'-deoxy-2'-fluoro-2'-C-methyluridine (0.15 g, 1 eq)and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF with vigorous stirring at room temperature, then the reaction was stirred overnight. Solvent was removed by reduced pressure. The resulting crude product was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrile gradient elution mobile phase. The acetonitrile and water were removed under reduced pressure to give the desired product (40 mg, 12%); 1H NMR (DMSO-d6) δ 1.20-1.26 (m, 6H), 3.57 (d, J=2.8 Hz, 3H), 3.84 (s, 1H), 3.97-4.03 (m, 1H), 4.21-4.25 (m, 1H), 4.33-4.37 (m, 2H), 5.54-5.60 (m, 1H), 5.83-5.89 (m, 1H), 5.98-6.19 (m, 1H), 7.16 (t, J=10.2 Hz, 2H), 7.52-7.57 (m, 3H), 11.52 (s, 1H); MS, m/e 580(M+1)+.
  • 7
  • [ 863329-66-2 ]
  • [ 40615-36-9 ]
  • [ 1244762-79-5 ]
YieldReaction ConditionsOperation in experiment
93% With pyridine at 0 - 20℃; for 8h;
88.9% With dmap; triethylamine In ethyl acetate at 50℃; for 3h; Inert atmosphere; 1 Synthesis of 5'-O-(4,4-dimethoxytrityl)-2'-deoxy-2'-fluoro-2'-C-methyluridine: In a 250ml two-necked bottle, add 100ml of ethyl acetate,2.6 g (10 mmol) of 2'-deoxy-2'-fluoro-2'-C-methyluridine,2.0 g (20 mmol) of triethylamine and 0.2 g (2 mmol) of DMAP,Under nitrogen atmosphere, 4.4 g (13 mmol) of 4,4'-bismethoxytrityl chloride solid was added, and the reaction was stirred at 50 ° C for 3 hours. After the TLC detects the reaction,Wash the water three times (50mlx3), dry with anhydrous sodium sulfate, and spin dry the solvent.Column chromatography (dichloromethane / methanol = 30:1) to give 5.0 g5'-O-(4,4-dimethoxytrityl)-2'-C-methyluridine,The yield was 88.9%.
With pyridine In N,N-dimethyl-formamide 22.1 Example 22 Synthesis of alpha-2′-fluoro-beta-2′-methyl-3′-deoxy-5′-deuterouridine phosphoramidate Compounds In step 1, the nucleoside is treated with dimethoxytrityl chloride in pyridine and DMF. Once the reaction is determined to be complete by HPLC analysis, the volatiles were removed and residue is diluted with aq. NaHCO3 and extracted with DCM. The organic layer is concentrated in vacuo and the product (trityl protected nucleoside) is used as is in the next step. In step 2, the product (trityl protected nucleoside) is then reacted with TBDMS-chloride in DMF in presence of imidazole to give the silyl protected trityl nucleoside. In step 3, the trityl group is then removed by treating the product with trichloroacetic acid and methanol to give TBDMS-protected nucleoside after evaporation of all volatiles and purifying the product by chromatography over silica gel. In step 4 the TBDMS-protected nucleoside is treated with an oxidizing agent such as pyridinium dichromate in a mixture of organic solvents such as t-butanol and dichloromethane and an anhydride such as acetic anhydride. In step 5, the TBDMS protecting group is removed with TBAF (tetrabutylammonium fluoride) in DCM and the product is purified by chromatography and reduced with sodium borodeuteride in a combination of protic solvents such as D2O and deuterated ethanol. In step 6, the nucleoside was treated with a phosphate diester to generate the product according to the method of Ross et al., J. Org. Chem., 76, 8311 (2011). (0726) 1H NMR (400 MHz, MeOH-d4, 300 K): δ 1.21 (d, 6H), 1.34 (2d, 6H), 3.92 (m, 1H), 4.10 (m, 1H), 4.96 (m, 1H), 5.62 (d, 1H), 6.13 (d, 1H), 7.20 (m, 1H), 7.26 (m, 2H), 7.37 (m, 2H), 7.61 (d, 1H); LC-MS: 532 amu (M+1).
With pyridine In dichloromethane at 0℃; for 4h; 2-1 To a solution of compound (1-1) (1.289 g, 4.95 mmol in pyridine (6.52 mL, were added DCM (6.52 mL. The solution was cooled to 0°C. To the solution was added 4,4'-dimethoxytrityl chloride (1.846 g, 5.45 mmol). The solution was stirred at 0°C for 4 h. Methanol (0.6 mL) was added to quench the reaction. The solution was concentrated to dryness under reduced pressure and the residue was partitioned between EtOAc (65 mL) and water (7 mL). The organic solution was washed with brine (10 mL), dried over a2S04, filtered, and concentrated to give a crude compound (2-l)(3.41 g) which was used directly in next step. MS (ESI): m/e 585.25 (M+23).

  • 8
  • [ 863329-66-2 ]
  • [ 18162-48-6 ]
  • [ 1160557-97-0 ]
YieldReaction ConditionsOperation in experiment
100% In pyridine at 20℃; for 24h; 15.1 To a stirred solution of 2'-deoxy-2'-fluoro-2'-C-methyluridine (3, 81.1 g, 312 mmol) in dry pyridine (750 mL) was added drop-wise a solution of TBDMSCl (103.19 g, 685.6 mmol) in dry pyridine (500 mL) over a period of 45 min at ambient temperature. The reaction was allowed to stir at ambient temperature for 24 h. Methanol (85 mL) was added to the reaction mixture and it was allowed to stir for 10 min and then the solvents were distilled off under reduced pressure. Hot water (45C) (1 L) was added to the reaction mass and the mixture extracted with ethyl acetate (2 x 500 mL), washed with water (1 x 500 mL). The organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was distilled off and the residue obtained was co-evaporated with toluene (2 x 500 mL) to give crude 9 as a white foam. Yield = 116.9 g (quantitative). 1H NMR (CDCl3, 300 MHz): δ 0.1 (s,6H), 0.91 (s, 9H), 1.22 (d, 3H, J = 21 Hz), 2.50 (s, 2H), 3.75-4.05 (m,4H), 5.54 (d, IH, J = 9 Hz), 5.73 (s, IH), 6.0 (d, IH, J = 18 Hz), 7.81 (d, IH, J = 9 Hz), 8.57 (br, s, IH), 11.1 (s, IH).
100% With pyridine; 1-methyl-1H-imidazole at 0 - 5℃; for 3h; 4 General Procedure for Preparing 1-((2R, 3R, 4R, 5R)-5-((tert-butyldimethylsilyloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-diones (10a,b) Example 4 General Procedure for Preparing 1-((2R, 3R, 4R, 5R)-5-((tert-butyldimethylsilyloxy)methyl)-4-hydroxy-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-diones (10a,b) To a solution 1.3 g (5 mmol) of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (9a) in 10 mL of pyridine was added tert-butylchlorodimethylsilane (866 mg, 5.75 mmol) at 0-5° C. followed by an addition of 1-methylimidazole (0.399 mL, 5 mmol). The mixture was stirred for 3 h, then 3 mL of methanol was added and stirred for 1 h more. The mixture was rotovapped, dissolved in DCM, washed with 5% citric acid solution, with brine, dried over Na2SO4 and rotovapped to afford 1-((2R,3R,4R,5R)-5-((tert-butyldimethylsilyloxy)methyl)-3-fluoro-4-hydroxy-3-methyl-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (10a) with quantitative yield. LC-MS (ESI) 375 (M+H)+, 1H NMR (DMSO-d6, 400 MHz) δ: 11.51 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 6.00 (d, J=18.8 Hz, 1H), 5.73 (d, J=6.8 Hz, 1H), 5.54 (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 4.02 (dd, J1=12.0 Hz, J2=1.2 Hz, 1H), 3.89 (m, 1H), 3.80 (m, 2H), 1.27 (d, J=22.4 Hz, 3H), 0.90 (s, 9H), 0.10 (d, J=2.4 Hz, 6H).
93% With pyridine; 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere;
With pyridine; 1H-imidazole at 0 - 20℃; Inert atmosphere; 4.1.1. 5'-O-tert-Butyldimethylsilyl-N4-2',3'-O-tris-benzyloxycarbonylcytidine (3a) General procedure: To a solution of cytidine (3.60 g, 14.3 mmol) in 30 mL of anhydrous pyridine was added imidazole (1.25 g, 18.40 mmol) and tert-butyldimethylsilyl chloride (TBDMSCl, 2.40 g, 15.7 mmol) at 0 °C under a N2 atmosphere. The reaction mixture was stirred at rt for 12 h and then treated with methanol (8.0 mL). After stirring for 60 min, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc=10:1 to 1:4 v/v) to give (5.12 g, 12.5 mmol) in 97% yield. Subsequently, to a solution of protected cytidine (2.68 g, 7.50 mmol) and DMAP (5.50 g, 45.0 mmol) in 50 mL of anhydrous CH2Cl2 was added benzyl chloroformate (CbzCl, 4.76 mL, 33.74 mmol) at 0 °C under N2 atmosphere. After stirring for 72 h at rt, the reaction mixture was diluted with CH2Cl2 (200 mL) and then washed with cold 1.0 M HCl aqueous solution (50 mL) then water (100 mL). The solution was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (hexane/EtOAc=10:1 to 1:1 v/v) to give 3a (5.47 g, 7.20 mmol) in 93% yield.
With pyridine
With pyridine at 20℃; for 24h; 1-1 To a stirred solution of 2'-deoxy-2'-fluoro-2'-C-methyluridine (1-1) (5 g, 19.21 mmol.) in dry pyridine (77 mL), was added portionwise TBDMSC1 (6.37 g, 42.3 mmol.) at rt. The reaction was stirred at room temperature for 24 h. MeOH (7.77 mL, 192 mmol.) was added to the reaction mixture and it was allowed to stir for 10 min at rt. Then the solvent was removed under reduced pressure. Water (50 mL) was added to the reaction mixture. The mixture extracted with ethyl acetate (2 x 50 mL), washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, ethyl acetate was distilled off and the residue obtained was co- evaporated with toluene (twice) to give crude compound (1-2) (7.15 g, 99% yield). XH NMR (500 MHz, CD3OD) δ 8.07 (d, J= 8.0 Hz, 1H), 6.15 (d, J= 18.0 Hz, 1H), 5.65 (d, J= 8.0 Hz, 1H), 4.17 (d, J= 12.0 Hz, 1H), 4.08 - 3.90 (m, 3H), 1.38 (d, J= 22.0 Hz, 3H), 0.99 (s, 9H), 0.19 (s, 3H), 0.18 (s, 3H).

  • 9
  • [ 863329-66-2 ]
  • [ 18162-48-6 ]
  • [ 1244762-86-4 ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With pyridine; 4,4'-dimethoxytrityl chloride In dichloromethane at 0℃; Stage #2: tert-butyldimethylsilyl chloride With 1H-imidazole In dichloromethane at 20℃; Stage #3: With trifluoroacetic acid In dichloromethane at 20℃; for 2h; 1 1-[(2R,3R,4R,5R)-4-(tert-butyldimethylsilyloxy)-3-fluoro-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl]pyrimidine-2,4(1H,3H)-dione To 211 (5.0 g, 19.21 mmol) was added pyridine (30 mL) and dichloromethane (30 mL) and the solution was cooled to 0 ° C.4,4'-Dimethoxytrityl chloride (7.16 g, 21.14 mmol) was added to the solution and the mixture was stirred at 0 ° C overnight.Methanol (5 mL) was added to quench the reaction and the reaction mixture was concentrated to dryness under reduced pressure. Ethyl acetate (300 mL) and water (30 mL) were added to the residue.The organic layer was washed with brine (40 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane (100 mL).Imidazole (3.92 g, 57.5 mmol) and t-butyldimethylsilyl chloride (4.34 g, 28.8 mmol) were added to the solution.After the reaction mixture was stirred at room temperature overnight, methanol (5 mL) was added and the mixture was stirred for ten minutes. The solvent was removed under reduced pressure. Ethyl acetate (300 mL) and water (50 mL) were added to the residue.The organic layer was separated, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (0-40% ethyl acetate in hexanes)5'-O-Dimethoxytrityl-3'-oxy-t-butyldimethylsilyl intermediate product.A 1% solution of trifluoroacetic acid in dichloromethane (80 mL) was added and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was then added and stirring continued for 1 hour at room temperature. Methanol (5 mL) was added slowly and the solution stirred at room temperature for 1 hour.The pH of the solution is adjusted to 7 with aqueous ammonia. The organic layer was separated and dried over sodium sulphate. The solvent was removed by evaporation and the residue was purified by column chromatography on silica gel (0-5% methanol in dichloromethane) to give the product 212 as a white solid (3.81 g) in 53% yield %.
50% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With pyridine; 4,4'-dimethoxytrityl chloride In dichloromethane at 0℃; for 5h; Stage #2: tert-butyldimethylsilyl chloride With 1H-imidazole In dichloromethane at 20℃; for 16h; Stage #3: With water; trifluoroacetic acid In dichloromethane at 20℃; for 2h; 17.1 To a solution of 3 (10. Og, 38.43 mmol) in pyridine (50 mL) were added dichloromethane (50 mL). The solution was cooled to 0C. To the solution was added 4,4'-dimethoxytrityl chloride (14.32 g, 42.27 mmol) and the solution was stirred at 0C for 5 h. Methanol (5 mL) was added to quench the reaction. The solution was concentrated to dryness under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and water (50 mL). The organic solution was washed with brine (50 mL) and dried (sodium sulfate, 4 g). The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (100 rnL). To the solution were added imidazole (7.83 g, 115 mmol) and t-butyldimethylsilyl chloride (8.68 g, 57.6 mmol). The solution was stirred at ambient temperature for 16 h. Methanol was added to quench the reaction (5 mL) and the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and water (50 mL). The organic solution was dried (sodium sulfate, 4 g) and evaporated under reduced pressure. The residue was purifed by column chromatography (10-40% EtOAc in Hexane) to give S'-O-DMT-S'-O-tBDMS intermediate product. This is turn was treated with 1% trifluoroacetic acid in dichloromethane (200 mL). The solution was stirred at ambient temperature for Ih. Water (20 mL) was added and the solution was stirred at ambient for another Ih. Methanol (5 mL) was slowly added and the solution was stirred at ambient for another Ih. Ammonium hydroxide was added to adjust the solution pH to 7. The organic solution was separated, dried (sodium sulfate, 4 g) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1- 5% methanol in dichloromethane) to give 12 as a white solid 7.5g in 50% yield over the three steps. 1H NMR (DMSO-d6) δ (ppm) 11.48 (br s, IH, NH), 7.94 (d, 1Η, Η- 6), 6.00 (d, 1Η, Η-l '), 5.69 (d, IH, H-5), 4.06 (dd, IH, 3'-H), 3.85 (m, 2H, H-5'a, H- 4'), 3.58 ( br d, IH, H-5'b), 1.27 (d, 3 H, 2-CH3), 0.89 (s, 9H, C(CH3)3), 0.12 (s, 6Η, Si(CH^)2).
  • 10
  • [ 863329-66-2 ]
  • [ 69304-37-6 ]
  • [ 1256490-55-7 ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine; 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane In pyridine at 20℃; for 16h; Stage #2: With water; trifluoroacetic acid In tetrahydrofuran at 0℃; for 6h; 17.2 To a stirred solution of 3 in pyridine (20 mL) at 0C was added TIPDS-Cl drop-wise over a period of 15 min. The mixture was slowly allowed to warm to room temperature at which temperature it was stirred for 16 h. The pyridine was evaporated and the residue was co-evaporated with toluene (50 mL). The residue was then triturated with hexanes and the white precipitate was filtered off using a pad of Celite. The filtrate was concentrated under reduced pressure to give a foamy solid (12.97 g). The crude product (13) was redissolved in tetrahydrofuran (75mL) and was added an aqueous solution of TFA (75mL, 1:1 TF A/water) at 0C over a period of 20 min. The mixture was stirred at this temperature for 6 h. TLC indicated -5% of starting material. The reaction mixture was quenched with saturated aqueous NaHCO3 until pH 8 and then extracted with ethyl acetate. The combined organic extract was washed with water, dried and concentrated to give white crystalline solid. Further trituration of the solid with hexanes (30 mL) gave white solid which was filtered and dried under high vacuum to give 3d (10.1 g, 84 % yield over 2 steps). 1H NMR (400 MHz, CDCl3): δ 8.83 (bs, IH), 7.94 (bd, J-6.0Hz, IH), 6.10(bd, J=18.4Hz, IH), 5.71 (d, J=8.2Hz, IH), 4.43 (bs, IH), 4.36 (dd, J-22.6, 9.0Hz, IH), 4.27 (bs, IH), 4.10(d, J=I 3.2Hz, IH), 4.03 (d, J=9.2Hz, IH), 3.92 (d, J=I 3.2Hz, IH), 1.39 (d, J=22.0Hz, 3H), 1.11-0.92 (m, 28H).
  • 11
  • [ 863329-66-2 ]
  • [ 1256490-49-9 ]
  • [ 1256490-31-9 ]
  • [ 1190307-88-0 ]
  • [ 1190308-01-0 ]
YieldReaction ConditionsOperation in experiment
To a stirred solution of l-((2R,3R,4R,5R)-3-Fluoro-4-hydroxy-5- hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)- 1 H-pyrimidine-2,4-dione (130mg, 0.5mmol) in dry THF (1.5mL) was added a 1.0M solution of tert-butylmagnesium chloride (1.05mL, 1.05mmol, 2.1 equiv)) at room temperature over a period of 5min. After 30min, a solution of (S)-2-[(4-nitro-phenoxy)-phenoxy-phosphorylamino] propionic acid isopropyl ester (1:1 mixture of isomers, 408mg, lmmol) in THF (1.5mL) was added drop-wise over a period of 5min. The mixture was allowed to stir at room temperature for 48h and then quenched with saturated aqueous NH4Cl (2OmL). The mixture was partitioned between ethyl acetate (5OmL) and water (2OmL). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow residue. Column chromatography of the residue using 0-2% MeOH/dichloromethane gradient gave a white foamy solid (125mg, 47% yield, mixture of Sp-4/Rp-4 in about 3.05:1.0 ratio
  • 12
  • [ 863329-66-2 ]
  • [ 1256490-52-4 ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
90.5% (1) Under the protection of nitrogen, 10 g of 1-((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2 was sequentially added to the reactor. -Yl) pyrimidine-2,4 (1H, 3H) -dione (compound 1)2.44 g of anhydrous lithium chloride and 140 mL of tetrahydrofuran, cool and keep at 0 to 5 C, and dropwise add 22.6 mL of 1.7 mol / L tert-butyl magnesium chloride under stirring,After dripping, stir at 0 ~ 5 for 1h.Cool and keep at -10 ~ -5 ,20.9 g of isopropyl (S)-(perfluorophenoxy) (phenoxy) phosphate) -L-alanine was added dropwise with stirring.(Compound 2) in tetrahydrofuran,After dripping, the reaction was stirred at -10 ~ -5 for 24h.Add another 5.6mL of 1.7mol / L tert-butylmagnesium chloride, and continue holding the reaction for 6 ~ 8 hours.If HPLC detects the raw material 1-((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrimidine-2,4 (1H , 3H) -dione (compound 1) is greater than 2.5%,Then continue to add 5.6mL of 1.7mol / L tert-butylmagnesium chloride until the raw material 1-((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3- Methyltetrahydrofuran-2-yl) pyrimidine-2,4 (1H, 3H) -dione (compound 1) remaining content is less than 2.5%,A reaction solution was obtained.(2) The reaction solution obtained in step (2) was quenched with ethyl acetate hydrochloride at a temperature below 10 C, and the pH of the system was adjusted to 7 ~ 8. The organic phase was concentrated under reduced pressure at 40 C to remove tetrahydrofuran, and 100 mL of ethyl acetate was added. The organic phase was washed once with 70 mL of 1 mol / L hydrochloric acid, and the organic phase was adjusted to pH = 6.5 ~ 7.5 with 40 mL of a 10% aqueous sodium hydrogen carbonate solution. The aqueous phase was separated, and the organic phase was distilled under reduced pressure to a distillate-free state and 20 mL was added. Methyl tert-butyl ether was dissolved.(3) Pour the lysate obtained in step (2) onto a pre-coated silica gel column (silica gel 50g, R = 6cm, silica gel column height to diameter ratio 0.8: 1), and then use 300mL ethyl acetate / The mixed solution of n-heptane (1: 5 by volume of ethyl acetate to n-heptane) was washed with 750 mL of ethyl acetate, and the ethyl acetate portion was collected.(4) The ethyl acetate obtained in step (3) was concentrated under reduced pressure to remove the ethyl acetate, cooled to an internal temperature of 35 to 40 C, and 140 mL of dichloromethane was added to dissolve to obtain a homogeneous solution, and then stirred and crystallized at 30 to 35 C. After 4 ~ 6 hours, the program is cooled down to 0 ~ 5 and kept at 0 ~ 5 for 1 ~ 2 hours, then filtered, the filter cake is washed with cold dichloromethane solvent, and the cake is dried under vacuum at 40 until the weight loss is less than 0.5%. To get the product white powder 18.1g, The molar yield is 90.5%, the product is easy to absorb moisture,After drying, it should be sealed and stored immediately.Pay attention to moisture.
61.4% With tert-butylmagnesium chloride; In tetrahydrofuran; at -20 - 20℃;Inert atmosphere; [0060] Sofosbuvir form 1 was prepared according to the following procedure: (0074) [0061] l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (100 g) along with L-Alanine, N- [(S)-(2,3,4,5,6-pentafluorophenoxy) phenoxyphosphinyl]-, 1-methylethyl ester (209 g) was taken in a four necked round bottomed flask followed by addition of THF (1.5 L) at 25-30 C under nitrogen atmosphere. Reaction mixture was subsequently cooled to -20 C. To the stirred solution was added dropwise 1.7 M t-butylmagnesium chloride (248 mL) in THF during 60-90 min maintaining the temperature of the reaction between -20 to -10 C. (0075) Reaction was then gradually warmed to 15-20C and stirred for another 5-20 h. After the completion of the reaction, 15% aq. ammonium chloride solution (200 mL) was added dropwise at 0 to 10C to quench the reaction. THF was removed under vacuum and residue was dissolved in dichloromethane (1 L) and washed with 15% aq. ammonium chloride (1 L). Organic layer was then washed with 6% aq. sodium bicarbonate solution (2 X 1 L) and finally with 5% brine solution (1 L). Organic layer was filtered through celite and concentrated under vacuum. Dichloromethane/ di-isopropyl ether (6:3, 900 mL) was added to the residue and the slurry was stirred for 10-12 h, filtered. The white solid was washed with 1 : 1 mixture of dichloromethane/ di-isopropyl ether (400 mL). Wet cake thus obtained was again suspended in dicholoromethane (1 L). The slurry was stirred for 10-12 h at 20-25C. Slurry was filtered and washed with dichloromethane (2 X 200 mL) to afford 125 g (61.4 %) of sofosbuvir (Form-1). [0062] Amorphous Sofosbuvir may be prepared according to the following procedure: (0076) A 100 ml round bottom flask was charged with Sofosbuvir form 1 (5 g, 1 eq, 9.44 mmol) and acetonitrile (ACN, 50 ml, 10 V). The mixture was heated to reflux to obtain a clear solution. The solvent was then evaporated at room temperature to give Sofosbuvir as a white solid. The obtained solid was dried at the oven under reduced pressure over night at room temperature to provide amorphous form of Sofosbuvir.
To a stirred solution of l-((2R,3R,4R,5R)-3-Fluoro-4-hydroxy-5- hydroxymethyl-3 -methyl-tetrahydro-furan-2-yl)- 1 H-pyrimidine-2,4-dione (3 , 2.6g, 1 Ommol) in dry THF (5OmL) was added a 1.7M solution of tert-butylmagnesium chloride (12.4mL, 21mmol, 2.1 equiv)) at room temperature over a period of 15min. After 30min, a solution of crude racemic (2-[(2,3>;4,5,6-pentafluoro phenoxy)- phenoxy-phosphorylamino] propionic acid isopropyl ester (4.08g, 1 Ommol) in THF (15mL) was added drop wise over a period of lOmin. The mixture was allowed to stir at room temperature for 72h. TLC co-spot with authentic product showed around 40-50% of the desired product had formed compared to the starting nucleoside.
In the reaction flask, in under oxygen-free conditions, adding 12g intermediate type 2-5,120 ml tetrahydrofuran, stirring, lower the temperature to -30 C, dropwise 53.2g1 . 7M tert-butyl magnesium chloride; the drop finishes, stirring for 1 hour, then temperature to -10 C, dropwise 21.3gN-[ (S) - (2, 3, 4, 5, 6-penta fluorophenoxy) phenoxy phosphoryl]-L-alanine isopropyl ester of 100 ml tetrahydrofuran solution; the drop finishes, at -10 C reaction under 1 hour, then heating to room temperature reaction, TLC monitoring reaction. After the reaction, cooling to 0 C, and begin to drop and hydrochloric acid/water (50 ml/300 ml) quenching the reaction; reducing pressure and evaporating thf, then adding 200 ml diethyl ether, stirring the liquid, aqueous layer with ethyl ether (50 ml × 3) extraction, combined with the phase, with saturated sodium bicarbonate solution, saturated sodium chloride, dried anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to obtain 19.7g crude oily substance. For crude oily substance 5 times dichloromethane refining, shall be 13.5g white solid product
27 g 1) The 2'-deoxy-2'-fluoro-2'-C-methoxymethyl-2'-deoxy-2'-deoxy-(20 mg) was suspended in 300 ml of anhydrous tetrahydrofuran, and a suspension thereof was prepared. Then, 161 ml of a 1M solution of t-butylmagnesium chloride (tBuMgCl) in tetrahydrofuran was added dropwise over 1 hour. After completion of the dropwise addition, The reaction mixture was cooled to 5 C and a solution of 42 g of compound M (SP / RPSl: 1) dissolved in 200 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -5 C for 0.5 h, then warmed to 20 C, stirred for 0.5 h, Lh drop finished, stirring at 5 C for 20h, TLC detection to the reaction is complete;2) The reaction mixture was cooled to -5 C and 80 ml of 2N aqueous hydrochloric acid was added dropwise. The mixture was warmed to room temperature with stirring. After removing most of the tetrahydrofuran under reduced pressure, the distillation residue was transferred to a separatory funnel with 400 ml of toluene, Taking organic layer;3) The organic layer was washed with 1N hydrochloric acid aqueous solution (2 x 40 ml), water (40 ml), 5% sodium carbonate aqueous solution (4 x 40 ml), water (40 ml) and saturated brine (40 ml), and then dried over anhydrous sulfuric acid After drying with sodium, the solvent was evaporated under reduced pressure, 80 ml of methylene chloride was added to the residue, and the mixture was stirred at room temperature for 20 hours. The filtrate was filtered under reduced pressure, and the cake was washed with a mixture of tert-butyl methyl ether and methylene chloride 1, v / v) and dried to obtain crude GS7851;4) The GS7851 crude product was dissolved in 200ml of methylene chloride and stirred for 20h at room temperature. The filter cake was washed with 20ml of cold methylene chloride and dried to give pure GS7851 (SP / RP 1: 1) as a white solid.
68 g In the reaction flask, under anhydrous and anaerobic conditions,Add 48g (2'R)-2'-deoxy-2'-fluoro-2'-methylurea, 300mL tetrahydrofuran, stir,The temperature was lowered to -30 C, and 106 g of 2.0 M isopropylmagnesium chloride was added dropwise; after the dropwise addition, the reaction was stirred for 1 hour.Then heat up to -10 C,A solution of 99 g of <strong>[1256490-52-4]N-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester</strong> in 200 mL of tetrahydrofuran was added dropwise;The reaction was carried out at -10 C for 1 hour.The temperature was then raised to room temperature and the reaction was monitored by TLC.After the reaction was completed, the temperature was lowered to 0 C, and concentrated hydrochloric acid/water (100 mL/300 mL) was added dropwise to quench the reaction;The tetrahydrofuran was distilled off under reduced pressure, then 300 mL of diethyl ether was added, and the mixture was stirred. The aqueous layer was extracted with diethyl ether (200 mL×3), and the organic phase was combined.Saturated sodium chloride solution with saturated sodium bicarbonate solution,Dry over anhydrous sodium sulfate, suction filtration, and concentrated under reduced pressure.75 g of crude oil was obtained. Add 3 times of dichloromethane to the crude oil and heat to dissolve.Then, the temperature is lowered to 0-10 C and stirred for crystallization.Filtered and dried to obtain 68 g of sofosbuvir crude.

  • 13
  • [ 863329-66-2 ]
  • [ 1256490-48-8 ]
  • [ 1190307-88-0 ]
  • [ 1190308-01-0 ]
  • 14
  • [ 863329-66-2 ]
  • [ 1256490-31-9 ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
67.6% At room temperature,Add (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (1.30G, 5mol) and anhydrous tetrahydrofuran (30 ml) to the reaction flask, stir and dissolve, and add tert-butylmagnesium chloride dropwise. (2.28 g, 24 mol) in tetrahydrofuran (5 ml). After the dropwise addition, the reaction was stirred for 1 hour. Continue dropping of isopropyl (2S)-2-(((4-ylphenoxy)phenoxyphosphoryl)amino)propionate(4.90 g, 12 mol) in tetrahydrofuran (20 ml). After stirring for 48 hours at room temperature, the reaction was complete by TLC. The reaction solution was poured into 10 ml of saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the resulting oil was distilled under reduced pressure by silica gel column chromatography (dichloromethane/methanol= 10/1) and recrystallization from methyl tert-butyl ether/n-pentane gave 1.76 g of sofosbuvir as a white solid with a yield of 67.6%
Compound (S)-8To a dry, argon purged round-bottom flask were added compound 7 (prepared according to J. Med. Chem., 2005, 48, 5504-5508, 100 mg, 0.38 mmol), anhydrous THF (3 mL) and anhydrous NMP (1 mL). The slurry was stirred for 10 min. and the flask was place in a water bath at room temperature. i-Butylmagnesium chloride in THF (1.0 M, 0.76 mL) was dropwise added, and the mixture was stirred for an additional 10 min. A solution of (S)-C (313 mg, 0.76 mmol) in THF (2 mL) was then added. The flask was place in a heating oil bath pre-set at 55 C and the mixture was stirred until compound 7 was almost consumed. After ~2.5 h, the reaction mixture was cooled to room temperature, and methanol (1 mL) was added. Solvents were removed under reduced pressure and the residue was purified by RP-HPLC followed by silica gel column chromatography, affording (S)-8 (130 mg, 65%). 1H NMR (400 MHz, CDC13): 5 8.51 (brs, IH), 7.46 (d, IH), 7.2-7.4 (m, 5H), 6.28 (d, IH), 5.70 (dd, IH), 5.01 (m, IH), 4.49 (m, 2H), 3.8-4.1 (m, 4H), 1.41 (d, 3H), 1.35 (d, 3H), 1.24 (d, 6H). 31P NMR (162.1 MHz, CDC13): 5 3.70 (s). MS = 530.0 (M + H+), 528.0 (M - H+). Chiral HPLC retention time (Chiralpak AS-H, 250 x 4.6 mm 5 micron, 100% CH3CN, 1 mL/min flow rate); 6.5 min vs. 5.2 min for the R-isomer). Using the general procedures described for the preparation of Compound (S)- C or Compound (R)-C, Compounds 10-24 ma be re are .
  • 15
  • [ 863329-66-2 ]
  • [ 1334513-02-8 ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
86% With 2,6-dimethylpyridine; dimethylaluminum chloride; In tetrahydrofuran; hexane; at 0 - 45℃; for 20h; A solution of Int-8a (4.68 g, 18.0 mmol, made using the methods described in US Patent No. 8,906,880) and Int-8b (9.79 g, 21.60 mmol, made using the methods described in International Publication No. WO 2014/062596 ) in THF (70.3 mL) was cooled to 0 C and to the cooled solution was added dimethylaluminum chloride as a 1M solution in hexanes (10.00 mL, 9.00 mmol, 9 mL) followed by 2,6-lutidine (2.096 mL, 18.00 mmol). The reaction mixture was allowed to warm to room temperature then stir at that temperature for 16 hours, at which time the reaction appears to have reached 85% conversion with a 38: 1 dr and 41 : 1 mono:bis ratio. The reaction mixture was then heated to 45 C and allowed to stir at this temperature for 4 hours. The reaction mixture was then diluted with isopropyl acetate (10 vol) and quenched with 30% aqueous tartaric acid (10 vol). The reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed sequentially with 30% aqueous tartaric acid (5 vol) and brine (5 vol), the dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified using isco chromatography (0-8% methanol in dichloromethane) and the collected product was dried in vacuo. The product was then triturated with dichloromethane/hexanes and concentrated in vacuo and the product was dried overnight under vacuum to provide Compound A as a white, amorphous solid (8.18 g, 86% yield). HPLC indicates a 25: 1 diastereomeric ratio. XH NMR (500 MHz, OMSO-d6): delta 11.53 (s, 1H), 7.57-7.56 (m, 1H), 7.39-7.36 (m, 2H), 7.23-7.17 (m, 3H), 6.08-6.03 (m, 2H), 5.86 (m, 1H), 5.54 (d, J= 10Hz, 1H), 4.88-4.83 (m, 1H), 4.38-4.35 (m, 1H), 4.25-4.23 (m, 1H), 4.02-3.99 (m, 1H), 3.85-3.78 (m, 2H), 1.27-1.22 (m, 6H), 1.16 (d, J= 5.0 Hz, 6H).
83.3% With tert-butylmagnesium chloride; In tetrahydrofuran; water; at -5 - 5℃; To the reaction flask were added 10.0 g of compound 2, 100 g of tetrahydrofuran,761 mg of water, Cool to -5 C. Add 1.7M47.8 mL of tert-butylmagnesium chloride solution,22.6 g of a solution of Compound 3 in tetrahydrofuran (100 g) was added dropwise. And then reacted at 5 C., the reaction was stopped by HPLC when the content of sofosbuvir no longer increased. To the reaction mixture was added 2mol.L-1 dilute hydrochloric acid 40g quenched the reaction, extracted with 200g of ethyl acetate, points to the water phase; thereThe machine phase was washed three times with 15g of 8% sodium carbonate solution. The combined aqueous sodium carbonate phases were added with 50g of ethyl acetate for extraction. The combined organic phases were washed with 30g brine and evaporated to dryness under reduced pressure. 100g of dichloromethane was added and the crystals were filtered and dried to obtain 16.9g of pure sofosbuvir. Purity: 99.57%, Yield: 83.3%.
68% Under nitrogen, 50 g of (2'R) -2'-deoxy-2'-fluoro-2'-methylureridine obtained in Example 2 was added to the reaction flask, and 15 times by volume of the reaction flask Anhydrous THF, the reaction solution was cooled to -5 C. To the reaction solution was added 2.5 eq of t-BuMgCl. The reaction mixture was stirred at 0 C for 1 hour and then raised to 20 C. The mixture was stirred for 2 hours, Then, the reaction solution was cooled to about 0 C, and N - [(S) - (2,3,4,5,6-pentafluorophenoxy) phenoxyphosphoryl] -L-C was added to the reaction solution Isopropyl acetate (1.2 eq) in THF, and the reaction solution was added at 5 C to 7 C for about 20 hours. The reaction solution was cooled to 0 C and quenched by the addition of 2N HCl solution. The reaction was then quenched by adding 25 volumes of toluene to the reaction solution. The organic phases were washed with 1N HCl solution, 5% NaCO solution, saturated NaCl The solution was washed with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to obtain the crude product of cofloxacin. The purity was 99.3% and the SF-P content was 0.12%.(3 times the volume / 3 times volume) at room temperature for 4-6 hours, filtered and the filter cake was dried in vacuo to a constant weight to give the crude product which was purified by 30 volumes of DCM at atmospheric pressure After crystallization, the finished product of the product is the product of cordifluoride, the yield: 68%, purity 99.9%, SF-P content of 0.01%
53% To a flask provided with mechanical stirrer, reflux condenser, thermometer and under nitrogen atmosphere is added 1 -((2ft,3ft,4ft,5ft)-3-fluoro-4-hydroxy-5- (hydroxymethyl)-3-methyltetrahydrofuran-2-il)pyrimidin-2,4(1 H,3H)-dione (B) (10.0 g, 38.4 mmol) and tetrahydrofuran (140 imL). To the solution thus obtained and cooled to between -10 and -5 C is added /'so-propylmagnesium chloride complex 1 :1 with lithium chloride (1 .3 M in THF, 65 imL, 84.5 mmol), keeping the temperature below -5 C. When the addition is complete the reaction mixture is stirred between 0 and 5 C for 2 hours and a solution of the product of example 8 (23.5 g, 51 .9 mmol) in tetrahydrofuran (106 mL) is added over about 1 hour keeping the temperature below -5 C. Once the conversion is complete (after about 24 hours), the reaction mixture is poured, keeping the temperature below 10 ^, on a mixture of /'so-propyl acetate (120 mL), water (50 mL) and acetic acid (5 mL) cooled to 0-5 C. It is heated to 20-25 C, then the phases are separated, the organic phase is concentrated under vacuum to residue, then /'so-propyl acetate (120 mL) is added and the organic phase is washed with a 5% sodium carbonate solution and with water. The organic phase is concentrated to residue moving the residual solvents by co-evaporation with dichloromethane. The analysis of the three HPLC main peaks shows the following composition: 1 .1 ) and 95.1 % Sofosbuvir. The residue is crystallized by dichloromethane. It is filtered, washed with dichloromethane and dried to 40 C under vacuum, giving 10.8 g (53% yield) of product with a diastereomeric ratio of Sp:flp = 99.9:0.1 .
27 g In anhydrous, anaerobic, _5 C, stirring conditions,20 g of 2'-deoxy-2'-fluoro-2'-C-methyluridine obtained in Control 3 was suspended in 300 ml of anhydrous tetrahydrofuran to give a suspension, 1M t-butyl magnesium chloride ( BuMgCl) in tetrahydrofuran 161ml, drip completed within 1h; After adding dropwise, the mixture was stirred at -5 C for 0.5 h, the temperature was raised to 20 C, and the reaction mixture was stirred for 0.5 h. The reaction mixture was cooled to a temperature of 40 C and the temperature of the reaction mixture was reduced 5 C, dropwise 42g of compound XI (pure SP) dissolved in 200ml of tetrahydrofuran solution, dripping in lh, stirring at 5 C for 20h, TLC after the reaction to complete;2) The reaction mixture was cooled to -5 C, 80 ml of a 2N aqueous solution of hydrochloric acid was added dropwise, stirred, and allowed to warm to room temperature,After removing most of the tetrahydrofuran under reduced pressure,The distillation residue was transferred to a separatory funnel with 400 ml of toluene, and the organic layer was taken;3) The organic layer was washed successively with 1 N aqueous hydrochloric acid (2 x 40 ml), water (40 ml)5% aqueous sodium carbonate solution (4 x 40 ml), water(40 ml) and saturated brine (40 ml), and then dried over anhydrous sodium sulfate.The solvent was removed by distillation under reduced pressure, and the residue was distilled in a rotary evaporator80ml methylene chloride was added to the residue, stirred at room temperature for 20h, suction filtered under reduced pressure,The filter cake was t-butyl methyl ether and dichloromethane(1: 1, v / v), washed with water (2x40ml), dried,The crude product of GS7977;[0118] 4) The crude GS7977 obtained in step 3) was thermally dissolved in 200 ml of dichloromethane,Stirring at room temperature for 20h, vacuum filtration, filter cake washed with 20ml cold dichloromethane, dry,A pure GS7977 (pure SP) 27g, was a white solid.
48 g With tert-butylmagnesium chloride; In tetrahydrofuran; acetonitrile; at 10 - 20℃;Inert atmosphere; <strong>[1334513-02-8](S)-2-[(S)-(2,3,4,5,6-pentafluoro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester</strong> (100 g) obtained by following example- 1 or example-6 was charged to a solution of (2'R)-2'-Deoxy-2-fluoro-2'-methyluridine (40 g) in acetonitrile (250 mL) at 10C to 20C under nitrogen atmosphere. Solution of tert-butyl magnesium chloride (40 gm) in tetrahydrofuran (200 mL) was added at 10C to 20C and the reaction mass was stirred for 3-5 hours. Solution of ammomium chloride (20 g) in water was added at 10C to 20C. After completion of reaction, organic layer was separated and distilled under reduced pressure. MDC (130 ml) and diisopropyl ether (260 ml) were added to the residue and reaction mass was stirred for five hours. The reaction mixture was filtered and dried to get (Sp)-isomer of Sofosbuvir (48 g).

  • 16
  • [ 863329-66-2 ]
  • [ 1365255-67-9 ]
  • [ 1365634-52-1 ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine In tetrahydrofuran at 80℃; for 18h; Inert atmosphere; 5 2'-Deoxy-2'-fluoro-2'-methyluridine (200 mg, 0.62 mmol) was suspended in dry THF (20 mL) under N2. A solution of 2b in dry THF (3 mL, 3 mmol), DMAP (4-dimethylaminopyridine) (100 mg, 0.9 mmol) and triethylamine (1 mL, 7 mmol) were added at RT. The reaction was stirred at 80° C. for 18 hrs. The solvents were removed, and the residue was purified by column and RP HPLC (HCOOH system) to give 3c as a white solid (3.5 mg). 1H NMR (CDCl3) δ 8.49, 8.31 (m, 1H), 7.49, 7.43 (2d, J=8.0 Hz, 1H), 7.31, 7.26 (m, 2H), 7.19, 7.11 (m, 3H), 6.17, 6.11 (2d, J=7.2 Hz, 1H), 5.62, 5.53 (2d, 1H), 4.99, 4.93 (m, 1H), 4.54, 4.27 (m, 2H), 4.08, 4.02 (m, 3H), 3.89, 3.83 (m, 1H), 1.36, 1.22 (m, 6H), 1.20, 1.12 (m, 6H). 31P NMR (CDCl3) δ 68.08, 67.05. LCMS m/z 545.8 (MK).
  • 17
  • [ 863329-66-2 ]
  • [ 18162-48-6 ]
  • [ 1393526-40-3 ]
YieldReaction ConditionsOperation in experiment
57% With 1H-imidazole; dmap In dichloromethane for 18h; 140 A stirred suspension of nucleoside (190mg, 0.73mmol) in dichioromethane (14.6mL, .05M) was charged sequentially with DMAP (89mg, 0.73mmol), imidazole (124mg, 1 .83mmol),and TBSC1 (242mg, 1.6 lmmol) and was stirred overnight. After 1 8h reaction wasconcentrated, diluted in ether and filtered. The liqueur was concentrated and purified bysilica gel chromatography 5-50% ethyl acetate in hexanes to provide 200mg (5 7%) of desired bis TBS nucleoside. ‘H NMR (400 MHz, Chloroform-d) ö 7.89 (d, J 8.1 Hz, 1H), 6.18 (d, J = 17.8 Hz, 1H), 5.70 (d, J= 8.1 Hz, 1H), 4.17- 3.90 (m, 3H), 3.87 - 3.64 (m, 1H), 1.31 (d, J= 21.7 Hz, 3H), 0.90 (d, J= 10.2 Hz, 18H), 0.10 (s, 12H).
57% With 1H-imidazole; dmap In dichloromethane 141 A stirred suspension of nucleoside (190mg, 0.73mmol) in dichloromethane (14.6mL, .05M) was charged sequentially with DMAP (89mg, 0.73mmol), imidazole (124mg, 1.83mmol), and TBSCl (242mg, 1.61mmol) and was stirred overnight. After 18h reaction was concentrated, diluted in ether and filtered. The liqueur was concentrated and purified by silica gel chromatography 5-50% ethyl acetate in hexanes to provide 200mg (57%) of desired bis TBS nucleoside.1H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.1 Hz, 1H), 6.18 (d, J = 17.8 Hz, 1H), 5.70 (d, J = 8.1 Hz, 1H), 4.17- 3.90 (m, 3H), 3.87- 3.64 (m, 1H), 1.31 (d, J = 21.7 Hz, 3H), 0.90 (d, J = 10.2 Hz, 18H), 0.10 (s, 12H).
1.27 g With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere;
With 1H-imidazole In N,N-dimethyl-formamide at 50℃; for 6h; 1.1 Step 1: (2S, 3R, 4R, 5R) -4 - ((tert-butyldimethylsilyl) oxy) -5 - ((tert-butyldimethylsilyl) ) -3-fluoro-3-methyltetrahydrofuran-2-yl) pyrimidine-2,4 (1H, 3H) -dione (SF-2) At room temperature,To 1 - ((3R) -3- fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl-tetrahydrofuran-2-yl) pyrimidine -2,4 (1H, 3H) - dione (the SF- 1) (10.4 g, 40 mmol)And imidazole (8.2 g, 120 mmol)Of DMF solution (200 mL)Was slowly added dropwise TBSCl (9.0 g, 60 mmol)Of DMF solution (25 mL).The reaction was stirred at 50 ° C for 6 h,TLC shows that after completion of the reaction,Cooled to room temperature, add water 150mL extraction reaction,EA extraction (100 mL x 4).The combined organic phases were dried over anhydrous Na2SO4,Evaporated in vacuo to give the crude title compound 20g about SF-2 as a white solid,No need to go directly to the next step.
11 g With 1H-imidazole In N,N-dimethyl-formamide at 20℃; 1.1 Step (1) Synthesis of Compound PA2001-2 6.0 g (23.07 mmol) of compound PA2001-1 was added into a 250 mL eggplant-shaped flask to which 60 mL of DMF was added and stirred for complete dissolution. 9.4 g (138.46 mmol) of imidazole was added to the reaction system and dissolved under stirring. Then 13.85 g (92.30 mmol) of TBSCI was added, and the reaction mixture was stirred at room temperature overnight. When the compound PA2001-1 was confirmed by thin layer chromatography (TLC) (a mixture of PE and EA in a ratio of 2:1 was used as the mobile phase) to be absent, the reaction mixture was diluted with 50 mL of water and extracted three times with EA each for 150 mL. The three organic phases were combined and evaporated under rotation to remove the solvent. The resulting product was purified by column chromatography with an eluent of PE and EA at a volume ratio of 5:1 to obtain 11 g of a white solid product.
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Inert atmosphere;

  • 18
  • [ 863329-66-2 ]
  • [ 23429-44-9 ]
  • C30H29FN2O5 [ No CAS ]
  • 19
  • [ 863329-66-2 ]
  • [ 1365257-00-6 ]
YieldReaction ConditionsOperation in experiment
94% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With 1H-imidazole; triphenylphosphine In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran at 20℃; for 18.5h; Inert atmosphere; Preparation 1. Preparation of intermediate chiral l-((2R,3R,4R,5S)-3-fluoro-4-hydroxy-5- (iodomethyl)-3-methyl-tetrahyd rofuran-2-yl)pyrimidine-2,4(lH,3H)-dione Preparation 1. Preparation of intermediate chiral l-((2R,3R,4R,5S)-3-fluoro-4-hydroxy-5- (iodomethyl)-3-methyl-tetrahyd rofuran-2-yl)pyrimidine-2,4(lH,3H)-dione M.W. 370.12 C10H12FIN2O4 Chiral l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro- furan-2-yl)-lH-pyrimidine-2,4-dione (6.14 g, 23.6 mmol), ΡΡ1 (9 g, 34.4 mmol), imidazole (2.4 g, 34.4 mmol) and dry THF (100 mL) were added into a 3-neck flask bottle (500 mL), the mixture was stirred at 20 °C under nitrogen atmosphere for 20 min. Then I2 (6.6 g, 26 mmol) dissolved in dry THF (100 mL) was added into the mixture dropwise at 20 °C during 30 min, after addition, the whole mixture was stirred at 20 °C under nitrogen atmosphere for 18 hrs. TLC showed that the SM was consumed, then water (50 mL) was added into it, the mixture was extracted by EA (150 mL><3), organic layer was washed with brine, dried over Na2S04, removed solvent by reduced pressure, residue was purified by silica gel chromatography column (DCM : MeOH = 100 : 1 to 50 : 1) to afford the title compound as a white solid (8.2 g, 94%). LC-MS (M+H) + = 371.0
85% With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 12h; 12 Example 12 To a solution of 25-1 (260 mg, 1 mmol), PPh3 (780 mg, 3 mmol) and pyridine (0.5 mL) in anhydrous THF (8 mL) were added I2 (504 mg, 2 mmol) at R.T., and the mixture was stirred at R.T. for 12 h. The mixture was diluted with EtOAc and washed with 1M HCl solution. The organic layer was dried over Na2SO4, filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 25-2 (190 mg, 85%) as a white solid.
85% With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 12h; 13 Compound 15 To a solution of 15-1 (260 mg, 1 mmol), PPh3 (780 mg, 3 mmol) and pyridine (0.5 mL) in anhydrous THF (8 mL) were added I2 (504 mg, 2 mmol) at RT, and the mixture was stirred at RT for 12 h. The mixture was diluted with EtOAc and washed with 1M HCl solution. The organic layer was dried over Na2SO4, filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 15-2 (190 mg, 85%) as a white solid
85% With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 12h; 13 To a solution of 15-1 (260mg, 1 mmol), PPh3 (780 mg, 3 mmol) and pyridine (0.5 mE) in anhydrous THF (8 mE) were added 12 (504 mg, 2 mmol) at RT, and the mixture was stirred at RT for 12 h. The mixture was diluted with EtOAc and washed with 1 M HC1 solution. The organic layer was dried over Na2SO4, filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOR in DCM) to give 15-2 (190 mg, 85%) as a white solid.
85% With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 12h; 13 Example 13 Compound 15 To a solution of 15-1 (260 mg, 1 mmol), PPh3 (780 mg, 3 mmol) and pyridine (0.5 mL) in anhydrous THF (8 mL) were added I2 (504 mg, 2 mmol) at RT, and the mixture was stirred at RT for 12 h. The mixture was diluted with EtOAc and washed with 1M HCl solution. The organic layer was dried over Na2SO4, filtered and concentrated at low pressure. The residue was purified by silica gel column (5% MeOH in DCM) to give 15-2 (190 mg, 85%) as a white solid.
72.4% With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 14h; 38.1 To a stirred suspension of compound 10-1 (1.46 g, 5.62 mmol), PPh3 (4.413 g, 16.84 mmol) and pyridine (5 mL) in anhydrous THF (40 mL) was added dropwise a solution of I2 (2.852 g, 11.23 mmol) in THF (20 mL) at 0° C. After addition, the mixture was warmed to R.T. and stirred for 14 hours. The solution was quenched with saturated aqueous Na2S2O3 (100 mL) and extracted with EA (100 mL 3 times). The organic layer was dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (DCM/MeOH=100:1 to 50:1) to afford compound 10-2 as a white solid (1.51 g, 72.4%).
51% With pyridine; iodine; triphenylphosphine In tetrahydrofuran at 20℃;
With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 10 - 20℃; for 21h; Large scale; 1.1.i Step 1: Preparation of 1-[(2R,3R,4R)-3-fluoro-4-hydroxy-3-methyl-5-methylideneoxolan-2-yl]-1,2,3,4-tetrahydropyrimidine-2,4-dione 2 0148] Step (i): To a stirred solution of 1-[(2R,3R,4R,5S)-3-fluoro-4-hydroxy-3-methyloxolan-2-yl]-1,2,3,4-tetrahydropyrimidine-2,4-dione 1 (2602g, 10.00 mol, 1 eq), PPh3 (3410 g, 13.00 mol,1.30 eq) and imidazole (885.0g, 13.00mol, 1.30eq) in THF (25 L) was added iodine (2665 g,10.50 mol, 1.05 eq) in portions during a period of 1 h while keeping inner temperature between10 °C-20 °C. The stirred reaction mixture was allowed to warm to ambient temperature for 20 h.The suspension was filtered and the filtrate was concentrated to give the crude product as a lightyellow oil. The residue was suspended in methanol (8.0 L), the solid was collected and washedwith petroleum ether (8 L), dried to give 3430 g of 1-[(2R,3R,4R,5S)-3-fluoro-4-hydroxy-5-(iodomethyl)-3-methyloxolan-2-yl]-1,2,3,4-tetrahydropyrimidine-2,4-dione (92.67%) as a whitesolid. 1HNMR (DMSO-d6,400MHz) OH 11.52 (s,1H), 7.61-7.63 (d, 1H), 5.91-6.05 (m, 2H),5.675.69 (d, J =20HZ, 1H), 4.06-4.10 (m, 1H), 3.77-3.80 (m, 1H), 3.49-3.65 (m, 3H), 1.21-1.27 ( d, 3H).

  • 20
  • [ 863329-66-2 ]
  • [ 770-12-7 ]
  • alanine isopropyl ester hydrochloride [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
45.7% Stage #1: O-phenyl phosphorodichloridate; alanine isopropyl ester hydrochloride With 1-methyl-1H-imidazole In dichloromethane at -5 - 5℃; for 1.5h; Stage #2: 2'-deoxy-2'-fluoro-2'-methyluridine In dichloromethane at 0 - 20℃; for 5h; 9 Preparation of (S)-2-[(1 R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-(R)-fluoro-3- hydroxy-4-methyl-tetrahydro-furan-2-yl-methoxy]-phenoxyphosphorylamino}-propionic acid isopropyl ester (from US2010/0298257 Example 2) A 5 L 3-necked flask was fitted with a mechanical stirrer, brine ice bath, internal thermometer, and a nitrogen atmosphere. The flask was charged with L-alanine isopropyl ester hydrochloride (82.0 g, 0.490 moles) and anhydrous dichloromethane (0.80 L). While this was stirring, phenyl dichlorophosphate (85.0 g, 0.40 moles) was added in one lot and stirred. While maintaining the internal temperature between -5 to 5 °C, a solution of N-methylimidazole (N I, 250 g, 3.07 moles) in dichloromethane (250 mL) was added over a period of a half hour. The solution was allowed to stir for 1 h in this temperature range. 2'-Deoxy-2'-fluoro-2'-C-methyl-uridine (3,80.0 g, 0.307 moles) was added at 0° C. in one portion and then the reaction flask was allowed to warm up slowly in the brine bath. At 1 h, the internal temperature was up to -2° C. TLC (5% Methanol in HCL) at 1 h showed that more than 50% of nucleoside was consumed. The bath was removed and the reaction flask reached ambient temperature over 1 h more. TLC after 3 h and at 5 h total showed 95% of the starting nucleoside was consumed. The reaction mixture was quenched by adding methanol (100 mL) and stirring the reaction for 5 minutes. The reaction mixture was washed with 1 HCI (2x500 mL) followed by saturated sodium bicarbonate solution (2x500 mL). The separated organic layer was dried over anhydrous sodium sulfate (50 g) and filtered. The solution was evaporated under reduced pressure and then under high vacuum to dryness to give the crude product as a viscous oil (170 g). NMRs of the crude product (31P and 1H) were taken. The 31P-NMR indicated about 1% of the total phosphorus integration was due to the presence of the 3' isomer 5. To the crude product was added anhydrous pyridine (1700 mL). The solvent was evaporated under reduced pressure and then under high vacuum in order to reduce the water content of the crude mixture through co-evaporation. The resulting oil was re-dissolved in anhydrous pyridine (500 ml) and then was added excess t-butyldimethylsilyl chloride (9.0 g, 60 m ). The reaction was stirred at ambient temperature. Reaction progress was monitored by UPLC/MS. After 3 hours, the 3' impurity 5 could no longer be detected and the reaction was quenched by the addition of methanol (50 mL). The reaction was evaporated under reduced pressure to an oil. The residue was dissolved in ethyl acetate (1.5 L) and washed with 1 N HCI (2x500 mL), followed by saturated sodium bicarbonate solution (2x500 mL). The organic layer was dried over anhydrous sodium sulfate (50 g), filtered and evaporated under reduced pressure to give the crude product as a pale yellow oil. The crude oil was diluted with the same volume of dichloromethane and loaded onto a 2.5 Kg silica gel cartridge n a radial compression module at 100 psi of air pressure. Using a gradient pump at 60 psi and a flow rate of 400 ml/min, the cartridge was washed with methylene chloride (4L) followed by a gradient 1-4% methanol in methylene chloride (48 L). Most of the major impurities (di-(isopropylalanyl) phenyl phosphate, 3',5'-bis phosphoramidate, 3'- phosphoramidate-5'-TBDMS adduct (7)) eluted with ~3% gradient. The desired product eluted between 3 and 4% methanol. The product containing fractions were sorted into two lots. The first contained small amounts of upper impurities and the latter was pure product. The first set of fractions contained small amounts of less polar impurities (upper impurities) such as the 3', 5'- bis phosphoramidate and the di-alanylphenyl phosphate and a mostly the Rp diastereomer and required a second column purification. (The relative terminology, upper vs. lower refers to the elution on normal phase silica-gel chromatography, where the "upper isomer" means the first eluting isomer.) The second set of fractions did not have a significant amount of impurities-just the remaining Rp and mostly the Sp diasterereomers. It was later recombined with the twice- columned fractions. The solvent was evaporated under reduced pressure and the resulting white foam was further dried (0.20mmHg) for 1 h to give 42 g of the impure lot (4:1 upper vs lower isomer based on 31P-NMR) and 38 g of the pure lot (1 :3 upper vs lower isomer). The impure lot was recolumned in a similar manner to give 3.8 g of 97% pure upper isomer (fraction set aside) and 36 g ofpure product in a 4: 1 ratio. The two main lots were dissolved in HCL, combined, evaporated under reduced pressure and dried (50° C, 0.2 mmHg, 24 h) to get 74 g (45.7%) of pure product (Compound 9) with a diastereomeric ratio of 48:51 , as a white foam, mp about 75-85° C. In order to produce an amorphous solid of the diastereomeric mixture, 74 g of the white foam was stirred in with t-butyl methyl ether (750 mL) resulting in a partial solution and a gummy solid residue. While stirring, heptanes (750 mL) was added slowly and the suspension was mechanically stirred for 1 hour until most of the gum was converted to a white solid. The solid was scraped up with a spatula and the resulting slurry was filtered. The solid was washed with heptanes (4x50mL) and dried under vacuum (50° C, 0.2mmHg, 24 h) to give a white, amorphous powder (64 g) with a broad melting range of ca 70-80° C. H and 31P NMR conformed to structure and HPLC showed a purity of 99.8% with a diastereomeric ratio of 46:54 (also confirmed by 3 P NMR). Alternative method to make a solid mixture of Compound 9. After chromatography, the residue was co-evaporated with dichloromethane twice (5 mlJg) and dried for 24 h at 35-40° C. at 35- 45 mTorr. The foam residue was sieved through a 250 micron screen and further dried under the same conditions until the residual dichloromethane fell below 400 ppm as measured by headspace GC. The resulting fine off-white to white amorphous powder has a glass transition temperature range of 53.7 to 63.5° C. Characterization of Compound 9 (mixture of isomers): 1H-NMR (CDCI3) 010.05 (brs, 1 H, NH, Sp), 10.00 (brs, 1 H, NH, Rp), 7.49 (d, 1 H, C6-H, Sp), 7.36 (m, 5H, C6-H, Rp, aromatic), 7.23-7.14 (m, 6H, Rp/Sp, aromatic), 6.18 (br d, 2H, Cl'-H, Rp/Sp), 5.63 (d, 1 H, C5-H, Sp), 5.58 (d, 1 H, C5-H, Rp), 5.01 (m, 2H, CH-(CH3)2 Rp/Sp), 4.46- 4.33 (m, 8H, C-5'-H2 , ala-NH, C3'-OH, Rp/Sp), 4.12 (m, 2H, ala-CHCH3, Rp/Sp), 4.01-3.85 (m, 4H, C3'-H, C4'-H, Rp/Sp), 1391.22 (m, 12H, all CH3, Rp/Sp). 31P-NMR (CDCI3) 03.60 (Rp ), 3.20 Sp relative to triphenylphosphate at -17.80 ppm. ES-MS M+1 530.2. Elemental Analysis: Calculated % (including 0.29% water as found by Karl Fisher analysis) C, 49.75; H, 5.54; N, 7.90, F, 3.58, P, 5.84. Found %: C, 49.50; H, 5.44; N, 7.85; F, 3.62; P, 6.05.
  • 21
  • [ 863329-66-2 ]
  • C20H19F5NO5P [ No CAS ]
  • C24H31FN3O9P [ No CAS ]
YieldReaction ConditionsOperation in experiment
170 mg Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 20℃; Stage #2: C20H19F5NO5P In tetrahydrofuran at 20℃; for 14h; 15.15A Step 15A General procedure: To Nucleoside 15a-l (138 mg, 0.53 mmol) in THF (9 mL) at 0 °C was added t- BuMgCl (1.1 mL, 1.06 mmol, 1.0 M in THF) dropwise. The mixture resulted was stirred at room temperature for 30 min and to this mixture was added compound 12d-l (457 mg, 0.954 mmol) in THF (3 mL) dropwise and the resulted mixture was stirred at room temperature for 14 h. The reaction was quenched with NaHCC solution, and the volatiles were evaporated in vacuo. The residue was purified by column chromatography (silica, Hexane to 80% acetone in hexane) to give the desired compound 15a (170 mg). MS (ESI): m/z 556.34 (M+H). (For synthesis of Nucleoside 15a-l sees: Clark, J. L. et al, J. Med. chem. 2005, 48, 5504.)
  • 22
  • [ 863329-66-2 ]
  • [ 1604813-64-0 ]
  • [ 1604813-57-1 ]
YieldReaction ConditionsOperation in experiment
With 1-methyl-1H-imidazole In tetrahydrofuran at -7 - 20℃; for 2h; 11 Example 11Preparation of Compound 11 Compound 11 was prepared according to the methodsdescribed herein Dichloromethane containing POC13 (1 equiv.) wascooled to -78° C. To this solution was added drop-wise amixture of compound (11-1, 1 equiv.) andEt3N (1.1 equiv.) inCH2Cl2 over a period of20 min and stirred at this temperaturefor 5 min. L-alanine isopropyl ester (1 equiv.) in was added in5 min. The resulting mixture was stirred at -70° C. for 1 handthen allowed to warm to RT. Reaction mixture was dilutedwith TBME, and insoluble solid was filtered, washed withTBME. Filtrates were combined and concentrated to give11-2 which was taken to the next step without purification. Toa THF solution of compound (11-2) was added a solution of11-3 (1 equiv.) and NMI (5.25 equiv.) in THF at -7° C. Thereaction mixture was brought toRT and stirred for 2 h. MeOHwas added to quench the reaction and the mixture was concentratedand then purified by HPLC, affording compound 11as a mixture of isomers (chemical purity 96.5% ). 1 H NMR (THF -d8, 400 MHz) o (ppm) 7.92 (s, lH),7.63 (m, lH), 7.55 (m, 2H), 7.26 (m, 2H) 6.25 (m, 2H) 5.55(m, 2H), 5.02 (m, lH), 4.89 (m, 2H), 4.60 (m, 5H), 4.16 (m,lH), 4.0 (m, 2H), 1.50-1.30 (m, ISH); 31P NMR (THF-d8,162 MHz) o (ppm) 2.03, 1.97, -15.05, -15.22; andMS (ESI,)m/z=917.44 (MW).
  • 23
  • [ 863329-66-2 ]
  • 2-cyanoethyl-3-hexadecyloxypropyl-N,N-diisopropylphosphoramidite [ No CAS ]
  • C32H55FN3O8P [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 1h; 30 Compound 231, 232, 233 Compound 231, 232, 233: The amidophosphite (compound 3) (0.114 g, 0.228 mmol) and 1- ((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione (0.065 g, 0.248 mmol) were dried by coevaporating with anhydrous DCM (4 x 10 ml), dissolved in 4 ml DCM and a solution of 3% lH-tetrazole in acetonitrile (0.75 ml, 0.320 mmol) was added. After 1 hour stirring at room temperature 5.5 M solution of tert-butyl peroxide (0.25 ml, 1.359 mmol) was added. After 40 minutes the solvents were evaporated and reaction mixture was dissolved in toluene and 1 ml TEA was added. It was stirred for 5 hours. All the solvents were evaporated and coevaporated with toluene (2 x 2 ml). Crude material was purified with column chromatography starting with CHC13 and increased the polarity slowly with CHC13:MeOH:NH40H (75:25:5) to give compound 319. 1H-NMR: (CDC13-CD30D, 3: 1) 1.024 (t, 3H, 6.4 Hz); 1.35-1.49 (m, 27H); 1.55 (d, 2H, 6.0 Hz); 1.63-1.70 (m, 2H); 2.011-2.067 (m, 2H); 3.47-3.49 (m, 2H); 3.54 (q; 2H, J=4.8 Hz); 3.65- 3.70 (m, 2H); 4.07-4.20 (m, 3H); 4.23-4.42 (m, 2H); 5.99 (d, 1H, J=8.4 Hz); 6.32 (dd, 1H, J=19.2, 5.2 Hz); 8.125 (t, 1H, J=8.0 Hz). 31 P-NMR: (CDC13-CD30D, 3: 1) 17.95 ppm. HRMS: 623.34722.
With 1H-tetrazole In dichloromethane; acetonitrile at 20℃; for 1h; 115 Compound 317 318, 319: The amidophosphite (compound 3) (0.114 g, 0.228 mmol) and 1- ((2R,3R,4R,5R)-3 -fluoro-4-hydroxy-5 -(hydroxymethyl)-3 -methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (0.065 g, 0.248 mmol) were dried by coevaporating with anhydrous DCM (4 x 10 ml), dissolved in 4 ml DCM and a solution of 3% 1H-tetrazole in acetonitrile (0.75 ml, 0.320 mmol) was added. After 1 hour stirring at room temperature 5.5 M solution of tert-butyl peroxide (0.25 ml, 1.359 mmol) was added. After 40 minutes thesolvents were evaporated and reaction mixture was dissolved in toluene and 1 ml TEA was added. It was stirred for 5 hours. All the solvents were evaporated and coevaporated with toluene (2 x 2 ml). Crude material was purified with column chromatography starting with CHC13 and increased the polarity slowly with CHC13 :MeOH:NH4OH (75:25:5) to give compound 319.‘H-NMR: (CDC13-CD3OD, 3:1) 1.024 (t, 3H, 6.4 Hz); 1.35-1.49 (m, 27H); 1.55 (d, 2H, 6.0 Hz); 1.63-1.70 (m, 2H); 2.011-2.067 (m, 2H); 3.47-3.49 (m, 2H); 3.54 (q; 2H, J4.8 Hz); 3.65-3.70 (m, 2H); 4.07-4.20 (m, 3H); 4.23-4.42 (m, 2H); 5.99 (d, 1H, J=8.4 Hz); 6.32 (dd, 1H, J=19.2, 5.2 Hz); 8.125 (t, 1H, J8.0 Hz). 31P-NMR: (CDC13-CD3OD, 3:1) 17.95 ppm.HRMS: 623.34722.
  • 24
  • [ 261909-49-3 ]
  • [ 863329-66-2 ]
  • [ 1190307-88-0 ]
  • [ 1190308-01-0 ]
YieldReaction ConditionsOperation in experiment
With silver trifluoromethanesulfonate; In acetonitrile; at 0 - 23℃; for 5h;Inert atmosphere; [0409] Chlorophosphoramidate 7 (441 mg, 1.44 mmol, 1.5 equiv) and nucleoside A-4A (250 mg, 0.96 mmol, 1.0 equiv) were charged to a vial followed by acetonitrile (3 mL). The vial was purged with nitrogen, cooled on an ice bath and charged with AgOTf (272 mg, 1.06 mmol, 1.1 equiv). The mixture was stirred at 0 C for 3 h, then warmed to 23 C and stirred for an additional 2 h to give 98.9% conversion to compound V-2 by HPLC. The mixture was cooled on an ice bath and quenched with 2 mL water. The suspension was warmed to room temperature, filtered, and the resulting solution was extracted with 5 mL dichloromethane. The extract was dried over Na2SO4, filtered, concentrated, and purified by silica gel flash chromatography using a 2 - 5% methanol in dichloromethane gradient to give a diastereomeric mixture of V-2 (283 mg, 56%).
  • 25
  • [ 863329-66-2 ]
  • C17H21N2O4PS [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
With trifluorormethanesulfonic acid In dichloromethane at 0 - 23℃; for 6.5h; 4B Example 4B: Diastereoselective preparation of (2S)-isopropyl 2- (((((2R3Rg4R,5R5(2g4-dioxo3g4dihydropyrimidim1 (2H)-yfl-4-fluoro-3-hydroxy-4- methvltetrahydrofuran-2-yflmethoxy)(phenoxy)phosphoryflamino)propanoate (Compound V-2). [04121 Nucleoside A-4A (100 mg, 0.0.3 8 mmol, 1.0 equiv) and compound 8 (175 mg, crude) were charged to a vial followed by dichioromethane (1 mL). The mixture was cooled on an ice bath and charged with triflic acid (86 tL, 2.53 equiv) over 5 mm. The mixture was stirred at 0 °C for 3 h, then warmed to 23 °C and stirred for an additional 3.5 h to give 36.5% conversion to compound V-2 by HPLC.
  • 26
  • [ 863329-66-2 ]
  • [ 108-24-7 ]
  • ((2R,3R,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With pyridine at 0 - 20℃; for 2h; 1 Preparation of Nucleoside Analog 206 Compound A2:To a solution of 1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-yl]pyrimidine-2,4-dione (compound A1, 19.21 mmol) in pyridine (2 mL/mmol) was added dropwise at 0° C. acetic anhydride (192.15 mmol). The reaction mixture was stirred 2 hours at room temperature. The reaction was monitored by LC/MS. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene to afford the expected compound as a white solid in quantitative yield. The crude compound was directly used in the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.57 (s, 1H), 7.72 (d, J=8.06 Hz, 1H), 6.03 (brs, 1H), 5.76-5.74 (m, 1H), 5.29 (brs, 1H), 4.35-4.31 (m, 1H), 4.29-4.25 (m, 2H), 2.14 (s, 3H), 2.06 (s, 3H), 1.33 (d, J=23.14 Hz, 3H); MS (ESI) m/z=345.1 (MH+)
81% With dmap; triethylamine at 20℃; for 2h; 73; 74 A brownish suspension of 2’-F-2’-Methyluracil (0.120 g, 0.461 mmol) in Ac20 (1.845 ml) in the presence of DMAP (5.63 mg, 0.046 mmol) was stirred at r.t. for 2 hrs. The reactionmixture became homogeneous upon stirring. The reaction was condensed on rotavap, and coevaporated with MeOH (5 mL x 2). The obtained residue was purified via ISCO (12g column, 40% - 80% EtOAc/Hexanes) to give a white solid with 81% yield.Physical data: ‘H NMR (400Hz, CDC13): ö 1.398 (d, 3H,J= 22Hz), 2.142 (s, 3H), 2.183 (s, 3H), 4.379 (m, 3H), 5.128 (dd, 1H, Jj = 21.2 Hz, J2 = 8.8 Hz), 5.788 (d, 1H, J 8.4 Hz),6.179 (d, 1H, J 18.4 Hz), 7.549 (d, 1H, J 8 Hz), 8.882 (s 1H); ‘3C NMR (100Hz, CDC13):o 17.113, 17.363, 20.490, 20.672, 61.457, 71.498, 71.665, 98.539, 100.390, 103.085, 138.990, 149.911, 162.312, 169.924; MS: mlz 345.0 (M-uracil+H); LC-MS 95% purity; HRMS Calc. for C,4H,8F07N2 (M+H): 345.10926, Found: 345.10906.
81% With dmap at 20℃; for 2h; 75 Example 75. A brownish suspension of 2'-F-2'-Methyluracil (0.120 g, 0.461 mmol) in Ac2O (1.845 ml) in the presence of DMAP (5.63 mg, 0.046 mmol) was stirred at r.t. for 2 hrs. The reaction mixture became homogeneous upon stirring. The reaction was condensed on rotavap, and co- evaporated with MeOH (5 mL x 2). The obtained residue was purified via ISCO (12g column, 40% ^ 80% EtOAc/Hexanes) to give a white solid with 81% yield. Physical data: 1H NMR (400Hz, CDCl3): δ 1.398 (d, 3H, J = 22 Hz), 2.142 (s, 3H), 2.183 (s, 3H), 4.379 (m, 3H), 5.128 (dd, 1H, J1 = 21.2 Hz, J2 = 8.8 Hz), 5.788 (d, 1H, J = 8.4 Hz), 6.179 (d, 1H, J = 18.4 Hz), 7.549 (d, 1H, J = 8 Hz), 8.882 (s 1H); 13C NMR (100Hz, CDCl3): δ 17.113, 17.363, 20.490, 20.672, 61.457, 71.498, 71.665, 98.539, 100.390, 103.085, 138.990, 149.911, 162.312, 169.924; MS: m/z 345.0 (M-uracil+H); LC-MS 95% purity; HRMS Calc. for C14H18FO7N2 (M+H): 345.10926, Found: 345.10906.
  • 27
  • [ 863329-66-2 ]
  • C14H21N2O7PS [ No CAS ]
  • C18H29FN3O9PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: C14H21N2O7PS In tetrahydrofuran for 2h; 1 Preparation of Intermediate 1-5 (0344) To a solution of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (0.5 mmol, 1 mol/eq) in anhydrous THF (1.5 mL) is added 1.0 M t-butyl magnesium chloride (1.05 mmol, 2.1 mol/eq) at rt. The resulting mixture is stirred at rt for 0.5 h, and intermediate 1-2 (1.0 mmol) in THF (1.5 mL) is added dropwise. The reaction mixture is stirred for 2 h, and then quenched by adding saturated aqueous ammonium chloride (20 mL), and extracted twice with EtOAc (20 mL×2). The organic layers are combined, dried from MgSO4, and concentrated till dryness to give a residue, which is separated by silica gel chromatography to give intermediate 1-5.
  • 28
  • [ 863329-66-2 ]
  • (2S)-2-((((S)-pentafluorophenoxy)([1,1'-biphenyl]-4-yloxy)phosphoryl)amino)propanoic acid isopropyl ester [ No CAS ]
  • (2S)-2-((([1,1'-biphenyl]-4-yloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propanoic acid isopropyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 4h; Inert atmosphere; Cooling with ice; Stage #2: (2S)-2-((((S)-pentafluorophenoxy)([1,1'-biphenyl]-4-yloxy)phosphoryl)amino)propanoic acid isopropyl ester In tetrahydrofuran at 20℃; Cooling with ice; Inert atmosphere; 1.2 Step 2: preparation of (2S)-2-((([1,1'-biphenyl]-4-yloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyri midin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)ph osphoryl)amino)propanoic acid isopropyl ester Step 2: preparation of (2S)-2-((([1,1'-biphenyl]-4-yloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyri midin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)ph osphoryl)amino)propanoic acid isopropyl ester To a reaction flask were added (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (26mg, 0.1mmol) and 1mL tetrahydrofuran. A solution of 1M tert-butyl magnesium chloride (0.25mmol) in THF (0.25mL) was added dropwise under nitrogen protection in an ice bath. After the addition was complete, the mixture was reacted for 4 hours at room temperature, and a solution of the above-obtained phosphate intermediate of p-phenylpheno (70mg, 0.13mmol) in tetrahydrofuran (1.5mL) was added dropwise in an ice bath. After the addition, the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction was quenched by adding 6mL of 2N HCl in an ice bath. The resultant mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried, concentrated, and separated and purified by silica gel column chromatography to give the title compound. 1HNMR(300MHz,DMSO)δ:11.51(s,1H,pyrimidineN-H),7.68-7.62(m,4H,Ar-H,pyrimi dine-H),7.60-7.56(d,1H,Ar-H),7.48-7.43(t,2H,Ar-H),7.38-7.30(m,3H,Ar-H),6.12-6.00 (m,2H,tetrahydrofuran-H),5.84(d,1H,pyrimidine-H),5.56(d,1H,P-NH),4.90-4.82(m,1 H,-(CH3)2C-H),4.62-4.34(m,1H,tetrahydrofuran-OH),4.30-4.22(m,1H,(CH3)C(NH)-H),4.06-4.00(m,1H,tetrahydrofuran-H),3.88-3.77(m,2H,P-O-CH2-H),1.30-1.20(m,9H, 3*CH3),1.58(d,3H,CH3). ESI-MS m/z: [M+H]+ =606.2.
  • 29
  • [ 863329-66-2 ]
  • isopropyl(((3-nitro-5-(trifluromethyl)pyridin-2-yl)oxy)phenoxy)phosphoryl-L-alaninate [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran; acetonitrile at 20℃; for 0.5h; Stage #2: isopropyl(((3-nitro-5-(trifluromethyl)pyridin-2-yl)oxy)phenoxy)phosphoryl-L-alaninate In tetrahydrofuran; acetonitrile at 20℃; 3 Example 3: Process for the preparation of Sofosbuvir by coupling of isopropyl(((3-nitro-5-(trifluromethyl)pyridin-2-yl)oxy)phenoxy)phosphoryl-L-alaninate with 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2- yl)pyrimidine-2,4(1H,3H)-dione To a solution of 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (0.2gm) in THF (4 ml), tertt-BUM9CI, butylmagnesium chloride (0.80m1, 1.7 M solution in THF) was added dropwise at room temperature and reaction mass was stined for 30 minutes. A solution of pyridine derivative from example 2 (0.36gm) in THF (4m1) was added dropwise to the reaction mass at room temperature. Completion of reaction was monitored using TLC. After completion of reaction,5 reaction mass was quenched by using saturated ammonium chloride solution (10m1). Reaction mass was extracted with ethyl acetate (50m1). Organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel & obtained solid product was characterized. MS, mle 530.2 (M+1) .
  • 30
  • [ 863329-66-2 ]
  • chlorophosphoramidate [ No CAS ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
0.21 g With 1-methyl-1H-imidazole; In tetrahydrofuran; at 20℃; (0045) 1.5 g of beta-D-2?-deoxy-2?-alpha-fluoro-2?-beta-C-methyluridine (Ji'nan Branch of A Chemical Co., Ltd., the purity of 98%) was dissolved in 30 ml of THF, and then 3 g of N-methylimidazole was added, and a solution of V2 in 20 ml of THF was added. It was stirred at room temperature overnight, filtered, and the filtrate was evaporated under reduced pressure to dryness. The residue was separated by silica gel column chromatography, eluted with dichloromethane containing 2% isopropanol, and the desired component was collected and evaporated under reduced pressure to dryness. The residue was dissolved with acetonitrile containing 20% isopropanol and separated by chiral preparative chromatography with the chromatography column of Diacel's Chiralpak AS, the mobile phase being acetonitrile solution containing 20% isopropanol, the flow rate being 8 ml/min, the second component was collected and evaporated under reduced pressure to dryness, to obtain 0.21 g of PSI-7977. H1-NMR delta (ppm, DMSO-d6); 11.21 (s, 1H); 7.52 (d, 1H); 7.36-7.30 (m, 2H); 7.20-7.12 (m, 3H); 6.05-5.95 (m, 2H); 5.80 (m, 1H); 5.51 (d, 1H); 4.81 (q, 1H); 4.36-4.30 (m, 1H); 4.21-4.16 (m, 1H); 4.00-3.94 (m, 1H) 3.82-3.70 (m, 2H); 1.21 (d, 3H); 1.18 (d, 3H); 1.10 (d, 6H).
  • 31
  • [ 863329-66-2 ]
  • C12H18OS2 [ No CAS ]
  • C22H28FN2O7PS2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With bis(diisopropylamino)chlorophosphine; N-ethyl-N,N-diisopropylamine In dichloromethane at -78 - 20℃; for 1h; Stage #2: With 4,5-dicyano-1H-imidazole In dichloromethane; acetonitrile for 1h; Stage #3: C12H18OS2 Further stages; 1 A solution of bis-(A/,A/-diisopropylamino)-chlorophosphine (0.13 g, 0.5 mmol) in dry dichloromethane (2.0 mL) was added dropwise to a solution of 2-Me-2'-F-uridine (0.13 g, 0.5 mmol) and A/,A/-diisopropylethylamine (0.094 mL, 0.55 mmol) in dry dichloromethane (3.0 mL) at -78 °C. The reaction mixture warmed to room temperature and stirred for 1 hour. A solution of 4,5-dicyanoimidazole (0.054g, 0.5mmol) in dry acetonitrile (3.0 mL) was added, and the resulting mixture was stirred for 1 hour. To this, a solution of the alcohol 1 (0.12g, 0.5 mmol) and 4,5-dicyanoimidazole (0.054 g, 0.5 mmol) in acetonitrile (5.0 mL) was added, and the resulting mixture was stirred overnight. f-Butyl hydroperoxide solution (0.1 mL, 5-6 M in decane) was added and the mixture was stirred for additional 30 min. Volatiles were removed in vacuo to afford a residue which was subjected to HPLC purification (acetonitrile/H20; 20% - 75%, 30 min) to give 0.01 1 g of the more polar diastereomer 7A and 0.039 g of the less polar diastereomer 7B as white solids.
  • 32
  • [ 863329-66-2 ]
  • C12H19O3PS2*C6H15N [ No CAS ]
  • C22H30FN2O7PS2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With pyridine; pivaloyl chloride at -15℃; for 1.5h; 1 A solution of compound 2 (0.49 g, 1.20 mmol) and 2'-Me-2'-F-deoxyuridine (0.26 g, 1.0 mmol) was co-evaporated with anhydrous pyridine twice and the residue was re-dissolved in 15.0 ml_ of anhydrous pyridine and cooled to -15 °C. To this mixture was added pivaloyl chloride (0.25 ml_, 2 mmol) dropwise and stirring continued at -15 °C for 1.5 hrs. The reaction mixture was diluted withdichloromethane (30.0 ml_) and quenched with aqueous ammonium chloride solution (0.5M, 20.0 ml_). Organic layer separated, and the aqueous layer was extracted with dichloromethane (2x 20.0 ml_). The combined organic layers were washed with aqueous ammonium chloride solution (0.5M) and brine, dried over anhydrous sodium sulfate. Volatiles were removed in vacuo to afford a residue, which was subjected to flash silica gel column purification on an ISCO companion (2-10% methanol/dichloromethane containing 1% acetic acid) to give 0.24 g (44%) of compound 3 as a white solid. 1H NMR (500 Hz, CDCI3): 58.25 (1H, s), 7.84 (1H, d, J8.5Hz), 7.56 (1H, d, J8.5 Hz), 7.39 (1H, dd, J6.5, 3.5 Hz), 7.27 (1H, m), 7.17 (2H, m), 6.85 (1H, d, J710Hz), 5.70 (1H, dd, J8.0Hz), 4.42-4.25 (4H, m), 4.04 (1H, d, J9.0Hz), 53.90 (1H, m), 3.27 (2H, t, J6.5Hz), 1.40 (3H, d, J22.0 Hz), 1.30 (9H, s). 31P NMR (202MHz, CDCI3): 514.25 (s), 14.21 (s).
  • 33
  • [ 863329-66-2 ]
  • 4-tert-Butyldisulfanyl-butan-1-ol [ No CAS ]
  • C18H28FN2O7PS2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With bis(diisopropylamino)chlorophosphine; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Stage #2: 4-tert-Butyldisulfanyl-butan-1-ol With 4,5-dicyano-1H-imidazole In dichloromethane; acetonitrile Stage #3: With tert.-butylhydroperoxide In dichloromethane; acetonitrile for 0.5h; 1 To a solution of 2'-Me-2'-F-deoxyuridine (0.13 g, 0.5 mmol) in dry dichloromethane (3.0 mL) at - 78 °C, bis-(A/,A/-diisopropylamino)-chlorophosphine (0.13 g, 0.5 mmol) in dry dichloromethane (2.0 mL) was added dropwise followed by A/,A/-diisopropylethylamine (0.094 mL, 0.55 mmol). The reaction mixture warmed to room temperature and was stirred for additional 1 hour. To this mixture, a solution of 4,5- dicyanoimidazole (0.054 g, 0.5 mmol) in dry acetonitrile (3.0 mL) was added, and the resulting mixture stirred for 1 hour followed by addition of acetonitrile (5.0 mL) solution of the alcohol 5 (0.097 g, 0.5 mmol), 4,5-dicyanoimidazole (0.054 g, 0.5 mmol) and stirring continued overnight. To this solution, f-butyl hydroperoxide (0.1 mL, 5-6 M in decane) was added and the mixture was stirred for additional 30 min. Volatiles were removed in vacuo to afford a residue, which was subjected to HPLC purification (acetonitrile/H20; 15% - 65%, 30 min) to give two isomers (0.028 g of the more polar diastereomer 6A and 0.041 g of the less polar diastereomer 6B) as white solids.
  • 34
  • [ 863329-66-2 ]
  • isopropyl ((S)‐(perfluorophenoxy)([4‐D]phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
  • isopropyl ((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl)methoxy)([4‐D]phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran; hexane at -10 - 20℃; for 2.66h; Inert atmosphere; Stage #2: isopropyl ((S)‐(perfluorophenoxy)([4‐D]phenoxy)phosphoryl)‐L‐alaninate In tetrahydrofuran; hexane at 5℃; for 19h; Inert atmosphere; 1.3 Preparation of compound 1 Compound 1-c in a vacuum oven at 50 ° C under reduced pressure overnight drying. Weighing compound 1-c (5.65mmol) and anhydrous tetrahydrofuran (30ml) in a three-necked flask, nitrogen protection device is placed in the low temperature reaction vessel and stirred at -10~-5 ° C range dropping 1. 0M t-butylmagnesium chloride in n-hexane (12ml, 12mmol), 70min completion of dropwise, maintaining the reaction -5~0 ° C for half an hour, warm to room temperature and stirred for 1 hour. Apparatus and was cooled to 5 ° C, solution of compound 1-a (3. 08g, 6. 78mmol) in anhydrous tetrahydrofuran (15ml), 60min completion of dropwise, maintaining the reaction 5 ° C 18h. After the reaction solution was cooled to _5 ° C, was slowly added dropwise 2Μ HC1 solution (18ml) quenched the reaction. The reaction mixture was added toluene (30ml) The layers were separated and the organic layer washed with 1Μ HCl (2Χ 10ml), water (IX 10ml), 5% Na2C03 solution (4Χ 10ml), water (2Χ 10ml), saturated brine (IX 10ml) wash. The combined aqueous phase was added toluene (10ml) The layers were separated and then the toluene layer was washed successively with 5% Na2CO3 solution (2 X 5ml), water (IX 5ml), saturated brine (IX 5ml) wash, the aqueous phase was discarded, and extracted twice the organic phases were combined, anhydrous sodium sulfate. Filter, filter cake washed with toluene(2x5), and the combined filtrate concentrated to give a pale yellow crude residue of compound 1, by baby gel column chromatography, methylene burn - isopropanol (100: 3, ν / ν) as eluent to give compound 1 (0. 99g , 1. 87mmol, yield 33%, HPLC assay 99.7% purity). 1H-NMR (CDCl3, 300ΜΗz):. Δ 8. 66 (s, 1Η, ΝΗ), 7. 47-7 45 (d, 1Η, C6-H), 7 · 36-7 34 (d. , 2H, square-aromatic), 7 · 26-7. 21 (t, 2H, m-aromatic), 6 · 20-6. 14 (br d, 1Η, Cr -Η), 5. 70-5. 68 (d, 1Η, C5-H), 5. 06-4. 97 (quint, 1Η, CH- (CH3) 2), 4.57-4.41 (m, 2H, C5 '-H2), 4. 12-4.09 ( d, 1H, C3 '-H), 4.04-3.92 (m, 3H, C3' -0H, C4 '-Η, Ala-CH-CH3), 3 · 79 (s, 1H, Ala-NH), 1 · 44-1 · 43 (d, 3H, C2 '-Η3) 1 · 37 (d3H, Ala-CH3), 1. 25-1 19 (t, 6Η, CH- (CH3) 2).; 31P-NMR (CDCl3, 300MHz, H3P04 internal standard): δ 3 · 57; MS (M + H): 531·5.
33% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; Stage #2: isopropyl ((S)‐(perfluorophenoxy)([4‐D]phenoxy)phosphoryl)‐L‐alaninate In tetrahydrofuran at 5℃;
  • 35
  • [ 863329-66-2 ]
  • (2S,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐carboxylicacid [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% With Jones reagent In acetone at 0 - 20℃; for 12h;
1.42 g With Jones reagent In acetone at 0 - 20℃; for 12h; 10.1 To a 250ml single-necked round-bottomed flask was added 2g Compound 1-c, 120ml of acetone was added, 4g baby diatomaceous earth, cooling down to 0 ° C, was added dropwise 8 · 5ml2. 5Μ Jones' Reagent, at room temperature for 12h after addition . Was added dropwise under ice-cooling the reaction was quenched L 5ml of isopropanol, filtered, 150ml THF filter cake was washed, the filtrate was concentrated to dryness to give a green liquid,With 30ml of ethyl acetate and 30ml of tetrahydrofuran was dissolved, washed with saturated aqueous sodium chloride until colorless, organic phase was dried over anhydrous magnesium sulfate, spin dried to give a foamy solid 3. 8g, methanol / water and recrystallized to give after drying a. 42g of white solid 25-b. 'H-NMRCDMSO-de, 300ΜΗζ) δ 11. 50 (br s, 1Η, ΝΗ) , 7. 98 (d, 1Η, C-6H), 6 07 (d1HCl’ -Η)5 73 (d1HC5-H)4 24 (d1HC4’ -Η)4 02 (dd1HC3’ -HI) 1 28(d, 3Η, C2’ -CH3). 13C-NMR(DMS0-d6, 300ΜΗζ) δ 171. 76, 162. 83, 150. 44, 139. 62, 102. 24, 99. 31, 79. 29, 75. 56, 75. 33, 16. 17 ;MS(M+H) :275 3
  • 36
  • [ 863329-66-2 ]
  • isopropyl ((S)‐(perfluorophenoxy)([2,3,4,5,6‐D5]phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
  • isopropyl ((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl)methoxy)([2,3,4,5,6‐D5]‐phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; Stage #2: isopropyl ((S)‐(perfluorophenoxy)([2,3,4,5,6‐D5]phenoxy)phosphoryl)‐L‐alaninate In tetrahydrofuran at 5℃;
0.68% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran; hexane at -5 - 20℃; for 2.17h; Inert atmosphere; Stage #2: isopropyl ((S)‐(perfluorophenoxy)([2,3,4,5,6‐D5]phenoxy)phosphoryl)‐L‐alaninate In tetrahydrofuran; hexane at 5℃; Inert atmosphere; 2.3 Compound 1-c in a vacuum oven at 50 ° C under reduced pressure overnight drying. Compound lc (l.18g, 4. 5mmol) and anhydrous tetrahydrofuran (20ml) in a three-necked flask, nitrogen protection device is placed in the low temperature reaction vessel and stirred at -5~0 ° C range dropping 1. 0M n-hexane solution of t-butyl chloride (11. 4ml, 11. 4mmo 1), 20min completion of dropwise, maintaining -5~0 ° C for 1 hour, warmed to room temperature for 1 hour. Apparatus and was cooled to 5 ° C, was added dropwise the compound 5-a (2. 50g, 5. 5mmol) in anhydrous tetrahydrofuran (20ml), 30min completion of dropwise, maintaining the reaction overnight at 5 ° C. The next day the reaction temperature was reduced to -5 ° C, was slowly added dropwise 2Μ HC1 solution (20ml) quenched the reaction. The reaction mixture was added toluene (50ml). The organic layer was washed with lMHCl (2X10ml), water (lX10ml), 5% Na2C03 solution (4x10 ml), water (2xl0ml), saturated brine (IX lml) wash. The combined aqueous phase was added toluene (20ml) standing layer, the toluene layer was then washed with 5% Na2C03 solution (2 X 10ml), water (IX 10ml), saturated brine (IX 10ml) wash, the aqueous phase was discarded, two second extracted organic phases were combined, anhydrous sodium sulfate. Filtered, the filter cake washed with toluene (2x15ml), The combined filtrate by rotary evaporation to give a pale yellow crude residue compound 5 by column chromatography on silica gel, dichloromethane - isopropyl alcohol (100: 3, v / v) as eluent to give compound 5 (0. 68g, 1 · 27mmol, yield 28. 3%, HPLC assay 99.5% purity). 'H-NMR (CDC 13, 300ΜΗζ) 68.63(s, lH,NH),7.47(d, 1H,C6-H), 6 20-6 14 (d, 1Η, Cl’ -Η)5 70-5 68 (d, 1Η, C5-H)5 05-4 97 (m, 1Η, CH- (CH3) 2) 4 57-4 41 (m2HC5-Η2)4 12-4 09 (d1HC3-Η)4 06-3 79 (m3HC3-OH, C4-Η Ala-CH-CH3)3. 79(s1HAla-NH)1 44(d3HC2’ -Η3)1 36-1 34(d3HAla-CH3) 1. 25-1. 23 (t, 6Η, CH-(CH3)2). 31P-NMR(CDC13, 300MHzH3P04 δ 3 54 MS (Μ+Η) :535 5 ( >98. 7)
  • 37
  • [ 863329-66-2 ]
  • C12H16(2)HClNO4P [ No CAS ]
  • [2‐D]propan‐2‐yl ((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl)methoxy)(phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37.8% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; for 1h; Stage #2: C12H16(2)HClNO4P With lithium chloride In tetrahydrofuran at 5℃; 3.3 Preparation of Compound 6 To a 100ml three necked flask 15ml of dichloromethane, 2. 6g compound 6-b, cooling down to -70 ° C, 3. 27g of triethylamine was added dropwise, and then added dropwise 3. 26g dichlorophosphate phenyl ester and a mixed solution of 10mL of dichloromethane, -70 ° C for 30 minutes the reaction was raised to square ° C reaction was continued for one hour, i.e., the key intermediate 6-c (Sp: Rp = 1: 1 mixture). Into a 100ml three-necked flask was added 40ml of anhydrous tetrahydrofuran, 1.82g (2'R) -2'- deoxy-2'-fluoro-2'-methyl glycoside urea (Compound 1-c), to cool down _5 ° C, 15ml 1M solution of tert-butyl chloride, add -5 ° C after half an hour the reactionWhen the reaction warmed to room temperature and then after half an hour, was added lithium (7. 2mmol) chloride, and then dropping 3. 8g compound 6-c and 25ml tetrahydrofuran at 5 ° C, the addition was complete the reaction 5 ° C overnight. After completion of the reaction at _5 ° C the reaction was quenched with IN HC1, then warmed to room temperature, added 35ml of toluene, stirring, standing separation, the organic phases were washed with 12ml, 10ml of saturated sodium bicarbonate solution, saturated brine (2xl0ml), dried over anhydrous magnesium sulfate and the organic phase was dried, filtered, and concentrated to dryness to give an oil 3. 5g, using dichloromethane: isopropyl alcohol = 100: 6 (ν / ν) column chromatography to obtain 1. 4g foamy solid, i.e. compound 6 in a yield of 37.8%. 'H-NMR (CDC13, 500ΜΗζ) δ 8. 48 (br s, 1Η, ΝΗ) , 7. 46 (d, 1Η, C6-H), 7. 36 (t2Ho-aromatic)7. 18-7. 24 (m3Hmp-aromatic)6. 18 (br d1HCl-H) 5 70(d1HC5-H)4. 54(t1HC5’ -CH2)4. 45(t1HC5’ -CH2)4. 11 (d1HC3’ -Η) 3 94(m3HC3, -0HC4, -Hala-CH-CD3)3. 84(t1Hala-NH)1 42(d3HC2, -CH3) 1 36 (d3Hala-CH3)1 21 (d6HCD-(CH3)2) 31P-NMR(CDC13, 300MHzH3P04 δ 3 58 ;MS(M+H) :531 5
  • 38
  • [ 863329-66-2 ]
  • C12H10(2)H7N4O4P [ No CAS ]
  • C22H22(2)H7FN3O9P [ No CAS ]
YieldReaction ConditionsOperation in experiment
26.1% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 5 - 25℃; for 0.5h; Stage #2: C12H10(2)H7N4O4P With lithium chloride In tetrahydrofuran at 5℃; for 15h; 4.2 preparation of compound 7 5 ° C, the compound l_c (5. 20g, 20. Ommol) in anhydrous THF (30ml) in. Stirring, t-butyl chloride (1. 0Μ THF solution, 42ml, 42. Ommol). The reaction temperature rose to 25 ° C, and the mixture was stirred for 30 minutes. Was added lithium (21. Ommol) chloride was slowly added dropwise after compound 7-d (about 28. 4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ° C. Bi drops, stirred for 15 hours. With aqueous IN HC1 (25ml) quenched reaction mixture (HPLC measurement Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), the temperature rose to room temperature. The organic layer was washed with IN HC1, washed with water, 5% Na2C03 and brine, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure to give a solid which was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid, if necessary, can be obtained by repeated crystallization of pure compound 7 (2. 8g, yield 26. 1%, HPLC purity was determined 98 . 8 % ).
  • 39
  • [ 863329-66-2 ]
  • [1,1,1,3,3,3‐D6]propan‐2‐yl ((S)‐(perfluorophenoxy)(phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
  • [1,1,1,3,3,3‐D6]propan‐2‐yl ((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl)methoxy)(phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; Stage #2: [1,1,1,3,3,3‐D6]propan‐2‐yl ((S)‐(perfluorophenoxy)(phenoxy)phosphoryl)‐L‐alaninate In tetrahydrofuran at 5℃;
30.9% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5 - 20℃; for 1h; Stage #2: [1,1,1,3,3,3‐D6]propan‐2‐yl ((S)‐(perfluorophenoxy)(phenoxy)phosphoryl)‐L‐alaninate In tetrahydrofuran at 5℃; 5.4 Preparation of compound 8 To a 100ml two-necked flask 15ml of dichloromethane burning, 2 · 5g compound 8-b, cooling down to -70 ° C, a dropping force mouth 3. 07g of triethylamine and then added dropwise 3. 04g two chlorine mixed solution of phosphoric acid phenyl ester and 15ml of methylene chloride,-70 ° C for 30 minutes the reaction was raised to 0 ° C reaction was continued for one hour, and then added dropwise 2.65g of pentafluorophenol, and a mixed solution of 1.6g of triethylamine in 10mL dichloromethane burning, 0 ° C After the addition the reaction overnight. Filtered, the filter cake washed with dichloromethane, the filtrate was concentrated to dryness after adding appropriate amount of methyl tert-butyl ether, slurried, then filtered, the filtrate was concentrated to dryness to give the crude products after the ethyl acetate: n-hexane = 1: 4 (ν / ν) Beating , 3 · 17g obtain a white solid in 48% yield, i.e. compound 8-c. 1H-ΝΜΚ(αχ:3,300ΜΗζ) : δ738-734(π,2Η),726-7 19(m3H)5.01(d1Η),4 14(q1H)3. 97 (br m1H)1. 45 (d3Η) ;31P-NMR(CDC13, 300MHzH3PO4 δ -1.53
  • 40
  • [ 863329-66-2 ]
  • C18H16(2)H5N2O7P [ No CAS ]
  • isopropyl ((S)‐(((2R,3R,4R,5R)‐5‐(2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)‐4‐fluoro‐3‐hydroxy‐4‐methyltetrahydrofuran‐2‐yl)methoxy)([2,3,4,5,6‐D5]‐phenoxy)phosphoryl)‐L‐alaninate [ No CAS ]
YieldReaction ConditionsOperation in experiment
25.4% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Cooling with ice; Stage #2: C18H16(2)H5N2O7P In tetrahydrofuran at 20℃; for 24h; Cooling with ice; 1.2 (2) intermediate M812 synthesis of Nucleoside(S2,260mg, 1mmol) is added in the reaction bottle, using 6 ml dry tetrahydrofuran is dissolved (THF), under ice bath, nitrogen protection, dropping 1M tetrahydrofuran solution of T-butyl magnesium chloride 2.5 ml (2.5mmol), finish adding, stirring the mixture at room temperature for 30 min. Intermediate M811 (537 mg, 1 . 3mmol) with 6 ml of tetrahydrofuran is dissolved, in dropping Go, room temperature reaction 24h. Under ice bath, using 10 ml saturated ammonium chloride quenching the reaction, ethyl acetate extraction, saturated sodium bicarbonate solution, dried anhydrous sodium sulfate, concentrated, silica gel chromatographic column separation, purification to obtain a target compound, intermediate M812 (135 mg), yield 25.4%. MS (m/z):
  • 41
  • [ 863329-66-2 ]
  • (S)-2-[-(S)-(2,3,4,5,6-pentafluorophenoxy)(benzo[1,3]dioxapenta-5-yl-oxy)phosphoramide]isopropyl propionate [ No CAS ]
  • C23H29FN3O11P [ No CAS ]
YieldReaction ConditionsOperation in experiment
54.67% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -5℃; for 0.5h; Stage #2: (S)-2-[-(S)-(2,3,4,5,6-pentafluorophenoxy)(benzo[1,3]dioxapenta-5-yl-oxy)phosphoramide]isopropyl propionate In tetrahydrofuran at 3 - 7℃; 1.3 Step 3: 250 ml to four bottle 2gLK-A and 30 ml THF of the, oven to -5 ° C time, slowly dropping t-BuMgCl, maintain -5 ° C dropping complete after stirring 30 min, maintaining 3-7 °C dropwise LK-B THF solution of, after the dipping stirring overnight. Dropwise 2N the HCl and 40 ml toluene, stirring 20 min, divide the liquid. Organic column chromatographic analysis (dichloromethane/methanol) to obtain 2.4g white foam solid LK-001. Purity (HPLC) 99.87%, yield 54.67%.
  • 42
  • [ 863329-66-2 ]
  • C19H17F5NO7P [ No CAS ]
  • C23H29FN3O11P [ No CAS ]
YieldReaction ConditionsOperation in experiment
63.78% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -10℃; for 0.5h; Stage #2: C19H17F5NO7P at 2 - 6℃; 2.3 Step 3: 250 ml to four bottle 2gLK-A and 30 ml THF of the, oven to -10 ° C time, slowly dropping t-BuMgCl, maintain -10 ° C dropping complete after stirring 30 min, maintaining 2-6 °C dropwise LK-C THF solution of, after the dipping stirring overnight. Dropwise 2N the HCl and 40 ml toluene, stirring 20 min, divide the liquid. Organic column chromatographic analysis (dichloromethane/methanol) to obtain 2.8g white foam solid LK-002. Purity (HPLC) 99.85%, yield 63.78%.
  • 43
  • [ 863329-66-2 ]
  • C17H20ClN2O5P [ No CAS ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
80% With N-ethyl-N,N-diisopropylamine; zinc(II) chloride; In tetrahydrofuran; water; at 55℃; for 20h; The 1.59gA1,0.52gB, 0.44gZnCl2And 0.42gDIEA into 50mL single neck flask was added 10mL of anhydrous THF as solvent, 55 deg.] C oil bath for 20 hours, the reaction was complete by TLC, the natural cooling to room temperature, the reaction was diluted with 20mL ethyl acetate, was added 20mL saturated NH4Cl solution was quenched, extracted, the organic phase was washed with dilute hydrochloric acid and 20mL (0.5N) washing, extraction, the organic phase was washed with 20mL saturated sodium bicarbonate, the combined organic phases are washed with 2 × 20mL sodium carbonate (5%) and sodium bicarbonate ( 5%) buffer to wash, extraction, the organic phase was washed with 2 × 20mL brine, dry the organic phase rotation, with a mixed solution of crystallization 5mL dichloromethane / toluene = 1/1, filtered solids were washed with 5mL of ethyl acetate / diethyl beating a mixed solution of dichloromethane = 1/5, to give C0.42 g, mass yield: 80%.
  • 44
  • [ 863329-66-2 ]
  • N-[(S)-(2,3,4,5,6-pentafluorophenyl)phenoxyphosphoryl]-L-alanine isopropyl ester [ No CAS ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
202 g The preparation method of Sophistic of the present invention comprises the following steps:Preparation of Sophocarpine:In a reaction flask, under anhydrous anaerobic conditions.(2'R) -2'-deoxy-2'-fluoro-2'-methylurea urea,600 mL of dimethyl sulfoxide,Stirring, cooling to -30 , dropping.339g2.0M isopropyl magnesium chloride; drop complete,The reaction was stirred for 1 hour,Then, the temperature was raised to -10 C,A solution of 50 g of N - [(S) - (2,3,4,5,6-pentafluorophenoxy) phenoxyphosphoryl] -L-alanine isopropyl ester in 500 mL of dimethylsulfoxide was added dropwise; Drop Bi,The reaction was carried out at -10 C for 1 hour, followed by heating to room temperature,TLC monitored the reaction. The reaction was completed, cooling to 0 C, began dropping concentrated hydrochloric acid / water 250mL / 700mL) quenching reaction; vacuum distillation of dimethyl sulfoxide, and then add 800mL ether, stirring, water layer with ether (300mL × 3 ), The combined organic extracts were dried over saturated sodium bicarbonate, saturated sodium chloride, anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 224 g of crude oil; , Heating dissolved, and then cooled to 0-10 C under stirring crystallization, filtration, drying 202g white solid products.
  • 45
  • [ 863329-66-2 ]
  • C12H17ClNO4P [ No CAS ]
  • 5′-[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxylphosphoryl]-β-D-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.21 g With 1-methyl-1H-imidazole In tetrahydrofuran at 20℃; 5 Preparation of 5′-[(S)-[[(S)-1-(isopropoxycarbonyl)-ethyl]-amino]-phenoxylphosphoryl]-β-D-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine (PSI-7977) 1.5 g of β-D-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine (Ji'nan Branch of A Chemical Co., Ltd., the purity of 98%) was dissolved in 30 ml of THF, and then 3 g of N-methylimidazole was added, and a solution of V2in 20 ml of THF was added. It was stirred at room temperature overnight, filtered, and the filtrate was evaporated under reduced pressure to dryness. The residue was separated by silica gel column chromatography, eluted with dichloromethane containing 2% isopropanol, and the desired component was collected and evaporated under reduced pressure to dryness. The residue was dissolved with acetonitrile containing 20% isopropanol and separated by chiral preparative chromatography with the chromatography column of Diacel's Chiralpak AS, the mobile phase being acetonitrile solution containing 20% isopropanol, the flow rate being 8 ml/min, the second component was collected and evaporated under reduced pressure to dryness, to obtain 0.21 g of PSI-7977.
  • 46
  • [ 863329-66-2 ]
  • [ 1256490-48-8 ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -30℃; for 1h; Stage #2: (S)-2-[(4-nitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester In tetrahydrofuran at -10℃; for 1h; 2 Preparation of Sofosbuvir In the reaction flask, in under oxygen-free conditions, adding 12g intermediate type 2-5,120 ml tetrahydrofuran, stirring, lower the temperature to -30 °C, dropwise 53.6g1 . 7M tert-butyl magnesium chloride; the drop finishes, stirring for 1 hour, then temperature to -10 °C, dropwise 19.6gN-[ (S) - (4, -nitrophenoxy) phenoxy phosphoryl]-L-alanine isopropyl ester of 120 ml tetrahydrofuran solution; the drop finishes, at -10 ° C reaction under 1 hour, then heating to room temperature reaction, TLC monitoring reaction. After the reaction, cooling to 0 °C, and begin to drop and hydrochloric acid/water (50 ml/300 ml) quenching the reaction; reducing pressure and evaporating thf, then adding 200 ml methyl tert-butyl ether, stirring the liquid, aqueous layer with methyl tert-butyl ether (50 ml × 3) extraction, combined with the phase, with saturated sodium bicarbonate solution, saturated sodium chloride, dried anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to obtain 22.9g crude oil. For crude oily substance 5 times dichloromethane refining, shall be 14.8g white solid product.
  • 47
  • [ 863329-66-2 ]
  • N-[(S)-(4-bromo-phenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at -30℃; for 1h; Stage #2: N-[(S)-(4-bromo-phenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester In tetrahydrofuran at -10℃; for 1h; 3 Preparation of Sofosbuvir In the reaction flask, in under oxygen-free conditions, adding 12g intermediate type 2-5,120 ml tetrahydrofuran, stirring, lower the temperature to -30 °C, dropwise 53g tert-butyl magnesium chloride; the drop finishes, stirring for 1 hour, then temperature to -10 °C, dropwise 20.9gN-[ (S) - (4-bromo-phenoxy) phenoxy phosphoryl]-L-alanine isopropyl ester of 150 ml tetrahydrofuran solution; the drop finishes, at -10 ° C reaction under 1 hour, then heating to room temperature reaction, TLC monitoring reaction. After the reaction, cooling to 0 °C, and begin to drop and hydrochloric acid/water (50 ml/300 ml) quenching the reaction; reducing pressure and evaporating thf, then adding 200 ml diethyl ether, stirring the liquid, aqueous layer with ethyl ether (50 ml × 3) extraction, combined with the phase, with saturated sodium bicarbonate solution, saturated sodium chloride, dried anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to obtain 24.5g crude oily substance. For crude oily substance 5 times dichloromethane refining, shall be 15.5g white solid product.
  • 48
  • [ 863329-66-2 ]
  • C17H20ClN2O5P [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
96.4% With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere; 7.1 1, to intermediate A1 as the starting material The 2 the the [...] -deoxy-2-fluoro -2 the [...][...] -C D-methyl uridine (2.6g, 10 . 0mmol, 1 . 0equiv.), intermediate A1 (7.96g, 20 . 0mmol, 2 . 0equiv.), N, N-diisopropyl ethylamine (DIEA, 1.95g, 15 . 0mmol, 1 . 5equiv.), zinc chloride (2.06g, 15 . 0mmol, 1 . 5equiv.) adding flask R 1 in, to 40 ml tetrahydrofuran as solvent. N 2 under the protection of the, heating to 55-60°C, stirring 15-40h. After the reaction, by adding 80 ml ethyl acetate, saturated ammonium chloride washing (40mLx1), 0.5M hydrochloric acid washing (40mLx1), Na 2 CO 3/NaHCO 3 buffer solution (40mLx1), saturated salt water washing (40mLx1), anhydrous sodium sulfate for drying. Remove the solvent to obtain oil turns on lathe does, using acetone/dichloromethane (1/8, V/V) beating crystallization. Product 2.5g, quality yield of 96.4%.
  • 49
  • [ 863329-66-2 ]
  • C17H20ClN2O5P [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
73.1% With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere; 7.2 2, to intermediate A2 as the starting material The 2 the the [...] -deoxy-2-fluoro -2 the [...][...] -C D-methyl uridine (2.6g, 10 . 0mmol, 1 . 0equiv.), intermediate A2 (7.96g, 20 . 0mmol, 2 . 0equiv.), N, N-diisopropyl ethylamine (DIEA, 1.95g, 15 . 0mmol, 1 . 5equiv.), zinc chloride (2.06g, 15 . 0mmol, 1 . 5equiv.) to join flask R 1 in, to 40 ml tetrahydrofuran as solvent. N 2 under the protection of the, heating to 55-60°C, stirring 15-40h. After the reaction, by adding 80 ml ethyl acetate, saturated ammonium chloride washing (40mLx1), 0.5M hydrochloric acid washing (40mLx1), Na 2 CO 3/NaHCO 3 buffer solution (40mLx1), saturated salt water washing (40mLx1), anhydrous sodium sulfate for drying. Remove the solvent to obtain oil turns on lathe does, using acetone/dichloromethane (1/8, V/V) beating crystallization. Product 1.9g, quality yield 73.1%
  • 50
  • [ 863329-66-2 ]
  • C17H20ClN2O5P [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
57.7% With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere; 7.3 3, to intermediate A3 as the starting material The 2 the the [...] -deoxy-2-fluoro -2 the [...][...] -C D-methyl uridine (2.6g, 10 . 0mmol, 1 . 0equiv.), intermediate A3 (7.96g, 20 . 0mmol, 2 . 0equiv.), N, N-diisopropyl ethylamine (DIEA, 1.95g, 15 . 0mmol, 1 . 5equiv.), zinc chloride (2.06g, 15 . 0mmol, 1 . 5equiv.) adding flask R 1 in, to 40 ml tetrahydrofuran as solvent. N 2 under the protection of the, heating to 55-60°C, stirring 15-40h. After the reaction, by adding 80 ml ethyl acetate, saturated ammonium chloride washing (40mLx1), 0.5M hydrochloric acid washing (40mLx1), Na 2 CO 3/NaHCO 3 buffer solution (40mLx1), saturated salt water washing (40mLx1), anhydrous sodium sulfate for drying. Remove the solvent to obtain oil turns on lathe does, using acetone/dichloromethane (1/8, V/V) beating crystallization. Product 1.5g, quality yield is 57.7%.
  • 51
  • [ 863329-66-2 ]
  • C17H20ClN2O5P [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
76.9% With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere; 7.4 4, to intermediate A4 as the starting material The 2 the the [...] -deoxy-2-fluoro -2 the [...][...] -C D-methyl uridine (2.6g, 10 . 0mmol, 1 . 0equiv.), intermediate A4 (7.96g, 20 . 0mmol, 2 . 0equiv.), N, N-diisopropyl ethylamine (DIEA, 1.95g, 15 . 0mmol, 1 . 5equiv.), zinc chloride (2.06g, 15 . 0mmol, 1 . 5equiv.) to join flask R 1 in, to 40 ml tetrahydrofuran as solvent. N 2 under the protection of the, heating to 55-60°C, stirring 15-40h. After the reaction, by adding 80 ml ethyl acetate, saturated ammonium chloride washing (40mLx1), 0.5M hydrochloric acid washing (40mLx1), Na 2 CO 3/NaHCO 3 buffer solution (40mLx1), saturated salt water washing (40mLx1), anhydrous sodium sulfate for drying. Remove the solvent to obtain oil turns on lathe does, using acetone/dichloromethane (1/8, V/V) beating crystallization. Product 2.0g, quality yield 76.9%.
  • 52
  • [ 863329-66-2 ]
  • C17H20ClN2O5P [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
84.6% With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere; 7.5 5, to intermediate A5 as the starting material The 2 the the [...] -deoxy-2-fluoro -2 the [...][...] -C D-methyl uridine (2.6g, 10 . 0mmol, 1 . 0equiv.), intermediate A5 (7.96g, 20 . 0mmol, 2 . 0equiv.), N, N-diisopropyl ethylamine (DIEA, 1.95g, 15 . 0mmol, 1 . 5equiv.), zinc chloride (2.06g, 15 . 0mmol, 1 . 5equiv.) adding flask R 1 in, to 40 ml tetrahydrofuran as solvent. N 2 under the protection of the, heating to 55-60°C, stirring 15-40h. After the reaction, by adding 80 ml ethyl acetate, saturated ammonium chloride washing (40mLx1), 0.5M hydrochloric acid washing (40mLx1), Na 2 CO 3/NaHCO 3 buffer solution (40mLx1), saturated salt water washing (40mLx1), anhydrous sodium sulfate for drying. Remove the solvent to obtain oil turns on lathe does, using acetone/dichloromethane (1/8, V/V) beating crystallization. Product 2.2g, quality yield 84.6%.
  • 53
  • [ 863329-66-2 ]
  • C17H20BrN2O5P [ No CAS ]
  • [ 1064684-44-1 ]
YieldReaction ConditionsOperation in experiment
69.2% With N-ethyl-N,N-diisopropylamine; zinc(II) chloride In tetrahydrofuran at 55 - 60℃; Inert atmosphere; 7.6 6, in order to intermediate A6 as the starting material The 2 the the [...] -deoxy-2-fluoro -2 the [...][...] -C D-methyl uridine (2.6g, 10 . 0mmol, 1 . 0equiv.), intermediate A6 (8.86g, 20 . 0mmol, 2 . 0equiv.), N, N-diisopropyl ethylamine (DIEA, 1.95g, 15 . 0mmol, 1 . 5equiv.), zinc chloride (2.06g, 15 . 0mmol, 1 . 5equiv.) to join flask R 1 in, to 40 ml tetrahydrofuran as solvent. N 2 under the protection of the, heating to 55-60°C, stirring 15-40h. After the reaction, by adding 80 ml ethyl acetate, saturated ammonium chloride washing (40mLx1), 0.5M hydrochloric acid washing (40mLx1), Na 2 CO 3/NaHCO 3 buffer solution (40mLx1), saturated salt water washing (40mLx1), anhydrous sodium sulfate for drying. Remove the solvent to obtain oil turns on lathe does, using acetone/dichloromethane (1/8, V/V) beating crystallization. Product 1.8g, quality yield 69.2%.
  • 54
  • [ 261909-49-3 ]
  • [ 863329-66-2 ]
  • [ 1190307-88-0 ]
  • [ 1190308-01-0 ]
  • C34H45FN4O13P2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-methyl-1H-imidazole; In tetrahydrofuran; at 0 - 20℃; for 2.75h;Inert atmosphere; To a two-neck round bottom flask equipped with a reflux condenser and purged with nitrogen was added 2' -deoxy-2' -fluoro-2' C-methyluridine III (100 mg, 0.38 mmol, 1 equiv) followed by a THF solution of chlorophosphate II (dr = 1 : 1, 1.15 mmol, 3 equiv in 3.52 mL THF). The slightly turbid solution was cooled to 0 C, charged with NMI (196 mL, 2.46 mmol, 6.4 equiv) and stirred at 0 C for 15 min and at room temperature for 2.5h. HPLC analysis with individual response factor correction indicated 78% of III, 9% of sofosbuvir (I) with dr = 41 :59 (Sp:Rp), and 13% of 3' ,5'-bis-phosphoramidate impurity 4 (dr not determined).
  • 55
  • [ 863329-66-2 ]
  • C16H21N2O7P [ No CAS ]
  • [ 1190307-88-0 ]
  • [ 1190308-01-0 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; zinc dibromide; In tetrahydrofuran; at 10℃; for 24h;Molecular sieve; Inert atmosphere; To a two-neck round bottom flask equipped with a reflux condenser and purged with nitrogen was added N-hydroxysuccinimide phosphoramidate II-a' with dr = 72:28 (Sp:Rp) (493 mg, 1.28 mmol, 1.67 equiv) prepared according to Example 1.1 (further crystallized in MTBE to obtain (Sp)-2 with a dr 72:28) and THF (2.5 mL, anhydrous) to obtain a clear solution. To this solution was added 2'-deoxy-2'-fluoro-2'C-methyluridine III (200 mg, 0.77 mmol, 1 equiv), followed by ZnBr2 (173 mg, 0.77 mmol, 1 equiv), 4A molecular sieves (235 mg) and Et3N (320 mL, 2.31 mmol, 3 equiv). The mixture was stirred at room temperature for 4 hours. HPLC analysis with individual response factor correction indicated complete conversion of III, 95% of sofosbuvir (I) with dr = 89 : 11 (Sp:Rp), and 5% of 3' ,5'-bis-phosphoramidate impurity 4 (dr not determined).
  • 56
  • [ 863329-66-2 ]
  • methyl 3,5-dibromo-4-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)benzoate [ No CAS ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
9 g With tert-butylmagnesium chloride; In tetrahydrofuran; at -30 - 20℃; [00123] To a 3-neck RBF was added l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy- 5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (5) (13 g, 0.0498 mol), 3,5-dibromo-4-(((((S)-l-isopropoxy-l-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)methyl benzoate (2a) (145 g, 0.1992 mol, prepared according to example 1), and THF (195 mL). This mixture was cooled to - 30 C followed by slow addition of 1.35M t-BuMgCl (59 mL, 0.08 mol) in 1 h. The reaction mixture was slowly warmed to RT over 5-6 h and stirred at that temperature overnight. 60% Aqueous acetic acid (130 mL) was slowly added, followed by heating the reaction mixture to 90 C for 4 h. The reaction mixture was then cooled to RT and filtered to remove the solid precipitate. The desired product was then extracted with DCM (130 mL x 2) followed by washing with 6% aqueous NaHC03 solution (150 mL). The organic layer was concentrated under vacuum to give a viscous oil. HPLC monitoring showed a ratio of diastereomers (Rp/Sp = 15/85). This oil was dissolved in DCM (52 mL) followed by addition of DIPE (108 mL) to give sofosbuvir as a white solid (9 g, 99.18% purity (Rp+Sp) mixture of diastereomers; Rp/Sp = 3.5/96.5). The product was further purified according to the procedure of example 10.
  • 57
  • C10H15FN2O5 [ No CAS ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
91% With manganese(IV) oxide In toluene at 20℃; for 2h; 12 Compound 11 was prepared 100 g of compound III, 300 g of Mn02, and toluene were added to the 500 mL reaction flask, and the reaction was carried out at room temperature for 2 hours. The mixture was filtered and concentrated toAbout 80mL, add ethyl acetate, stirring 30 minutes, filter cake 45 ° C vacuum drying 5 hours in white needle crystal 90g,Yield 91%, purity 99%
  • 58
  • [ 944476-43-1 ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
92.3% With potassium fluoride; 2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin In N,N-dimethyl-formamide; toluene for 5h; Reflux; 2 Preparation of compound 11 80mL of compound IV, 19.31g of potassium fluoride, 160mL of DMF, 160mL of toluene and 1g of benzo-18-crown-6-ether were charged into a 500mL reaction flask and refluxed for 5 hours to stop the reaction. At room temperature, slowly drippingAdd 200 ml of 1,4-dioxane, precipitate needle crystals, cool to 5-10 ° C, filter, filter cake 200mL beat with ethyl acetate 1 hour filtration, 45 ° C vacuum drying 5 hours in white needle crystal 80g, yield 92.3%, purity 98. 5%.
  • 60
  • [ 863329-66-2 ]
  • C18H23N2O7P [ No CAS ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
14 g t-butyl magnesium chloride (75.0 ml, 1.7M in THF) was added drop wise to the solution of 2,-deoxy-2'-fluoro-2'-methyluridine(15.8g) in THF(316.0ml) at 0-5C over a period of 40- 45min under nitrogen atmosphere. Allowed reaction mass to 25-30C and maintained for 30min at 25-30C. Formula- VI derived from ethyl cyanoacetateoxime (25. Og) in THF (79.0ml) was added to the reaction mass drop wise over the period of 30min at 0-5C, allowed to 25-30c and maintained for overnight. Quenched the reaction mass with 2NHCL(158.0mL) by adjusting pH to2.5 at 10-15C, separated two layers and extracted aqueous layer with ethyl acetate (79.0mL) and THF layer was concentrated and dissolved the residue in ethyl acetate(632. OmL). Combined two ethyl acetate layers and washed with brine solution(316.0mL) then added 5% sodium carbonate solution(316.0mL) at 10-15C and agitated the reaction mixture for 10-15min at 20-25C repeated this operation as thrice of times, then separated two layers then adjusted pH of the organic layer to 6.5-7.0 by adding IN HCl(1.5mL) at 10-15C,organic layers and washed the brine solution(316.0mL) as twice of times followed by activated charcoal(1.5g) treatment and filtered through celite bed .Filtrate was concentrated to obtainsofosbuvir. Yield: 14.0 g
  • 61
  • [ 863329-66-2 ]
  • (S)-2-((S)-(4-trifluoromethoxyphenoxy)phenoxyphosphorylamino)isopropyl propionate [ No CAS ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
38% With tert-butylmagnesium chloride; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; Under nitrogen, l0 mg (2'R) -2'_ deoxy-2'-fluoro-2'-methylurer (0.38 mmol) and anhydrous tetrahydrofuranLmL was added to the reaction flask and dropped to 0 C, and then a 1.3 M solution of t-butylmagnesium chloride (0.6 mL, 0.8 mmol) was slowly added dropwise. StirAfter 30 min, 280 mg of (S) -2_ [(S) - (4-bis-methoxy-phenoxy) -phenoxy-Ester (0.6 lmmo 1). The mixture was stirred at room temperature for 48 h and then quenched with saturated aqueous NH4C1 (10 mL). The mixture is in BEthyl acetate (30 mL) and water. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. Use 0-4% AThe residue was chromatographed by a gradient of alcohol / dichloromethane to give 85.6 mg of a white solid in a yield of 38%
  • 62
  • [ 879551-04-9 ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: lithium tri-t-butoxyaluminum hydride / tetrahydrofuran / 0.5 h / -20 - 0 °C 2.1: triethylamine / dichloromethane / 0.5 h / 0 - 20 °C 3.1: N,O-bis-(trimethylsilyl)-acetamide / chlorobenzene / 0.5 h / Reflux 3.2: Reflux 4.1: sodium methylate / methanol / Reflux
  • 63
  • [ 863329-66-2 ]
  • C20H19F5NO6P [ No CAS ]
  • C24H31FN3O10P [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 25℃; for 1h; Inert atmosphere; Stage #2: C20H19F5NO6P In tetrahydrofuran at 0 - 20℃; for 15h; Inert atmosphere; 1 (S) -isopropyl ((((2R, 3R, 4R, 5R) -5- (2,4-dicarbonyl-3,4-dihydropyrimidin-Yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (2,3-dihydrobenzofuran-Yl) phosphoryl) amino) propionate (K1) A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and argon was purged three times. Tert-butylmagnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 0 ° C and the reaction was carried out at 25 ° C for 1 hour.(S) -isopropyl-2 - (((pentafluorophenoxy) (2,3-dihydrobenzofuran-6-oxy) phosphoryl) amino group was added dropwise to a solution of the above intermediate compound ) Of propionate (493 mg, 1 mmol) in dry tetrahydrofuran (10 mL). After completion of the dropwise addition, the reaction was allowed to proceed to room temperature for 15 hours.Drop a few drops of 2M hydrochloric acid to the reaction system to clarify. Add water 30mL diluted, 2M hydrochloric acid transferred to neutral. The reaction system was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography, To give the title compound (K1) (250 mg, yield 55%).
  • 64
  • [ 863329-66-2 ]
  • C24H21F5NO6P [ No CAS ]
  • C28H33FN3O10P [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 30℃; for 1h; Inert atmosphere; Stage #2: C24H21F5NO6P In tetrahydrofuran at 0 - 25℃; for 10h; Inert atmosphere; 6 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and argon was purged three times.Tert-butylmagnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 0 ° C and the reaction was carried out at 30 ° C for 1 hour. (4) phenoxy (2-phenoxyphenoxy) phosphoryl) amino) propionate (545 mg, & lt; RTI ID = 0.0 & gt; 1 mmol) in dry tetrahydrofuran (10 mL).After completion of the dropwise addition, the reaction was allowed to proceed to 25 ° C for 10 hours. Drop a few drops of 2M hydrochloric acid to the reaction system to clarify.Add water 30mL diluted, 2M hydrochloric acid transferred to neutral.The reaction system was extracted with ethyl acetate and the combined organic phases were collected with saturated aqueous sodium bicarbonate solution,Washed with saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound (K6) (186 mg, yield 30%).
  • 65
  • [ 863329-66-2 ]
  • C23H16F6NO7P [ No CAS ]
  • C27H28F2N3O11P [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 30℃; for 3h; Inert atmosphere; Stage #2: C23H16F6NO7P In tetrahydrofuran at 0 - 20℃; for 10h; Inert atmosphere; 7 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and argon was purged three times.Tert-butyl magnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 0 ° C and the reaction was carried out at 30 ° C for 3 hours.(6-fluorobenzyl-2 - ((pentafluorophenoxy) (benzo [d] [1,3] dioxolane-5-oxo) was added dropwise to a solution of the above intermediate compound (S) Yl) phosphoryl) amino) propionate (563 mg, 1 mmol) in dry tetrahydrofuran (15 mL). After completion of the dropwise addition, the reaction was allowed to proceed to 20 ° C for 10 hours.Drop a few drops of 2M hydrochloric acid to the reaction system to clarify. Add water 30mL diluted, 2M hydrochloric acid transferred to neutral.The reaction mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound (K7) (200 mg, yield 31% ).
  • 66
  • [ 863329-66-2 ]
  • C25H21F5NO7P [ No CAS ]
  • C29H33FN3O11P [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 5 - 20℃; for 2h; Inert atmosphere; Stage #2: C25H21F5NO7P In tetrahydrofuran at 0 - 10℃; for 14h; Inert atmosphere; 10 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and argon was purged three times.Tert-butylmagnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 5 ° C, and the mixture was allowed to react at 20 ° C for 2 hours. (4) (benzo [d] [1,3] dioxolan-5-yl) was added dropwise to a solution of the above intermediate compound (S) -isopropyl 2 - ((pentafluorophenoxy) ) -phenoxy) phosphoryl) amino) propionate (573 mg, 1 mmol) in dry tetrahydrofuran (30 mL).After completion of the dropwise addition, the reaction was continued to 10 ° C for 14 hours. Drop a few drops of 2M hydrochloric acid to the reaction system to clarify. Add water 30mL diluted, 2M hydrochloric acid transferred to neutral.The reaction mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound (K10) (300 mg, yield 46% ).
  • 67
  • [ 863329-66-2 ]
  • C21H22F5N2O6P [ No CAS ]
  • C25H34FN4O10P [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 25℃; for 1h; Inert atmosphere; Stage #2: C21H22F5N2O6P In tetrahydrofuran at 0 - 25℃; for 15h; Inert atmosphere; 20 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and argon was purged three times.Tert-butylmagnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 0 ° C and the reaction was carried out at 25 ° C for 1 hour.(S) -isopropyl-2 - ((pentafluorophenoxy) 4-methyl-2H-benzo [b] [1,4] morpholine-8 Oxy) phosphoryl) amino) propionate (524 mg, 1 mmol) in dry tetrahydrofuran (10 mL).After completion of the dropwise addition, the reaction was brought to 25 ° C for 15 hours.Drop a few drops of 2M hydrochloric acid to the reaction system to clarify. Add 40mL of water diluted, 2M hydrochloric acid transferred to neutral. The reaction mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium bicarbonate and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound (K20) (245 mg, 41%).
  • 68
  • [ 863329-66-2 ]
  • C24H16F6NO6P [ No CAS ]
  • C28H28F2N3O10P [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 25℃; for 2h; Inert atmosphere; Stage #2: C24H16F6NO6P With triethylamine In tetrahydrofuran at 0 - 25℃; for 10h; Inert atmosphere; 24 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and argon was purged three times.Tert-butylmagnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 0 ° C and the reaction was carried out at 25 ° C for 2 hours. (6-fluorobenzyloxy) (benzofuran-6-oxy) phosphoryl) amino) propionate was added dropwise to a solution of the compound (S) -4-fluorobenzyl-2 - ((pentafluorophenoxy) 560 mg, 1 mmol) in dry tetrahydrofuran (10 mL).After completion of the dropwise addition, the reaction was allowed to proceed to 25 ° C for 10 hours.Drop a few drops of 2.5M hydrochloric acid to the reaction system to clarify. Add water 35mL diluted, 2M hydrochloric acid transferred to neutral.The reaction system was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography,To give the title compound (K24) (273 mg, yield 43%).
  • 69
  • [ 863329-66-2 ]
  • C24H20F6NO6P [ No CAS ]
  • C28H32F2N3O10P [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 5 - 25℃; for 2h; Inert atmosphere; Stage #2: C24H20F6NO6P In tetrahydrofuran at 0 - 25℃; for 15h; Inert atmosphere; 30 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and argon was purged three times.Tert-butyl magnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 5 ° C and the reaction was carried out at 25 ° C for 2 hours.(4- (4-fluorophenoxy) phenoxy) phosphoryl) amino) propionic acid was added dropwise to a solution of the above intermediate (S) -isopropyl-2 - ((pentafluorophenoxy) Ester (563 mg, 1 mmol) in dry tetrahydrofuran (10 mL).After completion of the dropwise addition, the reaction was brought to 25 ° C for 15 hours. Drop a few drops of 2M hydrochloric acid to the reaction system to clarify.Add water 30mL diluted, 2M hydrochloric acid transferred to neutral. The reaction mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium bicarbonate and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound (K30) (281 mg, yield 44% ).
  • 70
  • [ 863329-66-2 ]
  • C24H18F6NO7P [ No CAS ]
  • C28H30F2N3O11P [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 25℃; for 1h; Inert atmosphere; Stage #2: C24H18F6NO7P In tetrahydrofuran at 0 - 25℃; for 15h; Inert atmosphere; 31 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl)Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and argon was purged three times.Tert-Butylmagnesium chloride (1.0 mol / L, 3.5 mL, 3.5 mmol) was added dropwise at 0 ° C and the reaction was carried out at 25 ° C for 1 hour.(6-fluorobenzyl-2 - ((pentafluorophenoxy) (2,3-dihydrobenzo [1,4] dioxetane-5) was added dropwise to a solution of the above intermediate (S)-oxy) phosphoryl) amino) propionate (577 mg, 1 mmol) in dry tetrahydrofuran (20 mL).After completion of the dropwise addition, the reaction was brought to 25 ° C for 15 hours.Drop a few drops of 2M hydrochloric acid to the reaction system to clarify.Add water 30mL diluted, 2M hydrochloric acid transferred to neutral.The reaction mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound (K31) (294 mg, yield 45%).
  • 71
  • [ 863329-66-2 ]
  • C24H20ClF5NO6P [ No CAS ]
  • C28H32ClFN3O10P [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With methylmagnesium bromide In tetrahydrofuran at 0 - 25℃; for 1h; Inert atmosphere; Stage #2: C24H20ClF5NO6P In tetrahydrofuran at 0 - 30℃; for 15h; Inert atmosphere; 32 A solution of 1 - ((2R, 3R, 4R, 5R) -3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl)Diketone (260 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) and argon was purged three times.Methylmagnesium chloride (1.0 mol / L, 2.5 mL, 2.5 mmol) was added dropwise at 0 ° C and the reaction was carried out at 25 ° C for 1 hour.(4- (4-chlorophenoxy) phenoxy) phosphoryl) amino) propionic acid was added dropwise to a solution of the above intermediate (S) -isopropyl-2 - ((pentafluorophenoxy)Ester (580 mg, 1 mmol) in dry tetrahydrofuran (10 mL).After completion of the dropwise addition, the reaction was brought to 30 ° C for 15 hours.Drop a few drops of 2M hydrochloric acid to the reaction system to clarify.Add water 30mL diluted, 2M hydrochloric acid transferred to neutral.The reaction mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium bicarbonate and saturated brine, dried, filtered and concentrated. The residue was purified by column chromatography to give the title compound (K32) (249 mg, yield 38%).
  • 72
  • [ 863329-66-2 ]
  • C16H13F5NO5P [ No CAS ]
  • C20H25FN3O9P [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0 - 25℃; for 1h; Inert atmosphere; Stage #2: C16H13F5NO5P In tetrahydrofuran at 0 - 25℃; for 15h; Inert atmosphere; 60 2 - (( (( (2R, 3R, 4R, 5R) -5 - (2, 4 - dicarbonyl - 3, 4 - dihydro pyrimidine -1 (2H) - yl) -4 - fluoro -3 - hydroxy -4 - methyl tetrahydrofuran -2 - yl) methoxy) (phenoxy) phosphoryl) amino) ethyl acetate (K60) preparation The 1 - ((2R, 3R, 4R, 5R) -3 - fluoro -4 - hydroxy -5 - hydroxymethyl -3 - methyl tetrahydrofuran -2 - yl) pyrimidine - 2, 4 - (1H, 3H) - dione (260 mg, 1mmol) dissolved in anhydrous tetrahydrofuran (20 ml) in the, argon substitution three times. For 0 °C drop which is in butyl magnesium chloride (1.0 mol/L, 2.5 ml, 2 . 5mmol), up to 25 °C reaction 1 hours. Lowering the temperature to 0 °C, dropping the intermediate compound 2 - (( (five monofluoro-benzene oxygen radical) (phenoxy) phosphoryl) amino) ethyl acetate (425 mg, 1 . 0mmol) anhydrous tetrahydrofuran (10 ml) solution. The completion of the dropping, to rise to 25 °C reaction 15 hours. Dropwise 2M several drops of hydrochloric acid to the reaction system and variable clarification. Adding 30 ml dilution, 2M hydrochloric acid to neutral. The reaction system is extracted with ethyl acetate, the combined organic phase collected respectively saturated aqueous solution of sodium bicarbonate for, saturated salt water washing, drying, filtering and concentrating, the residue by column chromatography purification, to obtain a mixture of diastereoisomers (150 mg, 30%).
  • 73
  • [ 863329-66-2 ]
  • [ 1334513-02-8 ]
  • [ 1190307-88-0 ]
  • [ 1190308-01-0 ]
  • (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-2-((((S)-(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4-methyltetrahydrofuran-3-yl)oxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
  • 74
  • [ 863329-66-2 ]
  • [ 1334513-02-8 ]
  • [ 1190307-88-0 ]
  • (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-2-((((S)-(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-4-methyltetrahydrofuran-3-yl)oxy)(phenoxy)phosphoryl)amino)propanoate [ No CAS ]
  • 75
  • C19H39FO5Si2 [ No CAS ]
  • [ 66-22-8 ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
72% Stage #1: uracil With ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane In chlorobenzene Reflux; Stage #2: C19H39FO5Si2 With tin(IV) chloride In chlorobenzene at 50℃; Stage #3: With tetrabutyl ammonium fluoride In tetrahydrofuran at 55 - 60℃; 1.4 Preparation of To the reaction flask was added 168 g of hexamethyldisilazane,1000 mL of chlorobenzene, 5 g of ammonium sulfate, and 71 g of uracil, stirred, heated to reflux reaction, TLC monitoring reaction; reaction is completed,To the room temperature, then add the next step to the reaction of intermediate III, stirring, adding 163 g of tin tetrachloride, heating to 50 ° C reaction,TLC Monitoring reaction: After completion of the reaction, cooling to room temperature, adding 105 g of sodium bicarbonate and 100 g of glucomannan, stirring, filtering, filtering the cake and then chlorobenzene (500mL X 3) to fight the public, the organic phase, with saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give the intermediate.The intermediate was placed in 6-fold amount of tetrahydrofuran, stirred and dissolved, 20 g of tetrabutylammonium fluoride was added, the temperature was raised to 55-60 ° C, the incubation reaction and the TLC monitoring reaction were carried out. After completion of the reaction, the solvent was evaporated under reduced pressure to give crude product. The crude product was purified with 5-fold amount of isopropanol to give 72 g of a white solid product. Refined mother fluid stand. Yield: 72%.
  • 76
  • (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate [ No CAS ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
94% With ammonia In methanol at 0 - 15℃; for 27h; 5 preparation of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine At 0 °C, the embodiment (2'R) -2'-deoxy-2'-fluoro-2'-methyluridine3 ', 5'-benzoate obtained in Preparation Example 3 was dissolved in 0.6g 25% ammonia in methanol (10ml, 25% mass fraction), and 0°C maintained for 3 hours, warmed to 15 deg.] C and then stirred for 24 hours, filtered and the filtrate was concentrated under reduced pressure, slurried with ethyl acetate, to give 0.31g as a white solid, yield 94%, optical purity% 99.8%.
92.6% With methanol; triethylamine for 53h; Reflux; 7 General procedure: Add 4g of compound b (8.54mmol), 32g of anhydrous methanol, 4g of triethylamine (39.53mmol) into the reaction flask, stir, and the system becomes white and turbid; the temperature is raised to reflux until the solid disappears, which takes about 28h;After the reaction was carried out for 25 hours, samples were taken every 2 hours for HPLC control until the content of compound b was below 0.2%; After the reaction, the temperature is lowered to 50±5°C, 0.2g activated carbon is added and the temperature is raised to the reflux state and kept for 1h;After the decolorization is completed, control the temperature below 60°C, and adjust the vacuum to below -0.08MPa, carry out reduced pressure desolvation, and stop desolvation when no fraction flows out; Add 10.6g of dichloromethane, raise the temperature to 38±3, stir for 1h, then lower the temperature to 23±5, stir until there is solid precipitation, filter, the filter cake is the crude wet product of compound a;Add 10g of isopropanol to the crude wet product, heat to reflux and maintain this state for 1 hour,Then the temperature is lowered to room temperature, and then the temperature is lowered to 5±2° C., the temperature is kept for 2 hours to crystallize; it is filtered and dried to obtain compound a. The total yield is 93.8%, and the purity of the target product is 99.5%.
  • 77
  • ((2R,3R,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl acetate [ No CAS ]
  • [ 863329-66-2 ]
YieldReaction ConditionsOperation in experiment
92.5% With ammonia In methanol at 5 - 25℃; for 26h; 6 preparation of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine At 5°C , prepared in Example 4 to give the embodiment (2'R) -2'-deoxy-2'-fluoro-2'-methyl-uridine 3 ', 5'-diacetate was dissolved in ammonia 3g in methanol (20ml, 25% mass fraction), 5°C and maintained for 2 hours, warmed to 25 deg.] C and then stirred for 24 hours, filtered, and the filtrate was concentrated under reduced pressure, slurried with ethyl acetate, to give 2.1g white solid, yield 92.5%.
90.5% With methanol; triethylamine for 53h; Reflux; 6 General procedure: Add 4g of compound b (8.54mmol), 32g of anhydrous methanol, 4g of triethylamine (39.53mmol) into the reaction flask, stir, and the system becomes white and turbid; the temperature is raised to reflux until the solid disappears, which takes about 28h;After the reaction was carried out for 25 hours, samples were taken every 2 hours for HPLC control until the content of compound b was below 0.2%; After the reaction, the temperature is lowered to 50±5°C, 0.2g activated carbon is added and the temperature is raised to the reflux state and kept for 1h;After the decolorization is completed, control the temperature below 60°C, and adjust the vacuum to below -0.08MPa, carry out reduced pressure desolvation, and stop desolvation when no fraction flows out; Add 10.6g of dichloromethane, raise the temperature to 38±3, stir for 1h, then lower the temperature to 23±5, stir until there is solid precipitation, filter, the filter cake is the crude wet product of compound a;Add 10g of isopropanol to the crude wet product, heat to reflux and maintain this state for 1 hour,Then the temperature is lowered to room temperature, and then the temperature is lowered to 5±2° C., the temperature is kept for 2 hours to crystallize; it is filtered and dried to obtain compound a. The total yield is 93.8%, and the purity of the target product is 99.5%.
  • 78
  • [ 863329-66-2 ]
  • ((R)-([1,1'-biphenyl]-4-yloxy)(pentafluorophenoxy)phosphoryl)-D-alanine isopropyl ester [ No CAS ]
  • ((R)-([1,1'-biphenyl]-4-yloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)D-alanine isopropyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ((R)-([1,1'-biphenyl]-4-yloxy)(pentafluorophenoxy)phosphoryl)-D-alanine isopropyl ester In tetrahydrofuran at 0℃; for 24h; Heating; 9.2 synthesis of I - 23 b To 10 ml reaction tube joining the nucleoside 7 (130.1 mg, 0.5 mmol) and 3.0 ml anhydrous THF, the mixture in the ice water bath cooled to 0 °C. Drop which is in butyl magnesium chloride Grignard reagent (1.5 ml of 1 M THF solution, 1.5 mmol), the reaction mixture is stirred under O °C 30 min, then at 0 °C the dripping which contains reagent 12 (846 mg, 1.6 mmol) in 3 ml THF in solution. The resulting clear reaction solution temperature, stirring 1 day. Add saturated NH4 Cl (15 ml), stirring 5 minutes, the mixture of ethyl acetate (150 ml) dilution. Separating the organic phase, the aqueous layer of ethyl acetate (30 ml) extraction. The combined organic layer using water (30 ml), saturated NaHCO3 (2 x 3 OmL), brine (3 OmL) washing, and the Na2 SO4 Drying. Evaporating the solvent under reduced pressure, the residue by silica gel column chromatography (0 - 10% methanol in dichloromethane) purification, to obtain white solid product I - 23 to the b (176 mg), yield 58%).
  • 79
  • [ 863329-66-2 ]
  • ((S)-([1,1'-biphenyl]-4-yloxy)(pentafluorophenoxy)phosphoryl)-D-alanine isopropyl ester [ No CAS ]
  • ((S)-([1,1'-biphenyl]-4-yloxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)D-alanine isopropyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ((S)-([1,1'-biphenyl]-4-yloxy)(pentafluorophenoxy)phosphoryl)-D-alanine isopropyl ester In tetrahydrofuran at 0℃; for 24h; Heating; 10 Nucleoside 7 (130 mg, 0.5 mmol) and 3.0 mL of anhydrous THF were added to the lOmL reaction tube and the mixture was cooled to 0 ° C in an ice-water bath.A solution of tert-butylmagnesium chloride Grignard reagent (1.5 mL of 1 M in THF, 1.5 mmol) was added dropwise and the reaction mixture was stirred at 0 ° C for 30 min followed by the addition of phosphorus reagent 13 (846 mg, 1.6 mmol) THF solution.The resulting clear reaction solution was heated and stirred for 1 day. Saturated NH4C1 (15 mL) was added, stirred for 5 minutes, and the mixture was diluted with ethyl acetate (150 mL). The organic phase was separated and the aqueous layer was extracted with ethyl acetate (30 mL).The combined organic layers were washed with water (30 mL), saturated NaHC03 (2 x 30 mL), brine (30 mL) and dried over Na2S04.The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give the white solid product I-23c (158 mg) in 52% yield,
  • 80
  • [ 863329-66-2 ]
  • (R)-2-((R)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino)propionic acid isopropyl ester [ No CAS ]
  • ((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alanine isopropyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: (R)-2-((R)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino)propionic acid isopropyl ester In tetrahydrofuran at 0℃; for 24h; Heating; 1.2 synthesis of 1-01b To the lOmL reaction tube was added nucleoside 7 (260.2 mg, lmmol)And 5.0 mL of dry THF, and the mixture was cooled to 0 ° C in an ice-water bath.A solution of tert-butylmagnesium chloride Grignard reagent (3.0 mL of 1 M in THF, 3.0 mm) was added dropwise and the reaction mixture was stirred at 0 ° CFollowed by a dropwise addition of a solution of phosphorus reagent 5 (725 mg, 1.6 mmol) in 5 mL of THF at 0 ° C.The resulting clear reaction solution was heated and stirred for 1 day.Saturated NH4C1 (15 mL) was added, stirred for 5 minutes, and the mixture was diluted with ethyl acetate (200 mL).The organic phase was separated and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were saturated with water (30 mL)NaHC03 (2 x 30 mL), brine (30 mL) and dried over Na2S04.The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give the product 1-0113 (296mg) as a white solid, 56% yield)
  • 81
  • [ 863329-66-2 ]
  • ((R)-(4-cyclopropylphenoxy)(pentafluorophenyloxy)phosphoryl)-D-alanine isopropyl ester [ No CAS ]
  • ((R)-(4-cyclopropylphenoxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)-D-alanine isopropyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ((R)-(4-cyclopropylphenoxy)(pentafluorophenyloxy)phosphoryl)-D-alanine isopropyl ester In tetrahydrofuran at 0℃; for 24h; Heating; 13.2 synthesis of I-27b To 10 ml reaction tube joining the nucleoside 7 (130.1 mg, 0.5 mmol) and 3.0 ml anhydrous THF, the mixture in the ice water bath cooled to 0 °C. Drop which is in butyl magnesium chloride Grignard reagent (1.5 ml of 1 M THF solution, 1.5 mmol), the reaction mixture is stirred under O °C 30 min, then at 0 °C the dripping which contains reagent 15 (790 mg, 1.6 mmol) in 3 ml THF in solution. The resulting clear reaction solution temperature, stirring 1 day. Add saturated NH4 Cl (15 ml), stirring 5 minutes, the mixture of ethyl acetate (150 ml) dilution. Separating the organic phase, the aqueous layer of ethyl acetate (30 ml) extraction. The combined organic layer using water (30 ml), saturated NaHCO3 (2 x 3 OmL), brine (3 OmL) washing, and the Na2 SO4 Drying. Evaporating the solvent under reduced pressure, the residue by silica gel column chromatography (0 - 10% methanol in dichloromethane) purification, to obtain white solid product I - 27 the b (151 mg), yield 53%).
  • 82
  • [ 863329-66-2 ]
  • ((S)-(4-cyclopropylphenoxy)(pentafluorophenyloxy)phosphoryl)-D-alanine isopropyl ester [ No CAS ]
  • ((S)-(4-cyclopropylphenoxy)(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)-D-alanine isopropyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ((S)-(4-cyclopropylphenoxy)(pentafluorophenyloxy)phosphoryl)-D-alanine isopropyl ester In tetrahydrofuran at 0℃; for 24h; Heating; 14 To the 10 mL reaction tube was added nucleoside 7 (130. lmg, 0.5 mmol) and 3.0 mL of dry THF, and the mixture was cooled to 0 ° C in an ice-water bath.A solution of tert-butylmagnesium chloride Grignard reagent (1.5 mL of 1 M in THF, 1.5 mmol) was added dropwise and the reaction mixture was stirred at 0 ° C for 30 min followed by the addition of phosphorus reagent 16 (790 mg, 1.6 mmol) THF solution.The resulting clear reaction solution was heated and stirred for 1 day.Saturated NH4C1 (15 mL) was added, stirred for 5 minutes, and the mixture was diluted with ethyl acetate (150 mL).The organic phase was separated and the aqueous layer was extracted with ethyl acetate (30 mL).The combined organic layers were washed with water (30 mL), saturated NaHC03 (2 x 30 mL), brine (30 mL) and dried over Na2S04.The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give the white solid product I-27c (151 mg) in 53% yield.
  • 83
  • [ 863329-66-2 ]
  • ((R)-(pentafluorophenoxy)(phenoxy)phosphoryl)-D-alanine-isopropyl ester-d6 [ No CAS ]
  • C22H23(2)H6FN3O9P [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ((R)-(pentafluorophenoxy)(phenoxy)phosphoryl)-D-alanine-isopropyl ester-d6 In tetrahydrofuran at 0℃; for 24h; Heating; 24 To 10 ml reaction tube joining the nucleoside 7 (260.2 mg, 1 mmol) and 5.0 ml anhydrous THF, the mixture in the ice water bath cooled to 0 °C. Drop which is in butyl magnesium chloride Grignard reagent (3.0 ml of 1 M THF solution, 3.0 mmol), the reaction mixture is stirred under O °C 30 min, then at 0 °C the dripping which contains reagent 22 (735 mg, 1.6 mmol) in 5 ml THF in solution. The resulting clear reaction solution temperature, stirring 1 day. Add saturated NH4 Cl (15 ml), stirring 5 minutes, the mixture of ethyl acetate (200 ml) dilution. Separating the organic phase, the aqueous layer of ethyl acetate (30 ml) extraction. The combined organic layer using water (30 ml), saturated NaHCO3 (2 x 3 OmL), brine (3 OmL) washing, and the Na2 SO4 Drying. Evaporating the solvent under reduced pressure, the residue by silica gel column chromatography (0 - 10% methanol in dichloromethane) purification, to obtain white solid product III - 01 b
  • 84
  • [ 863329-66-2 ]
  • ((R)-(pentafluorophenoxy)(phenoxy)phosphoryl)-D-alanine-isopropyl ester-d6 [ No CAS ]
  • C22H23(2)H6FN3O9P [ No CAS ]
YieldReaction ConditionsOperation in experiment
56.6% Stage #1: 2'-deoxy-2'-fluoro-2'-methyluridine With tert-butylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: ((R)-(pentafluorophenoxy)(phenoxy)phosphoryl)-D-alanine-isopropyl ester-d6 In tetrahydrofuran at 0℃; for 24h; Heating; 25 To 10 ml reaction tube joining the nucleoside 7 (260.2 mg, 1 mmol) and 5.0 ml anhydrous THF, the mixture in the ice water bath cooled to 0 °C. Drop which is in butyl magnesium chloride Grignard reagent (3.0 ml of 1 M THF solution, 3.0 mmol), the reaction mixture is stirred under O °C 30 min, then at 0 °C the dripping which contains reagent 23 (735 mg, 1.6 mmol) in 5 ml THF in solution. The resulting clear reaction solution temperature, stirring 1 day. Add saturated NH4 Cl (15 ml), stirring 5 minutes, the mixture of ethyl acetate (200 ml) dilution. Separating the organic phase, the aqueous layer of ethyl acetate (30 ml) extraction. The combined organic layer using water (30 ml), saturated NaHCO3 (2 x 3 OmL), brine (3 OmL) washing, and the Na2 SO4 Drying. Evaporating the solvent under reduced pressure, the residue by silica gel column chromatography (0 - 10% methanol in dichloromethane) purification, to obtain white solid product III - 01 the c (303 mg), yield 56.6%).
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