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Preparation method of sofosbuvir

A technology of sofosbuvir and pentafluorophenol, applied in the field of preparation of anti-HCV drugs, can solve the problems of environmental impact, no mention of pentafluorophenol recovery and utilization, etc., achieves easy operation, easy control of impurities, and reduced impact Effect

Active Publication Date: 2016-06-15
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since a molecule of pentafluorophenol is removed during the synthesis of sofosbuvir, and pentafluorophenol is a high-value chemical raw material, and because of its certain toxicity, it has an impact on the environment. Pentafluorophenol was not mentioned in the original research patent The recovery and utilization of phenol, so the recovery and application of pentafluorophenol is of great significance

Method used

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  • Preparation method of sofosbuvir
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  • Preparation method of sofosbuvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation method of Sofosbuvir of the present invention comprises the following steps:

[0025] Preparation of Sofosbuvir:

[0026]

[0027] In the reaction flask, under anhydrous and oxygen-free conditions, add 120g (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine, 600mL tetrahydrofuran, stir, cool down to -30°C, Add 268g of 1.7M tert-butylmagnesium chloride dropwise; after dropping, stir the reaction for 1 hour, then raise the temperature to -10°C, add dropwise 230g of N-[(S)-(2,3,4,5,6-pentafluorophenoxy ) 500 mL tetrahydrofuran solution of phenoxyphosphoryl]-L-alanine isopropyl ester; after dropping, react at -10°C for 1 hour, then warm up to room temperature for reaction, and monitor the reaction by TLC. After the reaction is complete, cool down to 0°C, and start to drop concentrated hydrochloric acid / water (100mL / 600mL) to quench the reaction; distill off THF under reduced pressure, then add 800mL of diethyl ether, stir and separate the layers, and extract the ...

Embodiment 2

[0034] The preparation method of Sofosbuvir of the present invention comprises the following steps:

[0035] Preparation of Sofosbuvir:

[0036]

[0037] In the reaction flask, under anhydrous and oxygen-free conditions, add 95g (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine, 500mL tetrahydrofuran, stir, cool down to -30°C, Add 213g of 2.0M isopropylmagnesium chloride dropwise; after dropping, stir the reaction for 1 hour, then raise the temperature to -10°C, add dropwise 198g of N-[(S)-(2,3,4,5,6-pentafluorophenoxy ) 400 mL tetrahydrofuran solution of phenoxyphosphoryl]-L-alanine isopropyl ester; after dropping, react at -10°C for 1 hour, then warm up to room temperature for reaction, and monitor the reaction by TLC. After the reaction is complete, cool down to 0°C, and start to drop concentrated hydrochloric acid / water (200mL / 500mL) to quench the reaction; distill off tetrahydrofuran under reduced pressure, then add 600mL of diethyl ether, stir and separate the layers, and ex...

Embodiment 3

[0044] The preparation method of Sofosbuvir of the present invention comprises the following steps:

[0045] Preparation of Sofosbuvir:

[0046]

[0047] In the reaction flask, under anhydrous and oxygen-free conditions, add 140g (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine, 600mL dimethyl sulfoxide, stir, and cool down to -30°C, add 339g of 2.0M isopropylmagnesium chloride dropwise; after dropping, stir the reaction for 1 hour, then raise the temperature to -10°C, add dropwise 50g of N-[(S)-(2,3,4,5,6-penta Fluorophenoxy)phenoxyphosphoryl]-L-alanine isopropyl ester in 500mL dimethyl sulfoxide solution; dropwise, react at -10°C for 1 hour, then warm to room temperature for reaction, TLC monitors the reaction . After the reaction is complete, cool down to 0°C and start to drop concentrated hydrochloric acid / water (250mL / 700mL) to quench the reaction; distill off dimethyl sulfoxide under reduced pressure, then add 800mL ether, stir and separate the liquids, and wash the water ...

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Abstract

The invention discloses a preparation method of sofosbuvir. The preparation method includes following steps: in the absence of water and oxygen, enabling (2'R)-2'-deoxidized-2'-fluorine-2'-methyluridine, N-[(S)-(2, 3, 4, 5, 6-pentafluorophenoxy) phenoxy phosphoryl]-L-alanine isopropyl ester and Grignard reagent to react in the presence of a reaction solvent; dissolving mother liquid of sofosbuvir in a solvent, adding an adsorbent, depressurizing for concentration to be dry, adding solvent, pulping at room temperature, suction filtering, collecting filtrate, depressurizing for evaporation to dryness to obtain a oily product, adding solvent into the oily product, heating for dissolving to clearness, and cooling to 0-5 DEG C for crystallization to obtain recycled pentafluorophenyl; enabling D-alanine isopropyl ester and phenyl dichlorophosphate to be in reaction at minus 70-minus 80 DEG C, and adding a solvent solution of pentafluorophenyl and alkali for reaction to obtain a compound shown in a formula II. In the synthesis process of sofosbuvir, molecular pentafluorophenyl is removed, and pentafluorophenyl is recycled and used for preparation of an intermediate of sofosbuvir synthesis materials, so that pentafluorophenyl is recycled and influence on environment is reduced.

Description

technical field [0001] The invention relates to a preparation method of anti-HCV medicine, in particular to a preparation method of sofosbuvir. Background technique [0002] Sofosbuvir, Sofosbuvir, the Chinese chemical name is N-[(S)-2-(S)-(2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-di Hydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramido)isopropyl propionate (structural formula As shown in formula 2); CAS registration number: 1193037-88-0. Sofosbuvir was developed by Pharmasset pharmaceutical company in the United States, and developed and listed after the acquisition of Gilead Sciences (GileadSci), code-named GS-7977. U.S. Food and Drug Administration (FoodandDrugAdministration, FDA) approved listing for the first time on December 6, 2013, and preparation is tablet 400mg, trade name Sovaldi. The structure is as formula 1: [0003] [0004] Hepatitis C virus (referred to as hepatitis C, hepatitis C) is a viral hepatitis caused ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00
CPCC07H1/00C07H19/10
Inventor 李泽标朱明敏张庆海朱功凤张兆国林燕峰
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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