Novel method for preparing tenofovir

Abstract

The invention relates to a novel method for preparing tenofovir, in particular to a method for preparing a tenofovir compound, in particular the monohydrate of the tenofovir for resisting hepatitis B viruses and human immunodeficiency viruses. The method comprises the following steps of: using (substituted) triphenylchloromethane XIII to protect hydroxy in the end position of (R)-1,2-propanediol,condensing the obtained product with dialkyl sulfonyloxy methyl phosphonate V to obtain XV, hydrolyzing the XV in the aqueous solution of an organic acid to remove the protective group of the hydroxyl at the end position of XV to obtain an intermediate XI, condensing sulfonate XII of the intermediate XI with adenine to obtain an intermediate VII, transforming the intermediate VII into the corresponding trimethylsilyl phosphonate VIII by trimethylsilyl bromide (TMSBr), and hydrolyzing the VIII to obtain the target product. The method has the advantages of short process route, convenient operation, low cost and easy access of raw materials and favorability for large scale production.

Description

Technical field: The invention relates to a preparation method of tenofovir (Tenofovir, PMPA), an anti-hepatitis B virus and AIDS virus compound. Background technique: The chemical name of tenofovir (I) is (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid or (R) -9-(2-phosphonomethoxypropyl) adenine, its structural formula is: Tenofovir belongs to the class of acyclic nucleoside phosphonates. Since its preparation generally goes through a hydrolysis step, the product is provided in the form of tenofovir monohydrate (II): There are three synthetic routes of II reported in the literature, which are as follows. Synthetic route 1 In this route, the hydroxyl group in D-(+)-isobutyl lactate is protected with dihydropyran (DHP), and then the ester is reduced to alcohol III with bis(methoxyethoxy)aluminum hydride. After condensation of p-toluenesulfonate and adenine (Adenine), deprotection can give intermediate IV. Protect the hydroxyl group of IV w...

AI Technical Summary

Problems solved by technology

This route is comparatively brief, but this document (US5935946A1, 1999-08-10) points out simultaneously: the optical purity of the target object obtained is not high (R-type content is about 90~94%), can improve the purity of the product through chiral enrichment treatment. optical purity

However, the literature data show that the yield of chiral enrichment treatment is very unstable

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