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Improved mitiglinide calcium industrialized preparation method

A technology of mitiglinide calcium and benzylidene succinic acid, which is applied in the field of organic synthesis and preparation chemistry, can solve the problems of unsuitability for industrial production, many types of reagents, and lengthy steps, and achieve shortened production cycle, increased yield, and improved The effect of production efficiency

Inactive Publication Date: 2015-01-28
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the shortcomings of existing routes such as lengthy steps, many kinds of reagents, low yield, long cycle, high cost and unsuitable for industrialized production.

Method used

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  • Improved mitiglinide calcium industrialized preparation method
  • Improved mitiglinide calcium industrialized preparation method
  • Improved mitiglinide calcium industrialized preparation method

Examples

Experimental program
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Embodiment 1

[0036] Step 1: Preparation of 2-benzylidene succinic acid

[0037] Sodium methoxide (9kg) and methanol (48L) were put into a 100L reactor, stirred and dissolved, and poured into a 50L high-level tank. Dimethyl succinate (20kg) is dropped into 200L reaction kettle, heated to reflux, the methanol solution of sodium methylate in the high level tank is added dropwise rapidly, the dropwise reflux reaction is 30min, and benzaldehyde (10.9kg) is added dropwise under the reflux state, After dropping, reflux and stir for 3-5 hours. HPLC detects that the benzaldehyde reaction is complete. Add 4N NaOH aqueous solution (38L) dropwise, and react under reflux for 4-6 hours after dropping. Dried to obtain 19kg of light yellow solid, ie intermediate 1, with a yield of 90%. Step 2: Preparation of (S)-2-benzylsuccinic acid

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PUM

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Abstract

The invention provides an improved mitiglinide calcium (I) preparation method, and is characterized in that the preparation method successively comprises the steps: step 1, preparation of 2-benzyl succinic acid; step 2, preparation of (S)-2-benzyl succinic acid; step 3, preparation of 2-(S)-benzyl-4-oxo-(cis-perhydroisoindole-2-yl)butyric acid; and step 4, preparation of mitiglinide calcium. The invention provides the mitiglinide calcium industrialized preparation method having the advantages of being economical and practical, simple to operate, short in reaction period and high in yield.

Description

(1) Technical field [0001] The invention relates to the field of organic synthesis and preparation chemistry, in particular to an industrial preparation method of mitiglinide calcium. (2) Background technology [0002] Miglinide calcium (mitiglinide calcium), the chemical name is (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate calcium salt dihydrate, clinical use for the treatment of type 2 diabetes. It was developed by Kissei Pharmaceutical Company of Japan, and was first listed in Japan in May 2004. [0003] Miglinide calcium is the third meglitaide drug after repaglinide and nateglinide. It is an ATP-dependent potassium ion channel blocker and a derivative of phenylalanine. Its mechanism of action is Similar to sulfonylurea, but with faster onset and short half-life, it is not only beneficial to reduce postprandial blood sugar in diabetic patients, but also can avoid hypoglycemia caused by continuous blood sugar reduction, and has the reputation of "in...

Claims

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Application Information

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IPC IPC(8): C07D209/44
CPCC07D209/44
Inventor 刘文涛郑德强刘亚方毋立华王长斌赵国敏
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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