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Method for preparing improved mitiglinide calcium

A technology of mitiglinide calcium and dichloromethane, which is applied in the field of preparation of mitiglinide calcium, can solve the problems of waste of raw materials and high production costs, and achieve the effects of reducing energy consumption, avoiding harm to the human body, and shortening the reaction time

Inactive Publication Date: 2018-12-25
JIANGXI JIMINKEXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method of the present invention can effectively solve the generation of R-configuration isomers in the preparation process, and overcome the problems that the current mitiglinide production needs to discard the isomers by splitting, resulting in waste of raw materials, use of noble metal catalysts, and high production costs.

Method used

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  • Method for preparing improved mitiglinide calcium
  • Method for preparing improved mitiglinide calcium
  • Method for preparing improved mitiglinide calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Step (1): Preparation of acid chloride

[0048] Add 41.6g of S-benzylsuccinic acid (0.2mol), 0.6g of triethylamine, and 220mL of dichloromethane into a 500mL three-neck flask, stir at room temperature for 20min, and heat to reflux. Weigh 52.0 g of thionyl chloride (0.44 mol) and slowly add it dropwise. After the drop is completed, reflux for 3 h while stirring, and cool to room temperature.

[0049] Step (2): Preparation of Active Amide

[0050] Add 28.8g of imidazole (0.42mol), 81.2g of triethylamine (0.80mol), and 300mL of dichloromethane into a 1000mL three-neck flask, stir until completely dissolved, cool down to about -12°C in an ice-salt bath, and perform step (1) The middle reaction solution was transferred to the dropping funnel, and slowly added dropwise to the mixed solution of imidazole which had dropped to -12°C. After the drop was completed, the reaction was stirred for about 1 hour, and the temperature was lowered to below -12°C in an ice-salt bath.

[0...

Embodiment 2

[0056] Step (1): Preparation of acid chloride

[0057] Add 41.6g of S-benzylsuccinic acid (0.2mol), 0.6g of triethylamine, and 220mL of dichloromethane into a 500mL three-neck flask, stir at room temperature for 20min, and heat to reflux. Weigh 52.0 g of thionyl chloride (0.44 mol) and slowly add it dropwise. After the drop is completed, reflux for 3 h while stirring, and cool to room temperature.

[0058] Step (2): Preparation of Active Amide

[0059] Add 34.2g of imidazole (0.5mol), 81.2g of triethylamine (0.80mol), and 300mL of dichloromethane into a 1000mL three-neck flask, stir until completely dissolved, and cool down to about -8°C in an ice-salt bath. The middle reaction solution was transferred to the dropping funnel, and slowly added dropwise to the mixed solution of imidazole which had dropped to -8°C. After the drop was completed, the reaction was stirred for about 1 hour, and the temperature was lowered to below -8°C in an ice-salt bath.

[0060] Step (3): 2-(S)-...

Embodiment 3

[0065] Step (1): Preparation of acid chloride

[0066] Add 41.6g of S-benzylsuccinic acid (0.2mol), 0.6g of triethylamine, and 220mL of dichloromethane into a 500mL three-neck flask, stir at room temperature for 20min, and heat to reflux. Weigh 52.0 g of thionyl chloride (0.44 mol) and slowly add it dropwise. After the drop is completed, reflux for 3 h while stirring, and cool to room temperature.

[0067] Step (2): Preparation of Active Amide

[0068] Add 41.2g of imidazole (0.6mol), 81.2g of triethylamine (0.80mol), and 300mL of dichloromethane into a 1000mL three-neck flask, stir until completely dissolved, cool down to about -4°C in an ice-salt bath, and perform step (1) The middle reaction solution was transferred to the dropping funnel, and slowly added dropwise to the mixed solution of imidazole which had dropped to -4°C. After the drop was completed, the reaction was stirred for about 1 hour, and the temperature was cooled to below -4°C in an ice-salt bath.

[0069] ...

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PUM

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Abstract

The invention relates to a method for preparing improved mitiglinide calcium. The method sequentially includes the steps of 1), preparation of acyl chloride; 2), preparation of active amide; 3), preparation of 2-(S)-benzyl-4-oxo-(cis-perhydroisindole-2-base) butyric acid; 4), preparation of the mitiglinide calcium. The method is concise in process, high in yield and low in production cost; compared with an existing acid anhydride process, the process applying the method has the advantages that product purity is remarkably improved, and easiness in industrialized production is achieved.

Description

technical field [0001] The invention relates to the improvement of the preparation method of hypoglycemic drugs, more specifically a method for preparing mitiglinide calcium by using (S)-2-benzylsuccinic acid as raw material. Background technique [0002] Mitiglinide Calcium, [0003] [0004] The chemical name is bis(2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)-propionic acid monocalcium dihydrate, which is clinically used to treat type II diabetes. It was developed by Japanese orange (Kissei) pharmaceutical company, and it was listed in Japan for the first time in May 2004. [0005] The drug is the third meglitaide after repaglinide and nateglinide, and it is a derivative of phenylalanine. Compared with repaglinide, nateglinide and traditional sulfonylurea drugs, it has faster absorption, quicker onset and faster elimination, does not cause hypoglycemia, and has mild and long-lasting effects, which can be maintained at normal levels. Level. In the presence of ...

Claims

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Application Information

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IPC IPC(8): C07D209/44
CPCC07D209/44
Inventor 郭林峰彭常春文万江李义保何平清
Owner JIANGXI JIMINKEXIN PHARMA
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