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[ CAS No. 1190307-88-0 ]

{[proInfo.proName]} (Synonyms:GS-7977; PSI-7977) ,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 1190307-88-0
Chemical Structure| 1190307-88-0
Structure of 1190307-88-0 * Storage: {[proInfo.prStorage]}

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Product Details of [ 1190307-88-0 ]

CAS No. :1190307-88-0 MDL No. :MFCD26523124
Formula : C22H29FN3O9P Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :529.45 g/mol Pubchem ID :-
Synonyms :

1. Sofosbuvir

Safety of [ 1190307-88-0 ]

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

Application In Synthesis of [ 1190307-88-0 ]

  • Downstream synthetic route of [ 1190307-88-0 ]

[ 1190307-88-0 ] Synthesis Path-Downstream   1~25

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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
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  • (S)-2-[(1R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yI)-4-(R)-fluoro-3-(4-oxopentanoyl)-4-methyl-tetrahydrofuran-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid (S)-isopropyl ester [ No CAS ]
  • [ 1190307-88-0 ]
YieldReaction ConditionsOperation in experiment
100% With sodium sulfite; In tetrahydrofuran; water; at 20℃; for 4h; A solution of sodium sulfite was prepared by adding Na2S2O3 (1.51 g) andNa2S2O5 (0.57 g) in water (25 niL). To a solution of the levulinate (11, 250 mg, 0.40 mmol) in anhydrous THF (2.5 mL) was added 1.0 ml of the sodium sulfite solution. This was allowed to stir at room temperature for 4 h. The reaction mixture was poured in to water (15 mL) and extracted with ethyl acetate (3x25 mL) dried and evaporated to give quantitatively a white solid product with about 97% P chiral purity which matched the physical and spectral properties of Sp-4 produced directly from the unprotected nucleoside.
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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 .
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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).

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YieldReaction ConditionsOperation in experiment
3.11 g With hydrogenchloride; In di-isopropyl ether; water; at 22℃; for 72h; Example 10: Preparation of Compound 10 (from US2010/0298257) Direct precipitation of Compound 10 (from US2010/0298257; Example 4): To a stirred solution of L-alanine isopropyl ester hydrochloride (10.5 g, 61.5 mmol, azeotropically dried, two times, with 50 mL of toluene each time) in dichloromethane (100 mL) was added phenydichlorophosphate (7.5 mL, 50 mmol) at room temperature. The mixture was cooled to - 10 C. and then was added a solution of N-Methylimidazole (30.5 mL, 384.3 mmol) in 30 mL of dichloromethane over a period of 30 min. After completion of the addition, the mixture was stirred between -10 and -15 C. for 1 h. To the above mixture was added 2'-deoxy-2'-fluoro-2'- C-methyluridine (10 g, 38.4 mmol) (see US2010/0298257 Example 1) in one lot and the mixture was stirred below -10 C. for 3 h and then slowly allowed to warm to 20 C. (6 h). The mixture was stirred at this temperature overnight (15 h) and then quenched with 10 mL of methanol. The solvent was evaporated and the residue was re-dissolved in EtOAc (200 mL). The EtOAc layer was washed with water (100 mL), 1 N HCI (3x75 mL), 2% aqueous NaHC03 solution (50 mL) and brine (50 mL). The organic layer was dried over Na2S04 filtered and concentrated. The residue was dried under high vacuum for 2 h to give white foam (22 g). The above foam was dissolved in 33 mL of HCI and then was added 65 mL of isopropyl ether to give a saturated solution. The solution was filtered though a small pad of Celite and the filtrate was stirred with seeds of Compound 10 for 72 h at ambient temperature (about 22 C.-note that cooling the suspension to 0 C. led to oiling out the crude product). The white solid was filtered, washed with isopropyl ether (20 mL) and dried to give 4.58 g (-85:15 mixture of Compound 10: R isomer at P respectively as determined by 31 P NMR) of a white powder. The above solid was suspended in 23 mL of HCL and then refluxed for 3 h. The mixture was cooled to room temperature and stirred for 15 h. The white solid was filtered, washed with 4.5 mL of cold HCI and dried under high vacuum at 45 C. to give pure Compound 10, mp 93.9-104.7 C HPLC purity 99.74% (3.11 g, 15.2% from the uridine nucleoside). Compound 10: 1H-NMR (CDCI3) delta 8.63 (br s, 1H, NH), 7.47 (d, 1 H, C6-H), 7.30 (m, 2H, o- aromatic), 7.26-7.18 (m, 3H, m,p-aromatic), 6.18 (br d, IH, Cl'-H), 5.70 (d, IH, C5-H), 5.02 (sept, CH-(CH3)2), 4.53 (m, 2H, C-5'-H2), 4.11 (d, IH, C3'-H), 3.97 (m, 3H, C3'-OH, C4'-H, ala-CH- CH3), 3.77 (br s, IH, ala-NH), 1.39 (d, 3H.C2'- CH3), 1.37 (d, 3H, ala- CH3) 1.24 (d, 6H, CH- (CH3)2).
60 g In paraffin oil; at 20 - 60℃; L-alanine isopropyl ester hydrochloride (87.4 g) and toluene (500 mL) were heated to reflux azeotropically till complete removal of water. The reaction mass was then cooled to 50C and solvent was removed under reduced pressure. MDC was charged into the resultant solid and mass was cooled to -60 to -50C. Phenyldichloro phosphate (100.0 g) was charged into the reaction mass at -60C to -50C. N-methylimidazole (351.70 g) was charged into the reaction mass and the reaction mixture was stirred for 1 hour at - 60 to -50C. (2'R)-2'-Deoxy-2'-fluoro-2'-methyl uridine (94.89 g) was charged into the reaction mixture at -60 to -50C. The reaction mixture was allowed to warm to RT and stirred overnight. Reaction mass was monitored by HPLC (ratio of (Sp) : (Rp) = 55 : 45). The reaction mixture was concentrated under reduced pressure. Paraffin oil (500 mL) was charged into the residual mass and the reaction mixture was heated to 60C. The reaction mixture was stirred for 3 hours at 60C. The reaction mixture was cooled to RT and stirred overnight. The reaction was monitored by HPLC (ratio of (Sp) : (Rp) = 100 : ND). The reaction mixture was filtered and washed with MTBE (300 mL). The solid was dissolved in ethyl acetate and washed with IN HC1 solution (500mL). Ethyl acetate layer was separated from aqueous layer. Ethyl acetate layer was washed with saturated bicarbonate solution (500 mL followed by brine solution (500 mL). The reaction mixture was concentrated under reduced pressure. To residue, MDC (330 mL) and diisopropyl ether (660 mL) were added and stirred overnight at RT. The reaction mixture was filtered and washed with MTBE. The solid was further purified in MDC (500 mL) and filtered. The material was dried at 40-45C in under reduced pressure to get pure (Sp)-isomer (60 g) wherein (Rp)-isomer is not detectable on HPLC.
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  • 3',5'-O-dibenozyl-2'deoxy-2'-fluoro-2'-C-methyl-N4-benzoylcytidine [ No CAS ]
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  • (2‘R)-2‘-deoxy-2’-fluoro-2-methyluridine-3’,5’-dibenzoate [ No CAS ]
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  • [ 261909-49-3 ]
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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%).
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  • (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(4-(benzoylamino)-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl)tetrahydrofuran-2ylmethoxy)(phenoxy) phosphorylamino)propanoate [ No CAS ]
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YieldReaction ConditionsOperation in experiment
65% With water; acetic acid; In tetrahydrofuran; for 5h;Reflux; [00132] To a 3-neck RBF was added N-(l-((2R,3R,4R,5R)-3-fluoro-4- hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)benzamide (6a) (7 g, 0.02 mol), 2-(dimethylamino)ethyl 3,5- dibromo-4-(((((S)-l-isopropoxy-l-oxopropan-2- yl)amino)(phenoxy)phosphoryl)oxy)benzoate (2b) (Rp/Sp = 20/80) (27.2 g, 0.0428 mol), and THF (210 mL). This mixture was cooled to -30 C followed by slow addition of 1.35M t-BuMgCl (22.8 mL, 0.0297 mol) in 1 h. The reaction mixture was slowly warmed to RT over 5-6 h and stirred at that temperature overnight. HPLC monitoring showed Rp/Sp = 5/95 (at this stage). The reaction mixture was quenched by addition of 25% NH4C1 (aq) (14 mL), THF was removed by distillation. THF (38 mL) and sat. aq. NaHCC solution (140 mL) was added and stirred overnight at RT. The reaction mixture was then filtered and THF was removed by distillation under vacuum until 1-2 vol remained in the flask. Methylene dichloride (MDC - 210 mL) and 50% AcOH/H20 (100 mL) was added and the organic layer was separated. The organic layer was washed with sat. aq. NaHCC solution (425 mL) and concentrated under vacuum. The obtained oil was taken in MDC (28 mL) and DIPE (94 mL) and stirred overnight and filtered to give an off-white solid (7.5 g, 62% yield; 98.65% total mixture of diastereomers; Rp/Sp = 0.001/99.999). The solid was then refluxed in 60% aqueous acetic acid for 5 h and extracted with DCM. The DCM layer was washed with sat. aq. NaHC03 (250 mL) followed by distillation under vacuum. The obtained solid was crystallized from DCM (20 mL) to give sofosbuvir as a white solid (4 g, 65% yield, 99.85% purity, Sp = 99.85% diastereomeric purity).
3 g With acetic acid; In water; at 90 - 95℃; N-Benzoyl Sofosbuvir (6 g) was added to 70% w/w aqueous acetic acid (90 mL) and the contents were stirred at 90-95 C. After completion of the reaction, which was monitored by qualitative HPLC, the reaction mass was cooled to ambient temperature, diluted with water and filtered through a Hyflo filter. Thereafter, obtained filtrate was extracted with ethylacetate which was further washed with 4%w/w aqueous hydrochloric acid followed by 9%w/w aqueous sodium carbonate solution. Finally, the ethyl acetate layer was washed with water and dried. The dried layer was concentrated under reduced pressure at 60-65 C. Thereafter, the concentrated mass was dissolved in a mixture of 5% isopropanol in methylene dichloride and isopropyl ether was added to precipitate the product. After stirring at 0-5 Cfor 2 hours, the product was filtered, washed with methylene dichloride/isopropyl ether mixture, which was recrystallized with methylene dichloride/isopropyl ether mixture to yield sofosbuvir as white crystals (3 g).
3.6 g With citric acid; In 1,2-dimethoxyethane; water; at 75 - 80℃; N-benzoyl sofosbuvir (6 g) was added to a mixture of 1,2-dimethoxyethane (69 mL), water (60 mL), and citric acid (1.08 g) and the contents were stirred at 75-85 C for 40-50 hours. After completion of the reaction, the reaction mass was concentrated under reduced pressure and the obtained residue was dissolved in isopropyl acetate (60 mL). The solution was washed with -10% w/w aqueous hydrochloric acid (3x60 mL) and -10% w/v aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure at 50- 55 C and the resulting concentrated mass was dissolved in methylene dichloride (36 mL). Diisopropyl ether (126 mL) was added to precipitate the product. After stirring at 20-25 C for 16 hours, the solution was filtered to result in a solid which was washed with a methylene dichloride/diisopropyl ether mixture and dried under reduced pressure to yield sofosbuvir (3.6 g)
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  • chlorophosphoramidate [ No CAS ]
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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).
  • 21
  • [ 1190307-88-0 ]
  • C26H26ClNO3S [ No CAS ]
  • C48H54FN4O12PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With potassium carbonate; In acetone; for 6h;Reflux; 529mg (1.0mmol) III-1 was dissolved in 10mL of dry acetone, at room temperature was added 680mg (1.5mmol) IV-2, and potassium carbonate 414mg (3.0mmol), then was heated with stirring under reflux for 6h. Via TLC the reaction was complete. Filtered and the filtrate diluted with dichloromethane (30 mL), washed successively with water (10 mL) and saturated brine (10 mL) washed organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent.The residue was purified by silica gel column chromatography to give 306mg white solid V-1, a yield of 38%.
  • 22
  • [ 1190307-88-0 ]
  • C26H26ClNO3S [ No CAS ]
  • C29H40FN4O12PS [ No CAS ]
  • 23
  • [ 1190307-88-0 ]
  • C27H28ClNO4S [ No CAS ]
  • C49H56FN4O13PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
300 mg With potassium carbonate; In acetone; for 6h;Reflux; 529mg (1.0mmol) III-1 was dissolved in 10mL of dry acetone, at room temperature was added 690 mg IV-3, and potassium carbonate 414mg (3.0mmol), then was heated with stirring under reflux for 6h. Via TLC the reaction was complete. Filtered and the filtrate diluted with dichloromethane (30 mL), washed successively with water (10 mL) and saturated brine (10 mL) washed organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent.The residue was purified by silica gel column chromatography to give 300mg V-1, which was used directly in the next reaction
  • 24
  • [ 1190307-88-0 ]
  • C27H28ClNO4S [ No CAS ]
  • C30H42FN4O13PS [ No CAS ]
  • 25
  • [ 1190307-88-0 ]
  • C26H24ClNO4S [ No CAS ]
  • C48H52FN4O13PS [ No CAS ]
YieldReaction ConditionsOperation in experiment
400 mg With triethylamine; In acetone; at 20℃; for 6h; 529mg (1.0mmol) III-1 was dissolved in 10mL of dry acetone. And was added at room temperature 800mg IV-4 and triethylamine 500mg then stirred at room temperature for 6h. Via TLC the reaction was complete. Filter. The filtrate was diluted with dichloromethane (30 mL), washed successively with water (10 mL) and saturated brine (10 mL), dried organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography 400mg V-4, was used directly in the next reaction.
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