Anti-hepatitis B drug entecavir intermediate and synthesis thereof

Abstract

The invention belongs to the field of drug intermediates and provides a five-membered ring chiral intermediate (1R, 2S, 3S, 5R)-3-(1-phenylcyclo silicon)-6-oxa-bicyclo [3.1.0] hexane-1, 2-dimethyl carbinol for synthesis of entecavir and a synthesis of the five-membered ring chiral intermediate. A chiral five-membered carboatomic ring is obtained by reacting 1-phenyl-1-chlorocyclosilane with alkali metal salt of cyclopentadiene and introducing cyclosilane into a molecule to serve as a construction protecting group and by the aid of a chemical resolution method. Introduction of the cyclosilane enhances molecule rigidity to enable a solid product to be crystallized and purified more easily, and the synthesis method is simpler in reaction operation, cheap in raw materials, available to raw materials and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, and in particular relates to an entecavir intermediate and a synthesis method thereof. Background technique [0002] Entecavir (Entecavir) is a kind of deoxyguanosine compound that can effectively inhibit the replication of hepatitis B virus. It was developed by the U.S. Bristol-Myers Squibb company and was listed in the U.S. in April 2005. Hepatitis B drugs. In terms of synthesis, the construction of chiral five-membered ring intermediates determines the industrial prospects of the entire synthesis process. Therefore, people have launched research on the synthesis of intermediates. [0003] In 1993, Robert Zahler reported for the first time in the patent US5206244 the method for synthesizing entecavir with compounds of this type 15 as key intermediates. In this method, a chiral five-membered carbocyclic structure (15) is first obtained through asymmetric synthesis, and then combined...

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Problems solved by technology

[0016] At present, the defect that still exists in the synthesis of this type of intermediate (17) is that a large amount of tar is generated in the reaction, which makes product purification difficult and also affects the yield

In order to solve this difficult problem, in 2005, Maotang X.Zhou carried out further group modification to 17, designed the method (US20050272932) with intermediate 30 and 31 as key intermediate synthetic entecavir, the use of these two intermediates has reduced The production of tar in the late reaction, and the yield is high, but the synthesis steps are too long, and the overall economic benefit is not high

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