Method for preparing (2R,4R)-4-methyl-2-pipecolic acid

Abstract

The invention discloses a method for preparing (2R,4R)-4-methyl-2-pipecolic acid (I). The method comprises the following steps that: L-aspartic acid is subjected to selective esterification to obtain L-aspartic acid-4-alkyl ester hydrochlorate (II); the resulting (II) and acrylate are subjected to a reaction and an amino protection reaction to generate N-(2-carboalkoxy(aryloxy))ethyl-N-protective group-L-aspartic acid-4-alkyl ester (III); the resulting (III) is subjected to intramolecular ring closing and decarboxylation under an alkaline environment to generate (R)-N-protective group-4-oxopiperidine-2-formic acid (IV); the carboxyl of the resulting (IV) is subjected to esterification to generate (R)-N-protective group-4-oxopiperidine-2-formate (V); the resulting (V) is subjected to selective carbonyl reduction under an effect of a reducing agent to generate cis (2R,4S)-N-protective group-4-hydroxypiperidine-2-formate (VI); the hydroxyl of the resulting (VI) is activated to generate cis (2R,4S)-N-protective group-4-oxysulfonyl piperidine-2-formate (VII); the resulting (VII) and a nucleophilic methyl metal reagent SN2 are subjected to a substituted reaction to generate trans (2R,4R)-N-protective group-4-methyl piperidine-2-formte (VIII); and amino in the compound (VIII) and the protective group on the acid are removed to generate a target compound (2R,4R)-4-methyl-2-pipecolic acid (I). The method of the present invention has advantages of low cost, environmental friendliness, high selectivity, high yield, and the like, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of an argatroban intermediate (2R, 4R)-4-methyl-2-pipericolic acid (I). Background technique [0002] Pipecolic acid is a special class of six-membered aza compounds, especially trans 4-substituted pipecolic acid, which often has unique pharmaceutical activity and is a key intermediate of many antineoplastic drugs and thrombin inhibitors. For example, argatroban is one of the most important drugs. Since the anticoagulant activity of argatroban was first reported by Mitsubishi Corporation of Japan in 1978, scientists from all over the world have conducted in-depth research on its biological activity, chemical synthesis and drug value. Argatroban can be used as drugs for treating and preventing thrombosis and platelet aggregation inhibitors, treating chronic arterial blockage and treating cerebral thrombosis. It was listed in Japan for the first time in 1990 and in my country in 2002. The structure of arga...

AI Technical Summary

Problems solved by technology

However, the synthetic route is long, and the multi-step reaction needs to be purified by column chromatography

In addition, the starting materials are expensive and not easy to obtain, and the synthesis process also needs to use expensive Grubbs catalyst and catalysts such as platinum oxide, these defects make it difficult to industrialize

[0017] In summary, the synthetic routes reported in the above literature have such or such defects as expensive raw material reagents, low yield, low selectivity, long route, serious environmental pollution or difficult operation.

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