Preparation method of (S)-2-benzylsuccinic acid

A technology of benzyl succinic acid and benzyl succinate, applied in the field of medicine, can solve problems such as waste and pollution, achieve the effects of improving economic benefits, reducing waste solvents and other pollutants, and protecting the environment

Active Publication Date: 2016-03-23
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The route needs to be split, ( S The yield of )-2-benzylsuccinic acid is about 80%, with 20% ( S )-2-Benzyl...

Method used

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  • Preparation method of (S)-2-benzylsuccinic acid
  • Preparation method of (S)-2-benzylsuccinic acid
  • Preparation method of (S)-2-benzylsuccinic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Embodiment 1 catalyst blank test

[0024] will contain 100g 2-benzylsuccinic acid R -α-Phenylethylamine salt ( R / S =83 / 17) of the ethanol solution was concentrated under reduced pressure to recover ethanol, and then 500ml of water and 24g of sodium hydroxide were added to the remaining system and stirred to dissolve. The aqueous phase is extracted twice with dichloromethane, and the dichloromethane phase is combined to reclaim dichloromethane and ( R )-α-phenethylamine.

[0025] Heat the water phase to 80-90 oC Insulated for 12h, in the high performance liquid phase detection system ( R )-2-Benzylsuccinic acid and ( S )-2-benzylsuccinic acid ratio is 1:1, stop heating, cool down to 0-10 oC , add hydrochloric acid to the system to pH ≈ 1-2, at 0-10 o C for 2 hours, filter the system, and dry the solid. The yield is 95%.

[0026] The resulting 2-benzylsuccinic acid and R -α-Phenylethylamine is dissolved in ethanol by heating to reflux, and then crystallized o...

Embodiment 2

[0029] will contain 100g 2-benzylsuccinic acid R -α-Phenylethylamine salt ( R / S =85 / 15) of the ethanol solution was concentrated under reduced pressure to recover ethanol, and then 500ml of water and 35g of potassium hydroxide were added to the remaining system and stirred to dissolve. The aqueous phase is extracted twice with dichloromethane, and the dichloromethane phase is combined to reclaim dichloromethane and ( R )-α-phenethylamine.

[0030] Add 0.2g EDTA to the water phase and heat to 50-60 o C insulation for 4h, in the high performance liquid phase detection system ( R )-2-benzylsuccinic acid and (S)-2-benzylsuccinic acid ratio is 1:1, stop heating, cool down to 0-10 oC , add hydrochloric acid to the system to pH=1-2, at 0-10 o C for 2 hours, filter the system, and dry the solid. The yield is 96%.

[0031] The resulting 2-benzylsuccinic acid and R -α-Phenylethylamine salt crystallization in ethanol. Process by the method of embodiment 1, get S - Benzyl suc...

Embodiment 3

[0034] will contain 100g 2-benzylsuccinic acid R -α-Phenylethylamine salt ( R / S =85 / 15) of the ethanol solution was concentrated under reduced pressure to recover ethanol, and then 500ml of water and 80g of potassium carbonate were added to the remaining system and stirred to dissolve. The aqueous phase is extracted twice with dichloromethane, and the dichloromethane phase is combined to reclaim dichloromethane and ( R )-α-phenethylamine.

[0035] Add 0.4g EDTA to the water phase, then heat to 30-40 o C insulation for 3h, in the high performance liquid phase detection system ( R )-2-Benzylsuccinic acid and ( S )-2-benzylsuccinic acid ratio is 1:1, stop heating, cool down to 0-10 oC , add hydrochloric acid to the system to pH=1-2, at 0-10 o C for 2 hours, filter the system, and dry the solid. Yield 94.6%.

[0036] The obtained 2-benzylsuccinic acid and R-α-phenethylamine are salted and crystallized in ethanol. Process by the method of embodiment 1, get S - Benzyl s...

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Abstract

The invention provides a preparation method of (S)-2-benzylsuccinic acid, and relates to a method for preparing (S)-2-benzylsuccinic acid from (R)-2-benzylsuccinic acid. After EDTA is added in an alkaline aqueous solution containing the (R)-2-benzylsuccinic acid, racemization can be implemented effectively. By the method provided by the invention, the (S)-2-benzylsuccinic acid can be prepared from a solution of 2-benzylsuccinic acid (R)-alpha-phenylethanammonium generated in a production process of mitiglinide calcium, and economic benefit is improved further.

Description

technical field [0001] The present invention relates to a kind of by ( R )-2-benzylsuccinic acid preparation ( S )-2-benzyl succinic acid method, belongs to the technical field of medicine. Background technique [0002] Miglinide Calcium was synthesized by Tachibana Pharmaceutical Co., Ltd. in Japan. In December 2002, it was applied for the control of postprandial blood sugar in patients with type Ⅱ diabetes. It was launched in Japan in April 2004. Compared with repaglinide, nateglinide and traditional sulfonylurea drugs, it has the following advantages: (1) novel mechanism of action, faster onset and shorter duration of action; (2) stronger efficacy; ( 3) Flexible administration; (4) High safety and good tolerance. [0003] ( S )-2-benzylsuccinic acid is a key intermediate in the synthesis of mitiglinide calcium. The level of its production cost directly affects the production cost of mitiglinide calcium. Patents US6133454, WO9901430, and WO9832727 report the preparat...

Claims

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Application Information

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IPC IPC(8): C07C51/02C07C57/34
CPCC07C51/02C07C51/412C07C57/34
Inventor 鞠传平丛日刚李双民李鹏飞梁鑫蔡田成
Owner 迪嘉药业集团股份有限公司
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