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Preparation method of sofosbuvir

A technology of compound and alkyl, applied in the field of drug synthesis, can solve the problem of high cost

Active Publication Date: 2015-12-16
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process has certain advantages, but the total yield is only 15% with a single nitrophenol-substituted phosphoric ester as a reagent, and the cost of a single pentafluorophenol-substituted phosphoric ester is too high

Method used

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  • Preparation method of sofosbuvir
  • Preparation method of sofosbuvir
  • Preparation method of sofosbuvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The preparation of embodiment 1 Sofosbuvir

[0064]

[0065] Step (a):

[0066] At 0°C, phenyl dichlorophosphate (6.0g, 28.4mmol) was dissolved in anhydrous dichloromethane (30ml), and alanine isopropyl hydrochloride (4.8g, 28.4mmol) was added under stirring, and the mixture was After stirring and cooling to -55°C, a mixed solution of triethylamine (6.5g, 64mmol) and dichloromethane (30ml) was slowly added dropwise, keeping the temperature at -55°C during the period. Stir at -5°C for 2 hours, and monitor the completion of the reaction by TLC. Triethylamine hydrochloride was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to obtain compound 3-1 as a colorless oil (Sp / Rp=1 / 1).

[0067] 31 PNMR (CDCl 3 ,300Hz,H 3 PO 4 internal standard): δ8.25&7.94(1:1);

[0068] 1 HNMR (CDCl 3 ,300MHz):δ7.39-7.34(m,2H),7.27-7.18(m,3H),5.10-5.02(m,1H),4.51(br,1H),4.11(m,1H),1.49(d ,3H),1.29-1.24(m,6H);

[0069] 13 CNMR (CDCl 3 ...

Embodiment 2

[0075] The preparation of compound shown in embodiment 2 formula 3-2

[0076]

[0077] (1) The nucleophile is NaSCN, and the phase transfer catalyst is TBAB

[0078] The compound shown in formula 3-1 (the product of step (a) of Example 1) was dissolved in dichloromethane (20ml), TBAB (2.8mmol) was added, and a solution of NaSCN (35mmol) in water (2.0ml) was added dropwise Added to the above reaction solution. After dropping, stirring was continued for 60 minutes, and the solid was removed by filtration. After washing the filtrate with water, add MgSO 4 Let dry for 24 hours. After filtration, the filtrate was evaporated to remove the solvent under reduced pressure to obtain the compound shown in formula 3-2 (wherein X=SCN).

[0079] 1 HNMR (CDCl 3 ,500Hz):δ7.32-7.13(m,3H),7.08-7.02(m,2H),5.0-4.9(m,1H),3.92(m,1H),1.49(m,3H),1.23-1.17 (m,6H);

[0080] 31 PNMR (CDCl 3 ,300Hz,H 3 PO 4 as internal standard): δ-18.16 / -18.26.

[0081] (2) The nucleophile is NaSCN, and ...

Embodiment 3

[0093] The preparation of embodiment 3 Sofosbuvir

[0094]

[0095] (1) X is SCN

[0096] At 5°C, the compound represented by formula 2 (5.20 g, 20.0 mmol) was dissolved in anhydrous THF (30 ml). Tert-butylmagnesium chloride (1.0M solution in THF, 42ml, 42.0mmol) was added with stirring. The reaction temperature was raised to 25°C, and the mixture was stirred for 30 minutes. After adding lithium chloride (21.0 mmol), a mixed solution of the compound of formula 3-2 (about 28.4 mmol, prepared in Example 2) and THF (30 ml) was slowly added dropwise, while keeping the temperature at 5°C. After dropping, it was stirred for 15 hours. The reaction solution was quenched with 1N HCl aqueous solution (25 ml) (the ratio of Sp:Rp determined by HPLC was 6:1). After additional toluene (100ml) was added, the temperature rose to room temperature. Organic layer with 1N HCl, water, 5% Na 2 CO 3 and brine, dried over anhydrous magnesium sulfate, filtered, evaporated under reduced press...

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Abstract

The invention relates to a preparation method of sofosbuvir, and specifically provides a quite stereoselective preparation method, which can make the prepared required isomer enrich under the condition of not separating intermediate, so that the preparation method can reduce production cost greatly, and is suitable for commercial process.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of the hepatitis C drug sofosbuvir. Background technique [0002] After Gilead acquired Famoset, it developed and launched Sofosbuvir (sofosbuvir, PSI-7977, GS-7977, ). In 2013, the FDA approved the combination of sofosbuvir and ribavirin (RBV) for the oral treatment of HCV genotype 2 and 3 patients; and approved the combination of pegIFN and ribavirin for injection. Virin (RBV) in combination for the treatment of naive patients with HCV genotypes 1 and 4. The treatment cycle of sofosbuvir is long, usually 12-24 weeks, and the treatment cost is extremely expensive. At present, only a very small number of patients in the world can afford the treatment and benefit from it. [0003] The route currently used for the synthesis of sofosbuvir mainly includes the following two methods: [0004] [0005] Among them method I, the nucleophilic substitut...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/02C07F9/24C07F9/28
CPCC07H1/02C07H19/10
Inventor 张寅生敖汪伟王庆璘林志强饶娇
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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