Preparation method of mitiglinide calcium

A mitiglinide calcium and reaction technology, which is applied to the preparation field of the drug mitiglinide calcium, can solve the problems of many reaction steps, uneconomical, low yield and the like, saves the reaction time, is suitable for industrial production, and is easy to use. effect of operation

Inactive Publication Date: 2013-12-18
SHANXI DATONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0021] It can be seen that in the prior art, ( S The preparation reaction of )-2-benzylsuccinic acid needs more than three steps, and reaction steps is many, yield is low, be difficult to suitability for industrialized production, and must sacrifice ( R )-1-phenylethylamine to obtain chiral products, the amount of chirality does not increase, which is uneconomical

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Ⅰ ( S Synthesis of )-2-benzylsuccinic acid

[0046] Under stirring, add 0.46 g (20 mmol) of sodium metal into absolute ethanol, under the protection of nitrogen, heat and stir until the solution refluxes, and mix 50 mmol of benzaldehyde and diethyl succinate at a ratio of 1:1 under reflux Add 50 mmol into the reactor and react for 4 h. After cooling to room temperature, add 0.5 g of the asymmetric catalyst Ru1-SBA-16. Hydrogen gas is introduced by bubbling at room temperature. After stirring for 6 h, filter. The catalyst is recovered, the filtrate is acidified with 1:1 hydrochloric acid (PH≤2.0), concentrated and crystallized, and recrystallized with ethyl acetate to obtain ( S )-2-benzylsuccinic acid 9.5 g, yield 91.3%.

[0047] II (2 S Synthesis of )-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid

[0048] Cool 50 mmol of cis-hexahydroisoindole in dichloromethane to 0°C, add 20 mmol of thionyl chloride in 30 mL of dichloromethane dropwise, stir at 0°C...

Embodiment 2

[0053] Ⅰ ( S Synthesis of )-2-benzylsuccinic acid

[0054] Under stirring, metal sodium 0.23 g (10 mmol) is added in absolute ethanol, under nitrogen protection, heat and stir until the solution is refluxed, 1: 1 mixed benzaldehyde 50 mmol and diethyl succinate Add 50 mmol into the reactor, react for 4 h, cool to room temperature, then add the asymmetric catalyst Ru2-SBA-16 (0.1 g), pass hydrogen gas at room temperature, stir and react for 6 h, then filter. The catalyst is recovered, the filtrate is acidified with 1:1 hydrochloric acid (PH≤2.0), concentrated and crystallized, and recrystallized with ethyl acetate to obtain ( S )-2-benzylsuccinic acid 8.6 g, yield 83%.

[0055] II (2 S Synthesis of )-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid

[0056] Cool 45 mmol of cis-hexahydroisoindole in dichloromethane to 4°C, add 25 mL of 18 mmol of thionyl chloride in chloroform dropwise, stir at 5°C for 1 h, then add ( S )-2-benzylsuccinic acid 8.6 g, continue to...

Embodiment 3

[0060] Ⅰ ( S Synthesis of )-2-benzylsuccinic acid

[0061] Under stirring, metal sodium 1.15g (50mmol) is added in absolute ethanol, under nitrogen protection, heat and stir until the solution is refluxed, under the reflux state, 1: 1 mixed benzaldehyde 50 mmol and diethyl succinate 50 Add mmol into the reactor, react for 4 h, cool to room temperature, then add the asymmetric catalyst Ru3-SBA-160.8 g, pass in hydrogen at room temperature, stir for 6 h, and then filter. Catalyst recovery, filtrate after 1: 1 hydrochloric acid acidification (PH≤2.0), concentrated crystallization, with ethyl acetate recrystallization, obtains ( S )-2-benzylsuccinic acid 10 g, yield 96%.

[0062] II (2 S Synthesis of )-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid

[0063] Cool 50 mmol of cis-hexahydroisoindole in dichloromethane to 0°C, add 20 mL of thionyl chloride 20 mmol in toluene dropwise, stir at -5°C for 1 h, then add ( S )-2-benzylsuccinic acid 10 g, continue to stir f...

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Abstract

The invention discloses a preparation method of mitiglinide calcium. The preparation method comprises the following steps: (I) by taking diethyl succinate and benzaldehyde as raw materials, carrying out a reaction in a sodium ethoxide solution, and then, under the action of a multiphase asymmetric catalyst Ru-SBA-16, carrying out asymmetric hydrogenation to obtain a (S)-2-benzylsuccinic acid; (II) reacting the (S)-2-benzylsuccinic acid with perhydro-isoindole so as to generate mitiglinide; and (III) complexing the mitiglinide and calcium chloride so as to obtain a target compound mitiglinide calcium. According to the method, the reaction steps can be reduced, the reaction time can be shortened, and the chiral purity of mitiglinide calcium can be improved.

Description

technical field [0001] The invention relates to the fields of organic synthesis and heterogeneous asymmetric catalysis, in particular to a method for preparing mitiglinide calcium, a medicine for treating type II diabetes. Background technique [0002] Miglinide calcium, chemical name (2 S )-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl) calcium propionate dihydrate is an ATP-dependent potassium ion channel blocker developed by Japanese Kissei Pharmaceutical Company for the treatment of Type II diabetes. Miglinide calcium is a derivative of phenylalanine, and its mechanism of action is similar to that of sulfonylurea. It works quickly and has a short half-life, which is not only beneficial to reduce postprandial blood sugar in diabetic patients, but also avoids hypoglycemia caused by continuous blood sugar reduction. It has the reputation of "in vitro pancreas". [0003] Literature patents US6133454, WO9832727, and WO9901430 report the preparation method of mitiglinide ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/44
CPCY02P20/584
Inventor 吕存琴郭永晋春杨国臣孟双明刘建红沈腊珍
Owner SHANXI DATONG UNIV
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