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Method for preparing 4-methylpiperidine-2-carboxylate hydrochloride

A technology of ethyl carboxylate hydrochloride and methylpiperidine, applied in the field of preparation of ethyl 4-methylpiperidine-2-carboxylate hydrochloride, which can solve the complicated synthesis route of cyclization and the difficulty of product purification , industrialization difficulties and other problems, to achieve the effect of being conducive to industrial production, convenient purification, and high product quality

Active Publication Date: 2013-01-23
CHANGSHAN BIOCHEM PHARM JIANGSU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the reports on its preparation abroad use 4-methylpyridine-2-carboxylic acid to obtain 4-methylpiperidine-2-carboxylic acid, and then ethyl ester The target product is obtained by chemical reaction, the reaction process is high temperature and high pressure, the risk is high, the equipment requirements are high, the product purification is difficult, and it is not conducive to industrialization
There are other cyclization synthesis routes reported in other literatures that are more complicated, long routes, high toxicity and pollution, and difficult to industrialize

Method used

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  • Method for preparing 4-methylpiperidine-2-carboxylate hydrochloride
  • Method for preparing 4-methylpiperidine-2-carboxylate hydrochloride
  • Method for preparing 4-methylpiperidine-2-carboxylate hydrochloride

Examples

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Effect test

Embodiment 1

[0029] Preparation of ethyl 4-methylpyridine-2-carboxylate nitrogen oxide:

[0030] 50 grams (0.30 moles) of ethyl 4-picoline-2-carboxylate, 50 milliliters of purified water and 2.5 grams of phosphomolybdic acid are added in the reaction flask, and then 68 grams of 30% hydrogen peroxide are added dropwise, and the addition is completed. The temperature was raised to 70-80°C for reaction, followed by TLC until the reaction was complete. Cool the reaction solution to room temperature, adjust the pH value to about 9.0 with sodium carbonate, extract with 200 ml of dichloromethane*2, combine the organic layers, wash with 100 ml of purified water, separate the organic layer, dry with anhydrous magnesium sulfate, and concentrate To dryness, recrystallize from petroleum ether / ethyl acetate to obtain a light yellow solid with a yield of 92%.

[0031] Preparation of ethyl 4-methylpiperidine-2-carboxylate hydrochloride:

[0032] 50 grams (0.28 moles) of ethyl 4-picoline-2-carboxylate n...

Embodiment 2

[0034] Preparation of ethyl 4-methylpyridine-2-carboxylate nitrogen oxide:

[0035] 50 grams (0.30 moles) of ethyl 4-picoline-2-carboxylate, 50 milliliters of purified water and 2.5 grams of phosphomolybdic acid are added in the reaction flask, and then 68 grams of 30% hydrogen peroxide are added dropwise, and the addition is completed. The temperature was raised to 70-80°C for reaction, followed by TLC until the reaction was complete. Cool the reaction solution to room temperature, adjust the pH value to about 9.0 with sodium carbonate, extract with 200 ml of dichloromethane*2, combine the organic layers, wash with 100 ml of purified water, separate the organic layer, dry with anhydrous magnesium sulfate, and concentrate To dryness, recrystallize from petroleum ether / ethyl acetate to obtain a light yellow solid with a yield of 92%.

[0036] Preparation of ethyl 4-methylpiperidine-2-carboxylate hydrochloride:

[0037] 50 grams (0.28 moles) of ethyl 4-picoline-2-carboxylate n...

Embodiment 3

[0039] Preparation of ethyl 4-methylpyridine-2-carboxylate nitrogen oxide:

[0040] 50 grams (0.30 moles) of ethyl 4-picoline-2-carboxylate, 50 milliliters of purified water and 2.5 grams of phosphomolybdic acid are added in the reaction flask, and then 68 grams of 30% hydrogen peroxide are added dropwise, and the addition is completed. The temperature was raised to 70-80°C for reaction, followed by TLC until the reaction was complete. Cool the reaction solution to room temperature, adjust the pH value to about 9.0 with sodium carbonate, extract with 200 ml of dichloromethane*2, combine the organic layers, wash with 100 ml of purified water, separate the organic layer, dry with anhydrous magnesium sulfate, and concentrate To dryness, recrystallize from petroleum ether / ethyl acetate to obtain a light yellow solid with a yield of 92%.

[0041] Preparation of ethyl 4-methylpiperidine-2-carboxylate hydrochloride:

[0042] 50 grams (0.28 moles) of ethyl 4-methylpyridine-2-carboxy...

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Abstract

The invention relates to a method for preparing 4-methylpiperidine-2-carboxylate hydrochloride which is an intermediate of argatroban active precursor (2R, 4R)-4-methylpiperidine-2-carboxylic acid ethyl ester. 4-methylpiperidine-2-carboxylic acid ethyl ester is adopted as a raw material, phosphomolybdic acid is used as a catalyst, oxidizing is performed to obtain 4-methylpiperidine-2-carboxylic acid ethyl ester nitrogen oxide, methanol or ethanol is taken as a solvent, and 4-methylpiperidine-2-carboxylate hydrochloride is produced through reduction reaction. The method is simple to operate and has moderate conditions; phosphomolybdic acid is adopted to increase the activity of an oxidizing agent of hydrogen peroxide, the usage of the oxidizing agent is reduced, and the reaction yield is increased; the purification is convenient, the product quality is excellent, and good safety is obtained; and pollution is reduced, and industrial production is benefited.

Description

technical field [0001] The invention relates to an intermediate 4-methylpiperidine-2-carboxylate ethyl ester hydrochloride of the active precursor of argatroban (2R, 4R)-4-methylpiperidine-2-carboxylate method of preparation. Background technique [0002] Argatroban is the only synthetic drug approved in the world so far for the treatment of acute ischemic stroke. It was first synthesized by Mitsubishi Chemical Research Institute (Mitsubishi Pharmaceutical Co., Ltd.) in Japan in 1970, and it was first approved by Japan for the treatment of peripheral thrombosis. disease and acute stroke. Later, it was purchased and licensed by several pharmaceutical companies in the United States, France and the United Kingdom, and was successively approved by the U.S. FDA for thrombocytopenia and thrombosis syndrome induced by heparin. 4-Methylpiperidine-2-carboxylic acid ethyl ester hydrochloride is an intermediate of argatroban active precursor (2R,4R)-4-methylpiperidine-2-carboxylic ac...

Claims

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Application Information

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IPC IPC(8): C07D211/60
Inventor 沈洪春
Owner CHANGSHAN BIOCHEM PHARM JIANGSU CO LTD
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