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Method for preparing hypoglycemic drug mitiglinide calcium

A technology of mitiglinide calcium and medicine, which is applied in the field of medicine, can solve the problems of high production cost, use of precious metal catalysts, waste of raw materials, etc., and achieve the effects of reducing production cost, increasing total yield, and simple production process

Inactive Publication Date: 2016-10-12
HENAN UNIV OF CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of the above situation, in order to solve the defects of the prior art, the purpose of the present invention is to provide a preparation method of hypoglycemic drug mitiglinide calcium, which can effectively solve the production of R configuration isomers in the preparation process and overcome the current In the production of mitiglinide, the isomers need to be separated and discarded, resulting in waste of raw materials, the use of precious metal catalysts, and high production costs.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] The preparation method of the hypoglycemic drug mitiglinide calcium of the present invention: 31.3 g of 2-benzylidene-3-(cis-perhydroisoindolyl-2-carbonyl)propionic acid is dissolved in 400 ml at 0°C In tetrahydrofuran, add 2.8g (S)-diphenyl (pyrroline-2-yl)methanol, 10.8g potassium borohydride, 21g trimethylchlorosilane, stir and react for 6 hours, evaporate the solvent under reduced pressure, add water 500 ml, 5 ml of hydrochloric acid, extracted with ethyl acetate, after combining the extracts, dry and concentrate the extracts to obtain a concentrate, dissolve the concentrate in 500 mL of ethanol with a mass concentration of 75%, add 4 g of sodium hydroxide, and stir to dissolve Finally, add 11g of calcium chloride, precipitate out, and after the precipitate is suction-filtered, mitiglinide calcium is obtained.

[0016] Yield 95%, optical purity 98.6% e.e.

[0017] Proton NMR spectrum: 1 HNMR (CDCl 3 ) δ:1.26-1.71(10H, m), 2.18-2.29(2H, m), 2.79-3.26(7H, m), 7.20-...

Embodiment 2

[0021] The preparation method of the hypoglycemic drug mitiglinide calcium of the present invention: Dissolve 30 g of 2-benzylidene-3-(cis-perhydroisoindolyl-2-carbonyl)propionic acid in 200 ml at -5°C In dioxane, add 2g (S)-bis(4-methylphenyl)(pyrroline-2-yl)methanol, 8g sodium borohydride, 15g trimethylchlorosilane, stir for 4 hours, then reduce Evaporate the solvent under pressure, add 400 ml of water, 4 ml of hydrochloric acid, extract with ethyl acetate, combine the extracts, dry and concentrate the extracts to obtain a concentrate, dissolve the concentrate in 400 mL of ethanol with a mass concentration of 95%, add After stirring and dissolving 3g of sodium hydroxide, 8g of calcium chloride was added to precipitate out, and the precipitate was suction-filtered to obtain mitiglinide calcium.

[0022] Yield 96%, optical purity 98.8% e.e.

[0023] Proton NMR spectrum: 1 HNMR (CDCl 3 ) δ:1.26-1.71(10H, m), 2.18-2.29(2H, m), 2.79-3.26(7H, m), 7.20-7.31(5H, m), 13.5-14.4(1H,...

Embodiment 3

[0027] The preparation method of the hypoglycemic drug mitiglinide calcium of the present invention: Dissolve 60 g of 2-benzylidene-3-(cis-perhydroisoindolyl-2-carbonyl)propionic acid in 500 ml at -10°C Add 5g (S)-bis(4-chlorophenyl)(pyrroline-2-yl)methanol, 15g potassium borohydride, and 25g trimethylchlorosilane to ethylene glycol dimethyl ether, and stir for 8 hours. Evaporate the solvent under reduced pressure, add 600 ml of water and 6 ml of hydrochloric acid, extract with ethyl acetate, combine the extracts, dry and concentrate the extracts to obtain a concentrate, and dissolve the concentrate in 600 mL of ethanol with a mass concentration of 80%. Add 5g of sodium hydroxide, stir to dissolve, add 12g of calcium chloride, precipitate out, and filter the precipitate to obtain mitiglinide calcium.

[0028] Yield 92%, optical purity 98.2% e.e.

[0029] Proton NMR spectrum: 1 HNMR (CDCl 3 ) δ:1.26-1.71(10H, m), 2.18-2.29(2H, m), 2.79-3.26(7H, m), 7.20-7.31(5H, m), 13.5-14....

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Abstract

The invention relates to a method for preparing a hypoglycemic drug mitiglinide calcium. According to the method, under the temperature of -5 DEG C-10 DEG C, 30-60g of 2-benzylidene-3-(cis-perhydro-isoindolyl-2-carbonyl)propionic acid is dissolved in 200-500 milliliters of a reaction solvent, 2-5 g of a S-configuration aminoalcohol catalyst, 8-15 g of a borohydride and 15-25 g of trimethylchlorosilane are added, the materials are stirred for a reaction for 4-8 hours, pressure reduction is carried out for steaming the solvent, 400-600 milliliters of water and 4-6 milliliters of hydrochloric acid are added, ethyl acetate is used for extraction, an extract is merged, the extract is dried and concentrated to obtain a concentrate, the concentrate is dissolved in 400-600 mL of ethanol with mass concentration of 75-95%, 3-5 g of sodium hydroxide is added, after stirring and dissolving the materials, 8-12 g of calcium chloride is added, precipitate is obtained, and then the precipitate is subjected to pumping filtration to obtain mitiglinide calcium. The preparing method has the advantages of simple process, energy saving and environmental protection, can greatly increase the overall yield and obviously reduce the production cost, is easy to industrial production, is an innovation of a medicine for treating diabetes, and has large economic and social benefits.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of mitiglinide calcium, a hypoglycemic drug. Background technique [0002] Mitiglinide Calcium (Mitiglinide Calcium) chemical name bis[(2S)-2-benzyl-3-(cis-perhydroisoindolyl-2-carbonyl)propionic acid]-calcium dihydrate, is phenylpropanoid Derivatives of amino acid, its mechanism of action is similar to that of sulfonylurea, but its onset is faster, its effect is stronger, and its half-life is shorter, so the side effects are small, and it can effectively reduce postprandial blood sugar while avoiding hypoglycemia caused by continuous hypoglycemia , a hypoglycemic drug used alone for type 2 diabetes whose hyperglycemia cannot be effectively controlled by diet and exercise therapy. [0003] There are three main methods for the synthesis of mitiglinide calcium: the first is to prepare racemic 2-benzyl-3-(cis-perhydroisoindolyl-2-carbonyl)propionic acid, and then obtain...

Claims

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Application Information

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IPC IPC(8): C07D209/44
CPCC07D209/44
Inventor 钟铮王新灵冯卫生孙德梅赵原庆冯燕伟
Owner HENAN UNIV OF CHINESE MEDICINE
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