Improved production process for repaglinide

A process, the technology of reggae acid, applied in the field of medicine, can solve the problems of low yield and product purity, and achieve the effects of simple operation, low risk and easy control

Inactive Publication Date: 2015-12-23
TIANJIN PHARMA GROUP GENCOM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, domestic manufacturers of preparations mainly rely on imported repaglinide raw materials for sub-

Method used

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  • Improved production process for repaglinide
  • Improved production process for repaglinide
  • Improved production process for repaglinide

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Embodiment 1: the improved process of producing repaglinide

[0025] (1) Preparation of compound (S)-(+)-3-methyl-1-(2-piperidinyl-phenyl) butylamine (2), the reaction formula is as (I):

[0026] Get 1.0kg of compound (S)-(+)-3-methyl-1-(2-piperidinyl-phenyl)butylamine-N-acetyl-L-glutamic acid (1) and add 1.5kg of water and 5.0 kg of toluene mixed solution, then add 3.5kg of ammonia and stir until fully dissolved, extract the organic layer after the reaction, dry, filter, and concentrate under reduced pressure, the obtained compound (S)-(+)-3-methyl-1-( 2-Piperidinyl-phenyl)butylamine (2).

[0027]

[0028] (2) Preparation of compound (S)-2-ethoxy-4-[2-[3-methyl-1-[2-(1-piperidinyl)-phenyl]-butanyl]-amino] -2-carbonylethylbenzoic acid ethyl ester (4), reaction formula such as (II):

[0029] Pump 3.0kg of toluene into the reaction tank and put in 680g of Regal acid (3), put in 310g of triethylamine, add the mixture of pivaloyl chloride and toluene dropwise at -5~0°...

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Abstract

The invention provides an improved production process for repaglinide. The process is characterized by comprising the following steps: with (S,S')-3-methyl-1-(2-(1-piperidinyl)phenyl)butylamine, N-acetyl-glutamate as a main material, adding ammonia water to prepare chiral amine (S)-(+)-3-methyl-1-(2-piperidinyl-phenyl)butyl amine; then adding triethylamine and adding a mixed liquid of pivaloyl chloride and toluene drop by drop; subjecting a product obtained in the previous step and 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid to a condensation reaction so as to prepare a compound (S)-2-ethoxy-4[2-[3-methyl-1-[2-(1-piperidinyl)-phenyl]-butyl]-amino]-2-carbonylehtyl ethyl benzoate; hydrolyzing the compound in ethanol and a sodium hydroxide solution so as to obtain a crude repaglinide product; and dissolving the obtained crude repaglinide product in a mixed solution of ethanol and water for purification so as to prepare a refined repaglinide product. The improved production process provided by the invention further simplifies synthesis and purification steps, has the advantages of high efficiency, low toxicity, low danger, easy operation, etc. and has the characteristics of simplicity and easiness in control and industrial production.

Description

technical field [0001] The invention relates to an improved process for producing repaglinide, which belongs to the technical field of medicine. Background technique [0002] Repaglinide, the chemical name is (S)-2-ethoxy-4-[2-[[methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino ]-2-oxoethyl]benzoic acid is a non-sulfonylurea insulin secretagogue developed by Boehringer Ingelheim, Germany. It was first launched in the United States in 1998 and in China in 2000. It is mainly used clinically for the treatment of diet control and For type 2 diabetes whose hyperglycemia cannot be effectively controlled by exercise, the drug has definite curative effect, small dosage and low side effects. [0003] This product can specifically bind to the 36KDA protein on the ATP-dependent potassium ion channel outside the islet β cell membrane, close the potassium channel, depolarize the β cell, open the calcium channel, and promote the influx of calcium ions to promote insulin secretion. Sulfonylu...

Claims

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Application Information

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IPC IPC(8): C07D295/135
CPCC07D295/135C07B2200/13
Inventor 张齐陈亚光刘伟王臣
Owner TIANJIN PHARMA GROUP GENCOM PHARMA
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