Preparation method of argatroban and intermediate thereof

Abstract

According to the method, N-Boc-N '-nitro-L-arginine methyl ester and ethyl (2R, 4R)-4-methyl-2-piperidinecarboxylate are used as raw materials, and the argatroban intermediate (2R, 4R)-4-methyl-2-piperidinecarboxylate is synthesized under the catalysis of tert-butyl alcohol alkali metal salt, so that the argatroban intermediate (2R, 4R)-4-methyl-2-piperidinecarboxylate is obtained. The preparation method comprises the following steps: adding (4R, 4R)-ethyl-1-((S)-2-(tert-butoxyacylamino-5-(3-nitroguanidine) valeryl)-4-methylpiperidine-2-carboxylic acid ethyl ester into a reaction kettle; compared with existing literature methods, the preparation method has the advantages of milder conditions, cheap and relatively safe reagents, simple post-treatment, high yield and the like, has better comprehensive performance, and is suitable for industrial production.

Description

A kind of preparation method of argatroban and its intermediate technical field The invention belongs to the field of pharmaceutical synthesis, be specifically related to a kind of preparation method of argatroban and its intermediate. Background technique Argatroban (Argatroban anhydrous) is an anticoagulant, and clinically it is mainly used for the onset of disease within 48 hours. Neurological symptoms (motor paralysis), daily activities (walking, standing, sitting, eating) in patients with acute ischemic cerebral infarction improvement. (2R,4R)-ethyl-1-((S)-2-(tert-butoxyamido-5-(3-nitroguanidine)valeryl)-4-methylpiperidine- Ethyl 2-carboxylate is a key intermediate containing the core skeleton of argatroban, and the current methods for synthesizing this compound are basically the same. The arginine of peramino protection and (2R, 4R)-4-methyl-2-piperidine carboxylic acid ethyl ester are prepared by condensation reaction under the participation of condensing age...

AI Technical Summary

Problems solved by technology

[0010] However, the condensing agents used in these synthetic methods are basically toxic and / or expensive, and there are also problems such as low yield, difficult purification, and complicated reaction operations.

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