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CAS No. : | 1190307-88-0 | MDL No. : | MFCD26523124 |
Formula : | C22H29FN3O9P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 529.45 | Pubchem ID : | - |
Synonyms : |
GS-7977;PSI-7977;Resof;Hepcvir;Hepcinat;Vosevi;Virunon;Sovaldi;GI-7977
|
Num. heavy atoms : | 36 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 11 |
Num. H-bond acceptors : | 11.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 125.53 |
TPSA : | 167.99 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -8.83 cm/s |
Log Po/w (iLOGP) : | 3.27 |
Log Po/w (XLOGP3) : | 0.99 |
Log Po/w (WLOGP) : | 1.75 |
Log Po/w (MLOGP) : | 0.42 |
Log Po/w (SILICOS-IT) : | 0.61 |
Consensus Log Po/w : | 1.41 |
Lipinski : | 2.0 |
Ghose : | None |
Veber : | 2.0 |
Egan : | 1.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.17 |
Log S (ESOL) : | -3.27 |
Solubility : | 0.286 mg/ml ; 0.000541 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.11 |
Solubility : | 0.0414 mg/ml ; 0.0000783 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.09 |
Solubility : | 0.0432 mg/ml ; 0.0000817 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 6.02 |
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: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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 |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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 . |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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%). |
Yield | Reaction Conditions | Operation 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) |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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%. |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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-5, was used directly in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | 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-1 and potassium carbonate 414mg (3.0mmol), heated and stirred under reflux 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) washedThe 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 710mg white solid V-1, a yield of 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.1% | The Cbz-Gly-OH (209mg, 1mmol) with 2mlN, N- dimethylformamide (DMF) was dissolved, cooled to -5 deg. C, added with stirringThe DIC (63.1mg, 0.5mmol), at room temperature for 30min, continued to cool to -5 deg C , followed by adding S1 in (265mg, 0.5mmol)2mlDMF , then added triethylamine (60.7mg, 0.6mmol), and a catalytic amount of 4-dimethylaminopyridine (of DMAP), were added at room temperature for 4h.Completion of the reaction was poured into 10ml water, extracted with 10ml ethyl acetate 3 times, the organic layers combined, dried over anhydrous sodium sulfate, the solvent spin dry,Yellow solid, purified by silica gel column chromatography, to obtain white powder (M1) 217mg, 60.1% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.3% | The Cbz-Ala-OH (223mg, 1mmol) in 2mlN, N- dimethylformamide (DMF) was dissolved, cooled to -5 deg. C, was added with stirring DIC (63.1mg, 0.5mmol), the reaction at room temperature for 30min, continued to cool to -5 deg C , followed by adding S1 (265mg, 0.5mmol),in 2mlDMF the solution,added triethylamine (60.7mg, 0.6mmol), a catalytic amount of 4-dimethylaminopyridine (DMAP), at room temperature for 4., the reaction was poured into 10ml water ended, extracted three times with 10ml of ethyl acetate, the combined organic layers , dried over anhydrous sodium sulfate, the solvent spin dried to give a yellow solid, separated by silica gel column chromatography to give an off-white powder (M2) 214mg, 58.3% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.6% | The Cbz-Val-OH (251mg, 1mmol) in 2ml N, N- dimethylformamide (DMF) was dissolved, cooled to -5 deg. C, then added with stirring DIC (63.1mg, 0.5mmol), the reaction was carried out at room temperature for 30min, continued to cool to -5 deg C , followed by adding S1 (265mg, 0.5mmol)then in 2ml DMF solution, triethylamine (60.7mg, 0.6mmol), a catalytic amount of 4-dimethylaminopyridine (DMAP), were added at room temperature for 4h. the reaction was poured into 10ml water ended, extracted three times with 10ml of ethyl acetate, the combined organic layers , dried over anhydrous sodium sulfate, the solvent spin dried to give a yellow solid, separated by silica gel column chromatography to give an off-white powder (M3) 193mg, 50.6% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.2% | The Cbz-Trp (Boc) -OH (438mg, 1mmol) in 2mlN, N- dimethylformamide (DMF) was dissolved, cooled to -5 deg. C, stirred and added DIC (63.1mg, 0.5mmol), at room temperature for 30min, continued to cool to -5 deg C, followed by adding S1 (265mg, 0.5mmol)then in 2mlDMF the solution, triethylamine (60.7mg, 0.6mmol), a catalytic amount of 4-dimethylaminopyridine (of DMAP), were added at room temperature for 4h. Completion of the reaction was poured into 10ml water, extracted with 10ml ethyl acetate 3 times, the organic layers combined, dried over anhydrous sodium sulfate, the solvent spin dry,As a white solid, separated by silica gel column chromatography to obtain a white powder (M7) 300mg, 63.2% yield. |
Yield | Reaction Conditions | Operation 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%. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With manganese(IV) oxide; In toluene; at 20℃; for 2h; | A 100 mL reaction flask was charged with compound III7g,MnO220g,Toluene,The reaction was carried out at room temperature for 2 hours,Filtered, concentrated to a no fraction,Dichloromethane 50 mL,The autoclave was heated to 50 C for 1 hour,Slow cooling to 15 C filtration,The filter cake was washed with cold dichloromethane,Dried, white needle crystal 6g,Yield 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h; | The product obtained in example 3 (18.0 g, 25.4 mmol) dissolved in methanol (130 imL) is hydrogenated at room temperature and pressure using palladium on carbon as a catalyst (10% w/w, 50% wet, 54 mg, 0.025 mmol). Once the conversion is complete (after about 4 hours), the mixture is filtered on a celite pad washing with methanol, then it is concentrated to residue under vacuum. Methanol is removed by repeated co-evaporation with dichloromethane. 14 g of an amorphous residue are obtained (quantitative yield). The HPLC analysis of the residue (conducted as described in Biomed. Chromatogr. 2012; 26: 583-588) shows a diastereomeric ratio of Sp:flp = 83:17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 12h; | The product obtained in example 19 (16.9 g, 25.4 theoretical mmol) dissolved in methanol (200 imL) is hydrogenated at room pressure and temperature using palladium on carbon as a catalyst (10% w/w, 50% wet, 2.7 g, 1 .3 mmol). Once the conversion is complete (after about 12 hours), the mixture is filtered on a celite pad washing with methanol, then it is concentrated to residue under vacuum. Methanol is removed by repeated co-evaporation with dichloromethane. 14.1 g of residue are obtained (quantitative yield). HPLC analysis of the residue (carried out by means of a Symmetry C18 column (4.6 mm x 25 mm, 5 muiotaeta) as eluent H2O (+0.1 % H3PO3)/CH3CN 45:55 at 1 imL/min and UV 254 nm detector) shows a quantitative conversion and a diastereomeric ratio of Sp:flp = 92:8. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00136] 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 (6) (5 g, 0.013 mol), 3,5-diiodo-4-(((((S)-l- isopropoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl benzoate (2d) (28 g, 0.038 mol), and THF (150 mL). This mixture was cooled to -30 C, followed by slow addition of 1.35M t-BuMgCl (17 mL, 0.022 mol) in 1 h. The reaction mixture was slowly warmed to RT over 5-6 h and stirred at temperature overnight. 60% Aqueous acetic acid (50 mL) was slowly added, followed by heating the reaction mixture to 90 C for 5 h. The reaction mixture was then cooled to RT, filtered to remove the solid precipitate. The desired product was then extracted with DCM (50 mL) followed by washing with 6% aqueous NaHCCb solution (50 mL). The organic layer was concentrated under vacuum to give a viscous oil. HPLC monitoring showed ratio of diastereomers (Rp/Sp = 4.5/95.5). The product was further purified according to the procedure of example 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[00126] 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) (7.5 g, 0.0207 mol), 3,5-dibromo-4-(((((S)-l- isopropoxy- 1 -oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl benzoate (2a) (30.06 g, 0.0519 mol), and THF (81 mL). This mixture was cooled to -30 C, followed by slow addition of 1.35M t-BuMgCl (24.6 mL, 0.033 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 (50 mL) was slowly added followed by heating the reaction mixture to 90 C for 5 h. The reaction mixture was then cooled to RT and filtered to remove the solid precipitate. The desired product was then extracted with DCM (50 mL) followed by washing with 6% aqueous NaHCCb solution (50 mL). The organic layer was concentrated under vacuum to give viscous oil. HPLC monitoring showed a ratio of diastereomers (Rp/Sp = 15/85). This oil was dissolved in DCM (11 mL) followed by addition of DIPE (22 mL). The obtained solid was filtered and then crystallized from DCM (20 mL) to give sofosbuvir as a white solid (3.75 g, 44% yield, 90.1% total purity of diastereomers). Rp/Sp = 5/95. The product was further purified according to the procedure of example 10. |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In chloroform; at 20 - 45℃; for 2.5h; | Sofofibrate (purchased from Suri Pharmaceutical Technology Jiangyin Co., Ltd., 5.3g ,, 10mmol) andTrichloromethane (20 ml) was added to the reaction flask and stirred to prepare a solution.The obtained solution of <strong>[1190307-88-0]sofosbuvir</strong> chloroform solution was added to a solution of acetic acid (25mmol) and chloroform (10ml), the temperature was controlled at 35-45 , incubated for 1.5h,Cool to 20 C and continue stirring for 1 hour.After stirring at room temperature overnight, it was filtered to obtain a white solid (5.82 g, yield 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | To the reaction flask, 100 g of compound I, 51 g of anhydrous magnesium chloride, 200 g of compound IV and 600 mL of tetrahydrofuran were added and 60 g of DIPEA was added dropwise with stirring at a temperature of 30~40 C. After the addition was completed, the reaction was controlled at 30~40 C. and detected by HPLC Compound content ? 3.0%, stop the reaction. The reaction mixture was added with 10% (v / v) dilute hydrochloric acid 300mL, stirred for 30min, then added to extract 600g of dichloromethane, the aqueous phase was separated; the organic phase was washed three times with 140g of 10% sodium carbonate,The combined aqueous sodium carbonate phases were extracted twice with 100 g of dichloromethane,All dichloromethane phases were combined, washed once with 100 mL of water, evaporated to dryness,Then, 50 mL of isopropyl acetate was added, and after the evaporation was further continued, 1.2 L of isopropyl acetate was added to the resulting product. The mixture was heated to 60 C. to dissolve and then cooled to 20 C.,After stirring until solid precipitated, stirring was continued for 1 hour and 1 L of n-heptane was added dropwise.After the dropwise addition was completed, the mixture was stirred for 1 h to 2 h, cooled to 0 C. to 5 C., stirred for 1 h ~ 2 h, filtered, washed with n-heptane and dried in vacuo to obtain compound III179 g,Yield 88%, HPLC purity 98%. | |
67.5% | Under argon protection,A 500 mL four-necked flask was charged with 20.0 (77 mmol) of Compound 4,300 mL of tetrahydrofuran, stirring down to an internal temperature -5 ~ 0 ,Dropping 1.5M · L tert-butyl magnesium chloride 60 mL, dropping the internal temperature was maintained at -5 ~ 0 ,After the dropwise addition to maintain the internal temperature -5 ~ 0 C stirring 0.5 h,Warming to 20 ~ 30 , stirring 0.5 h. Down to the internal temperature 0 ~ 5 ,A solution of compound 5 in tetrahydrofuran (42 g in 200 mL of tetrahydrofuran) was added dropwise with stirring.Control dropping speed, at 3 ~ 3.5 h drop completed,Maintain the internal temperature of 10 ~ 15 stirring 16 ~ 18 h.Dropping 2M · L hydrochloric acid 90 mL, the dropping process to maintain the internal temperature of less than 30 ,Add 350 mL of toluene and stir for 20 min. Layered,The organic phase was washed twice with 40 mL of 1 M hydrochloric acid and one time with 40 mL of water,5% sodium carbonate 40 mL washed twice,Washed with saturated saline once, the organic phase separated, dried over anhydrous sodium sulfate 20 g,Concentrate at atmospheric pressure until almost no liquid drips.Add 100 mL of dichloromethane warmed to reflux stirring to dissolve,Dripped with 40 mL isopropyl ether, refluxed for 30 min,Slowly reduced to 30 ~ 35 , stirring for 30 min, white solid precipitation,Continue to cool to 20 ~ 25 for 1 ~ 2 h, filtered,It was washed once with 20 mL of dichloromethane-isopropyl ether (v / v = 1: 1)The crude product was obtained in the form of a white target product. The crude product was added to a 1 L reaction flask,Add 700 mL of dichloromethane reflux stirring stirring clear, atmospheric distillation 400 mL of methylene chloride,A small amount of solid precipitation,Cooling to 20 ~ 25 , stirring 4 ~ 5 h, filtered,Rinse once with 30 mL of dichloromethane,40 ~ 50 vacuum drying 5 ~ 6 h, 27.5 g of the desired product, the molar yield of 67.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 g | With 5%-palladium/activated carbon; In isopropyl alcohol; at 20 - 25℃; under 2250.23 Torr; for 10h; | Isopropyl alcohol (IPA, 70 mL), bromo-sofosbuvir (3.5 g, obtained from stage 3), and dry Pd/C (5% Pd/C, 0.35 g) were charged into a Parr Shaker cylinder at 20C to 25C. The reaction mixture was maintained under hydrogen gas pressure (3 kg/cm2) at20C to 25C for 10 hours. The reaction mass was filtered through a Hyflo, and then the bed was washed with IPA (10 mL). IPA was distilled out from the filtrate under vacuum at a temperature of less than 35C. Dichloromethane (105 mL) was added to the residue at 20C to 25C, and was then washed with deionized water (3x35 mL). Dichloromethane was distilled out under vacuum at a temperature of less than 30C. Dichloromethane (35 mL) was again charged to the residue at 20C to 25C, and then the mixture was heated to reflux at 35C to 40C. The reaction mixture was maintained under reflux for 30 minutes, and was then cooled to 20C to 25C, followed by stirring for 30 minutes. DIPE (14 mL) was charged to the reaction mixture at 20C to 25C, and the mixture was stirred at this temperature for 16 hours. The solid obtained was filtered, and the wet solid was washed with a mixture of dichloromethane and DIPE (1:1 mixture ratio, 7 mL), and then dried under vacuum at a temperature less than 35C for 2 hours to obtain the title product.Yield: 1.8gChromatographic purity (HPLC): 98.54 %Bromo-sofosbuvir: 0.22% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a 4 L of four-necked round bottom flask fitted with a mechanical stirrer and low temperature thermometer were added lOOgm of uridine intermediate and 1500ml of Tetrahydrofuran (THF) and stir for 5-10 min under nitrogen atmosphere at 25-30C, further added 54.8gm of MgC and stir for 2 hours, followed by slow addition of 261.0 gm of phosphramide intermediate and stir for 8-lOhrs at same temperature. After complies the reaction (checked by HPLC), distilled out THF completely at below 45C and allow to cool the reaction mass at 25-30C, added 1.0 Lit dichloromethane and 1.0 Lit of Aqueous ammonium chloride solution in to reaction mass, stirred at room temperature to separate the layers. (0052) The obtain organic layer was distilled out completely to get a residue, followed by addition of 300 mL of MDC & 300 mL MTBE and Stir for 6 hrs. at 25-30C and then cooled to 10-15C and stir for 2hrs. The resultant precipitated material was filtered, washed with mixture of dichloromethane and MTBE (1: 1) and dried under vacuum for 15 min at 50- 60C to isolate the title product (Yield: 70-80 %) |