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

A technology of -4-, pipecolic acid, which is applied in the field of preparation of the argatroban intermediate -4-methyl-2-pipericolic acid, can solve the problems of difficult industrialization, expensive starting materials, and high prices. question

Inactive Publication Date: 2012-12-05
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0061] The preparation of embodiment one L-aspartic acid-4-methyl ester hydrochloride (II)

[0062] Add 400g of L-aspartic acid into 1L of methanol, control the internal temperature at 0°C, and slowly add 350g of acetyl chloride dropwise to the system. After reacting for 20 hours, 5 L of diethyl ether was added to the system, and a solid was precipitated. After stirring for 2 hours, the solid was filtered and dried to obtain 460 g of a white solid, with a yield of 82%.

Embodiment 2

[0063] Preparation of Example Two N-(2-methoxycarbonyl) ethyl-N-benzyl-L-aspartic acid-4-methyl ester (III)

[0064] Add 860g of L-aspartic acid-4-methyl ester hydrochloride (II), 1200g of methyl acrylate, and 1500g of triethylamine into 3L of water, and react at room temperature for 12 hours. Subsequently, 3 L of diethyl ether was added to the reaction system, stirred for 1 hour, and the diethyl ether layer was separated and removed. Add 2200 g of benzyl bromide to the water layer, and stir at room temperature for 24 hours. Add 5 L of diethyl ether to the system, extract and separate to obtain the aqueous phase. 4N hydrochloric acid aqueous solution was added dropwise to the aqueous phase until the pH was 2, and then 5 L of diethyl ether was added to the aqueous phase for extraction and separation to obtain an organic phase. After the organic phase was dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure to obtain 1170 g of oil, with a...

Embodiment 3

[0065] The preparation of embodiment three (R)-N-benzyl-4-oxopiperidine-2-carboxylic acid (IV)

[0066] Dissolve 600g of N-(2-methoxycarbonyl)ethyl-N-benzyl-L-aspartic acid-4-methyl ester (III) in 2.5L of tetrahydrofuran, and add 1.2 L dissolved 300 g of sodium methoxide in methanol, followed by reflux for 5 hours. After cooling off, 3L of water was added to the system, and the reaction was further refluxed for 12 hours. After the reaction solution was cooled, most of the organic solvent was removed under reduced pressure. Add 3L of diethyl ether, extract and separate the aqueous phase. 4N hydrochloric acid aqueous solution was added to the aqueous phase until the pH of the system was 2, and ethyl acetate was added for extraction and separation to obtain an organic phase. Under stirring, 200 mL of tert-butylamine was added to the organic phase, and a solid appeared. After stirring for 5 hours, the solid was obtained by filtration. After drying, the solid was recrystallized...

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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...

Claims

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Application Information

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IPC IPC(8): C07D211/60
CPCY02P20/55
Inventor 竺伟陈宇梁俊
Owner SHANGHAI AOBO PHARMTECH INC LTD
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