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Improved method for preparation of mitiglinide

A compound and selected technology, applied in the direction of organic chemistry, can solve the problem of decreased controllability of the reaction, and achieve the effects of reducing the production of isomers, improving purity, and increasing yield

Inactive Publication Date: 2009-07-29
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent ZL98806779 uses dimethyl succinate and benzaldehyde as starting materials to prepare the final product through condensation, substitution, asymmetric hydrogenation, and salt formation. In the reaction, isomers are easily produced, which greatly reduces the controllability of the reaction

Method used

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  • Improved method for preparation of mitiglinide
  • Improved method for preparation of mitiglinide
  • Improved method for preparation of mitiglinide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 24.0g triethylamine (0.24mol), (2S)-benzyl succinic acid 12.0g (0.056mol), imidazole 8.0g (0.12mol), 120ml dichloromethane were added in a 500ml three-necked flask, and the ice-salt bath was cooled to -10°C, 13.0 g (0.12 mol) of thionyl chloride was slowly added dropwise, and the temperature control T was less than -10°C. After dropping, control the temperature below 0°C and react for 4 hours, add cis-perhydroisoindole hydrochloride 9.2g (0.072mol) below 0°C, control the temperature below 0°C and react for 8 hours, add 120ml of 1N hydrochloric acid to the reaction solution , liquid separation, 120ml of water to wash the organic phase once, add 120ml of 1N sodium hydroxide solution and stir for 1 hour, liquid separation, 2×60ml of ethyl acetate to wash the water phase twice, 1N hydrochloric acid to neutralize the water phase until the pH value is about 3, 2× Extract with 300ml of ethyl acetate, separate the layers, dry the organic phase with anhydrous sodium sulfate for ...

Embodiment 2

[0027] Add 24.0g of triethylamine (0.24mol), 12.0g (0.056mol) of (2S)-benzylsuccinic acid, and 120ml of acetone into a 500ml three-neck flask, cool down to -5°C in an ice-salt bath, and slowly add ethyl chloroformate dropwise 6.7 g (0.062 mol) of ester, the temperature control T is less than -5 °C. After dropping, control the temperature below 0°C and react for 4 hours, add cis-perhydroisoindole hydrochloride 9.2g (0.072mol) below 0°C, control the temperature below 0°C and react for 8 hours, add 120ml of 1N hydrochloric acid to the reaction solution , liquid separation, 120ml of water to wash the organic phase once, add 120ml of 1N sodium hydroxide solution and stir for 1 hour, liquid separation, 2×60ml of ethyl acetate to wash the water phase twice, 1N hydrochloric acid to neutralize the water phase until the pH value is about 3, 2× Extract with 300ml of ethyl acetate, separate the layers, dry the organic phase with anhydrous sodium sulfate for 3 hours, filter, and concentrat...

Embodiment 3

[0029] Add 24.0g of triethylamine (0.24mol), 12.0g (0.056mol) of (2S)-benzylsuccinic acid, and 120ml of dichloromethane into a 500ml three-necked flask, cool down to -10°C in an ice-salt bath, and slowly add grass Acid chloride 7.8g (0.062mol), temperature control T is less than -10 ℃. After dropping, control the temperature below 0°C and react for 5 hours, add cis-perhydroisoindole hydrochloride 9.2g (0.072mol) below 0°C, control the temperature below 0°C and react for 8 hours, add 120ml of 1N hydrochloric acid to the reaction solution , liquid separation, 120ml of water to wash the organic phase once, add 120ml of 1N sodium hydroxide solution and stir for 1 hour, liquid separation, 2×60ml of ethyl acetate to wash the water phase twice, 1N hydrochloric acid to neutralize the water phase until the pH value is about 3, 2× Extract with 300ml of ethyl acetate, separate the layers, dry the organic phase with anhydrous sodium sulfate for 3 hours, filter, and concentrate under reduc...

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Abstract

The invention relates to a method for preparing Mitiglinide. The method comprises the steps as follows: a compound (I) and a compound (II) are stirred in proper solvent and react for 1 to 20 hours; reaction solution is acidified by dilute acid solution for separating solution; an organic phase is washed in water and then is basified by alkaline solution for separating solution; a water phase is washed by organic solvent; the dilute acid solution is added for acidifying; the organic solvent is extracted, dried, decompressed and concentrated to obtain the Mitiglinide with high yield and high purity. The method for preparing the Mitiglinide has simple operation, high yield and low cost.

Description

Technical field [0001] The present invention relates to a kind of preparation method of industrial synthesis formula (III), more specifically, the present invention relates to a kind of preparation method of mitiglinide. [0002] Background technique [0003] The compound of formula (III) and its addition salt have particularly valuable pharmacological properties, it is an effective substance for promoting insulin secretion, and can be used for treating non-insulin-dependent diabetes. Formula (III) compound, its preparation method and therapeutic use are described in European Patent EP0507534, but the industrial preparation method of compound such as formula (III) needs to carry out in-depth research to all reaction steps, raw material, reagent solvent and just can obtain economical and practical production Process; the synthetic method described in the above-mentioned European patent cannot obtain the compound in an optimal yield. In fact, while preparing mitiglinide th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/44
Inventor 曹志华
Owner 北京华禧联合科技发展有限公司