One-pot method for synthesizing repaglinide for treating diabetes

A technology for oily substance and solvent, applied in the field of synthesizing repaglinide by method, can solve the problems of long production cycle, unstable production, expensive acetonitrile, etc., and achieve the effects of shortening the reaction route, simplifying the operation, and reducing pollution

Inactive Publication Date: 2012-08-15
ZHEJIANG ANGLIKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The route adopted in the literature is longer, which is likely to cause instability in production and too long production cycle, which is not conducive to industrial production; during the esterification reaction, triphenylphosphine/carbon tetrachloride is used to react, and the obtained product needs to be separated by a chromatographic column. Intermediates wi...

Method used

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  • One-pot method for synthesizing repaglinide for treating diabetes
  • One-pot method for synthesizing repaglinide for treating diabetes
  • One-pot method for synthesizing repaglinide for treating diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A: Preparation of (S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine

[0028] (S)-3-Methyl-1-(2-piperidinylphenyl)butylamine L-N-acetyl glutamate 16g, dichloromethane 75ml, tap water 20ml, stirring and cooling down to 0-5°C; add 1N hydrogen dropwise Sodium oxide solution, adjust the pH to 9-10, and dissolve all the solids. Stir at 0-5°C for 30 minutes, let stand to separate the organic phase. Add 20ml of dichloromethane to the aqueous phase and extract once more. The water phase was discarded, the combined organic phase was washed once with 100 ml of water, the water phase was discarded, and 5-10 g of anhydrous sodium sulfate was added to the organic phase, stirred and dehydrated at room temperature for 1 hour, and suction filtered. Dichloromethane was evaporated from the oil layer to dryness under reduced pressure; 30 ml of toluene was added to dissolve it, and it was directly used in the next reaction.

Embodiment 2

[0030] A: Preparation of (S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butylamine

[0031] The extraction solvent is replaced with ethyl acetate, toluene, cyclohexane, etc. and the rest are the same.

Embodiment 3

[0033] B: (S)-4-(2-((4-methoxybenzyl)(3-methyl-1-(2-(1-piperidinyl)phenyl)butyl)amino)-2- Preparation of ethyl oxoethyl)-2-ethoxybenzoate

[0034] 9.25g of 4-ethoxycarbonyl-3-ethoxyphenylacetic acid, 50ml of toluene, and 4.4g of triethylamine were dissolved by stirring. Cool down to -10~-20°C, add a solution of 5g trimethylacetyl chloride and 10ml toluene, and keep it warm for 1 hour; add the (S)-3-methyl-1-(2-piperidinylbenzene base) butylamine and toluene solution. The reaction was stirred for 10 hours. The end point of the reaction was monitored by TLC. After completion of the reaction, 60ml of water was added, stirred, allowed to stand, and the water phase was discarded. The organic phase was washed once with 50 ml of salt water, the water layer was discarded, and the organic phase was concentrated to dryness with toluene to obtain an intermediate oil.

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PUM

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Abstract

The invention relates to a one-pot method for synthesizing repaglinide. In the method, commercial (S)-3-methyl-1[2-(1-piperidyl) phenyl] butyl amine L-N-acetylglutamate and 4-ethoxycarbonyl-3-ethoxy phenylacetic acid are used as raw materials to prepare repaglinide, thereby greatly shortening the reaction route and facilitating the production stability and continuity; and in esterification reaction, an acylating agent/acid-binding agent replaces triphenyl phosphorus/carbon tetrachloride to perform reaction, the intermediate does not needed to be crystallized, direct hydrolysis is performed according to the one-pot method, the intermediate meeting the requirements is obtained by a crude product recrystallization method, the column chromatographic separation is not needed, waste liquid is easy to treat, the yield is greatly improved, and the industrial production is facilitated.

Description

technical field [0001] The invention relates to a one-pot method for synthesizing repaglinide, which belongs to the technical field of repaglinide synthesis in the chemical pharmaceutical industry. [0002] The structure of repaglinide is as follows: [0003] Background technique [0004] Repaglinide is a new type of non-sulfonylurea insulin secretagogue, which is mainly used clinically for the treatment of non-insulin-dependent (type II) diabetic patients who cannot be effectively controlled by diet control and exercise. It has the characteristics of definite curative effect, small dosage and low side effects. At present, for the preparation of repaglinide, usually first prepare 3-methyl-1- [2-(1-piperidinyl)phenyl]butylamine, resolved with N-acetyl-L-glutamic acid to give (S)-3-methyl-1-[2-(1-piperidinyl) ) phenyl] butylamine, followed by docking reaction and hydrolysis with 4-ethoxycarbonyl-3-ethoxyphenylacetic acid to obtain repaglinide final product, the specific ...

Claims

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Application Information

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IPC IPC(8): C07D295/135
Inventor 王明光邢良徐成苗杨国栋方南平
Owner ZHEJIANG ANGLIKANG PHARMA
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