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High-yield synthesis method of sofosbuvir and sofosbuvir prepared with method

A technology of sofosbuvir and a synthetic method, which is applied in the field of sofosbuvir, a synthetic method and the sofosbuvir prepared by the sofosbuvir, can solve the problems of rising cost and reduced yield, and achieves improved yield and reduced yield. The number of reaction steps and the effect of reducing costs

Active Publication Date: 2016-06-08
GUIZHOU INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the existing preparation method of sofosbuvir, the uridine moiety is generally prepared, and then connected with the phosphate side chain, and the synthesis steps need about 12 steps; the more reaction steps mean that the yield is reduced, and finally only Obtain 0.1eq. of Sofosbuvir, the cost rises significantly

Method used

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  • High-yield synthesis method of sofosbuvir and sofosbuvir prepared with method
  • High-yield synthesis method of sofosbuvir and sofosbuvir prepared with method

Examples

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Embodiment 1

[0029] The present embodiment provides a kind of synthetic method of high-yield sofosbuvir, such as figure 1 As shown, it includes the following steps:

[0030] (a) benzoic anhydride (Bz 2 O) Dissolve in 5L of N,N-dimethylformamide (DMF), stir and react at room temperature for 4 hours, then add water to quench the reaction, extract 3 times with 2L of ethyl acetate, add anhydrous sodium sulfate to dry , filtered and then rotary evaporated to remove ethyl acetate to obtain the first product; redissolve it in 5LDMF, add 1.1eq. of TIDPSCl 2 , stirred at room temperature for 8 hours, then added water to quench the reaction, extracted 3 times with 2L of ethyl acetate, combined the organic phases, added anhydrous sodium sulfate to dry, filtered, and rotary evaporated to remove ethyl acetate to obtain the second product;

[0031] (b) Dissolve the second product and 1.5eq. of dimethyl phthalate in 5L of dichloromethane, stir and react at room temperature for 5 hours, remove the dichl...

Embodiment 2

[0040] This implementation provides a kind of synthetic method of high-yield sofosbuvir, its synthetic steps are basically the same as in Example 1, the difference is: in step (h), also add 0.05eq. by benzoyl peroxide and The molar ratio of dicumyl peroxide is 1:1 as a catalyst to finally obtain 0.3eq. of sofosbuvir.

Embodiment 3

[0042] The present embodiment provides a kind of synthetic method of high-yield sofosbuvir, such as figure 1 As shown, it includes the following steps:

[0043] (a) 1kg of cytidine (molecular weight is 243.22, 4.11mol) and 1eq. of benzoic anhydride (Bz 2 O) Dissolve in 5L of N,N-dimethylformamide (DMF), stir and react at room temperature for 3 hours, then add water to quench the reaction, extract 5 times with 2L of ethyl acetate, add anhydrous sodium sulfate to dry , filtered and then rotary evaporated to remove ethyl acetate to obtain the first product; redissolve it in 5LDMF, add 1.05eq. of TIDPSCl 2 , stirred at room temperature for 7 hours, then added water to quench the reaction, extracted 5 times with 2L of ethyl acetate, added anhydrous sodium sulfate to dry, filtered, and rotary evaporated to remove ethyl acetate to obtain the second product;

[0044] (b) Dissolve the second product and 1.8eq. of dimethyl phthalate in 5L of dichloromethane, stir and react at room tem...

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Abstract

The invention relates to a high-yield synthesis method of sofosbuvir and sofosbuvir prepared with the method. The method comprises steps as follows: (a) cytidine and benzoic anhydride are dissolved in a first organic solvent for a reaction; TIDPSCl2 is added for a reaction; (b) a product and dimethyl phthalate are dissolved in a second organic solvent for a reaction; (c) a Grignard reagent is dissolved in tetrahydrofuran, and the temperature is reduced to subzero 35 DEG C to subzero 20 DEG C; tetrahydrofuran containing a third product is dropwise added and has a reaction, and a fourth product is obtained through purification; (d) the fourth product is dissolved in acetic acid containing tetrabutylammonium fluoride and has a reaction, and a sixth product is obtained through purification; (e) the sixth product is dissolved in the second solvent, phosphorus tribromide is added and has a reaction, and a seventh product is obtained through purification; (f) the seventh product is dissolved in methanol containing sodium methoxide and has a reaction, and an eighth product is obtained through purification. Accordingly, the reaction steps are reduced, the cost is greatly reduced, and the yield of the product is increased.

Description

technical field [0001] The invention belongs to the field of antiviral drugs and relates to a sofosbuvir, in particular to a high-yield sofosbuvir synthesis method and the sofosbuvir prepared therefrom. Background technique [0002] Hepatitis C virus (HCV) infection is a major health problem leading to chronic liver diseases such as cirrhosis and liver cancer. There are a large number of infected individuals, estimated at 2-15% of the world's population. Current treatments for HCV infection are limited by Immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin has achieved limited clinical benefit. Furthermore, no vaccine has been established for HCV. Therefore, there is an urgent need for improved therapeutic agents that are effective against chronic HCV infection. [0003] Sofosbuvir is an NS5B polymerase inhibitor developed by GleadSciences that, alone or in combination with other drugs, blocks a specific HCV required for...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00
CPCC07H1/00C07H19/10
Inventor 刘可
Owner GUIZHOU INST OF TECH
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