Synthesis method of sofosbuvir

A synthesis method and compound technology, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve the problems of difficult industrial production, incomplete reaction, slow reaction, etc., to reduce the generation of solid waste and ensure safety Improved performance and less solid waste

Active Publication Date: 2017-06-30
ZHEJIANG FORESTRY UNIVERSITY
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  • Claims
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Problems solved by technology

[0004] The original research process is docked with N-benzoylcytosine and uses tin tetrachloride with high activity, which is not easy for industrial production, and post-processing produces a lot of solid waste
[0005] In the original research process, the compound reacted with ammonia-methanol solution to debenzoylate, but the reaction was slow, the reaction time was more than 24 hours, and the reaction was incomplete, and the yield was only 78%.

Method used

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  • Synthesis method of sofosbuvir
  • Synthesis method of sofosbuvir
  • Synthesis method of sofosbuvir

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Embodiment 1

[0033] Embodiment 1, with reference to attached Figure 1-9 As shown, a synthetic method of sofosbuvir of the present invention, ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxyl-4-methyltetrahydrofuran-2 - Base) Methyl benzoate generates compound 1 through Mitsunobu reaction to generate sulfonate; compound 1 is docked with N-benzoylcytosine to generate compound 2, and compound 2 is used to obtain sofosbuvir. The method adopts Mitsunobu reaction to avoid the generation of isomers, and the isomers can be reduced to below 5%; the method uses sulfonate esters to dock with N-benzoylcytosine, avoiding the use of tin tetrachloride raw materials, and the yield Higher, the post-processing produces less solid waste, and is suitable for large-scale industrial production.

[0034] A kind of synthetic method of sofosbuvir, compound 2 generates compound 3 under the heating of acetic acid aqueous solution.

[0035] A method for synthesizing sofosbuvir, wherein compound 3 is deprotected by ad...

Embodiment 2

[0059] Embodiment 2, with reference to attached Figure 1-9As indicated, 18.6 g (50 mmol) of (2R)-2-deoxy-2-fluoro-2-methyl-D-erythropentanoic acid GAMMA-lactone 3,5-diphenyl was added to a 250 mL reaction bottle Formate and 120 mL of dichloromethane, stir and cool down to 0~10 °C, add the prepared trifluoroethanol-red aluminum toluene solution dropwise into the reaction, keep the temperature below 10 °C, keep stirring after the addition After 2~3 h, there is no remaining raw material for spotting, and ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl)benzene Methyl formate.

[0060] A kind of synthetic method of sofosbuvir, trifluoroethanol-red aluminum toluene solution is to take by weighing 23.3 g (80.74 mmol) red aluminum (70% toluene solution) and 50 mL toluene and add in 100 mL reaction bottle, argon protection Lower the temperature to 0-10 °C, slowly add 8.0 g (80 mmol) of trifluoroethanol dropwise, keep the temperature below 10 °C during the ...

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Abstract

The invention provides a synthesis method of sofosbuvir. The synthesis method of the sofosbuvir comprises the following steps: performing mitsunobu reaction on ((2R,3R,4R)-3-benzoyloxy)-4-fluorine-5-hydroxyl-4-methyltetrahydrofuran-2-yl)methyl benzoate to produce sulfonate to obtain a compound 1; abutting the compound 1 and N-benzoylcytosine to produce a compound 2. The method adopts mitsunobu reaction to avoid production of an isomer, and the isomer is reduced to 5 percent or below; according to the method, sulfonate and N-benzoylcytosine are abutted, so the use ofa stannic chloride raw material is avoided; furthermore, the yield is high and few solid waste is generated during aftertreatment, so that the method is suitable for large-scale industrialized production.

Description

technical field [0001] The present invention relates to a synthetic method of sofosbuvir, in particular to a method of using Mitsunobu reaction to avoid the generation of isomers, which can reduce the isomers by less than 5%, and docking with N-benzoylcytosine with sulfonate , the synthetic method of sofosbuvir with high yield. Background technique [0002] In the original process, sulfuryl chloride was used to chlorinate hydroxy and then docked with N-benzoylcytosine under the action of tin tetrachloride to obtain the compound. [0003] In the original process, the ratio of chlorinated compounds to isomers is about 4:1, and about 20% of the isomers are in the reaction solution. [0004] The original research process uses tin tetrachloride with high activity in docking with N-benzoylcytosine, which is not easy for industrial production, and post-processing produces a large amount of solid waste. [0005] In the original research process, the compound reacted with ammonia-m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/02
CPCC07H1/02C07H19/10
Inventor 李洁郇伟伟王俊龙
Owner ZHEJIANG FORESTRY UNIVERSITY
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