Preparation method of mitiglinide calcium

A technology of mitiglinide calcium and calcium salt, applied in the direction of organic chemistry, can solve the problems of rising process cost and low yield, avoiding the use of chiral catalysts or resolution reagents, simple reaction process and low price Effect

Active Publication Date: 2012-04-25
JIANGSU SIHUAN BIOENGINEERING PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the yield of high temperature decarboxylation is too low, which makes the whole process cost rise

Method used

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  • Preparation method of mitiglinide calcium
  • Preparation method of mitiglinide calcium
  • Preparation method of mitiglinide calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] like Figure 1 to Figure 6 Shown, a kind of preparation method of preparing mitiglinide calcium, the steps are as follows:

[0068] Step 1: Hydrolyze D-phenylalanine under strong acid to obtain 2-hydroxyphenylpropionic acid

[0069] In a 5L reaction flask, add 3L of 6N sulfuric acid, add 330g (2mol) of D-phenylalanine under ice-salt bath cooling, stir, add 850g of 36% sodium nitrite aqueous solution dropwise at -5°C, and finish the reaction at room temperature. Overnight, the reaction mixture was extracted with ethyl acetate, combined and dried by adding an appropriate amount of anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 320 g of light yellow solid with a yield of 95.0%.

[0070] Step 2: 2-hydroxyphenylpropionic acid protects the hydroxyl group with sulfonate under alkaline conditions to obtain hydroxyphenylpropionic acid sulfonate

[0071] In a 5L reaction flask, add 3L of pyridine, and dissolve the hydroxyphenylalanin...

Embodiment 2

[0081] Step 1: Hydrolyze D-phenylalanine under strong acid to obtain 2-hydroxyphenylpropionic acid

[0082] In a 5L reaction flask, add 3L of 6N sulfuric acid, add 330g (2mol) of D-phenylalanine under ice-salt bath cooling, stir, add 850g of 36% sodium nitrite aqueous solution dropwise below 5°C, and react overnight at room temperature after dropping. The reaction mixture was extracted with ethyl acetate, combined and dried by adding an appropriate amount of anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 320 g of light yellow solid with a yield of 95.0%.

[0083] Step 2: 2-hydroxyphenylpropionic acid protects the hydroxyl group with sulfonate under alkaline conditions to obtain hydroxyphenylpropionic acid sulfonate

[0084] In a 5L reaction flask, add 3L of triethylamine, and dissolve the hydroxyphenylalanine obtained in the previous step. Slowly add 252g of p-methanesulfonyl chloride under 0°C, and react overnight at room temperatu...

Embodiment 3

[0094] Step 1: Hydrolyze D-phenylalanine under strong acid to obtain 2-hydroxyphenylpropionic acid

[0095]In a 5L reaction flask, add 3L of 6N sulfuric acid, add 330g (2mol) of D-phenylalanine under ice-salt bath cooling, stir, add 850g of 36% sodium nitrite aqueous solution dropwise below 0°C, and react overnight at room temperature after dropping. The reaction mixture was extracted with ethyl acetate, combined and dried by adding an appropriate amount of anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 320 g of light yellow solid with a yield of 95.0%.

[0096] Step 2: 2-hydroxyphenylpropionic acid protects the hydroxyl group with sulfonate under alkaline conditions to obtain hydroxyphenylpropionic acid sulfonate

[0097] In a 5L reaction flask, add 3L of pyridine, and dissolve the hydroxyphenylalanine obtained in the previous step. Slowly add 400g of p-toluenesulfonyl chloride at a temperature below 0°C, and react overnight at roo...

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Abstract

The invention discloses a preparation method of mitiglinide calcium, and the preparation method adopts (D)-phenylalanine as a raw material, and prepares mitiglinide calcium with a high yield through reactions of diazotization, hydroxy and carboxyl protection, nucleophilic substitution, hydrolysis, etc. The raw material used in the process provided by the invention has a wide source and a low price; the total yield is up to 47%; the optical purity is more than 99%; the reaction condition is mild; the reaction process is simple; disadvantages of low yield and long reaction steps of methods such as resolution, high pressure hydrogenation and the like reported in literature are avoided; and the invention provides a new selection for the preparation and production of mitiglinide calcium.

Description

technical field [0001] The invention relates to a preparation method of a hypoglycemic drug, in particular to a preparation method of mitiglinide calcium. Background technique [0002] Miglinide Calcium was synthesized by Japan Tachibana Pharmaceutical Co., Ltd. in December 2002 for the control of postprandial blood sugar in patients with type II diabetes, and was launched in Japan in April 2004. Jusheng Pharmaceutical has authorized the drug to Choongwae Company of South Korea, Servier Company of France and Takeda Company of Japan in March 2003, and it is in pre-clinical, phase III clinical and registration stages respectively. At the same time, the phase III trials of the drug in the United States, Canada, Mexico and authorized by the French company Servier in Europe, Africa and some other regions have also been fully launched. The basic information of the drug is as follows: [0003] English name of Mitiglinide Calcium: Mitiglinide Calcium [0004] Chemical name: bis(2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/44
Inventor 吴鹏程徐建国姚黎孙明张海滨
Owner JIANGSU SIHUAN BIOENGINEERING PHARM CO LTD
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