High purity mitiglinide calcium preparation method

A mitiglinide calcium and high-purity technology is applied in the field of preparation of high-purity mitiglinide calcium, can solve the problems of high reagent price, difficult liquid purification and storage, complicated process, etc., and achieves good reaction area selectivity, Ease of purification and preservation, and the effect of simplifying the synthesis route

Inactive Publication Date: 2014-04-09
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the synthesis process of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) calcium propionate dihydrate recorded in the literature has high reagent prices and equipment Disadvantages such as high requirements, complicated process and low yield
The U.S. patent (US6133454A) introduces a synthetic pathway for industrially synthesizing mitiglinide calcium (also see Chinese Patent Publication No. CN1261879A), but an asymmetric catalyst is used in it - complex rhodium, which is expensive and difficult to prepare. The cost of this synthetic route is relatively high, and in fact, when the acid anhydride and perhydroisoindole react, isomers are easily produced, and the whole process does not have regioselectivity
Chinese Patent Publication No. CN101492411A reports the synthesis method of mitiglinide, but reagents such as thionyl chloride and ethyl chloroformate are used in it, which either cause serious environmental pollution or are highly toxic reagents, which are not suitable for industrial production
In addition, mitiglinide acid is a liquid that is not easy to purify and preserve. To obtain a product with higher purity and to facilitate the realization of industrialization, the above problems must be solved.

Method used

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  • High purity mitiglinide calcium preparation method
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  • High purity mitiglinide calcium preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: The preparation method of the high-purity mitiglinide calcium adopts the following specific process steps.

[0028] (1) (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid shown in the preparation formula (VII):

[0029]

[0030] Add 81.7g of N,N-carbonyldiimidazole and 500mL of dichloromethane solution into the reaction bottle, cool down to -10°C, add 50.0g (240mmoL) of S-benzylsuccinic acid, and keep the reaction at low temperature for 5 hours after addition; 39.2 g (242 mmoL) of cis-perhydroisoindole hydrochloride in 80 mL of dichloromethane was reacted at -10°C, spotted on TLC until the reaction was complete, and 6N HCl was added dropwise into the reaction bottle to adjust the pH to 1-2, and stirred for 1 After 1 hour, the organic phase was separated, and the organic phase was washed with distilled water to obtain a dichloromethane solution of (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid.

[0031] (2) (2S)-2-benzy...

Embodiment 2

[0042] Embodiment 2: The preparation method of the high-purity mitiglinide calcium adopts the following specific process steps.

[0043] (1) Preparation of (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid:

[0044] Add 16.4g of N,N-carbonyldiimidazole into 250mL of the reaction bottle, cool down the temperature of 100mL of dichloromethane solution to 0°C, add 10.0g (48mmoL) of S-benzylsuccinic acid, and keep the reaction at low temperature for 4.5 hours after adding 7.9g (49mmoL) of cis-perhydroisoindole hydrochloride in 30mL dichloromethane solution, react at 0°C, spot on TLC until the reaction is complete, drop 6N HCl into the reaction bottle to adjust the pH to 1~2, and stir for 1 hour , separated the organic phase, and washed the organic phase with distilled water to obtain a dichloromethane solution of (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid.

[0045] (2) Preparation of benzyl (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)p...

Embodiment 3

[0049] Example 3: The preparation method of the high-purity mitiglinide calcium is as follows.

[0050] (1) Preparation of (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid:

[0051] Add 9.8g of N,N-carbonyldiimidazole into the 250mL reaction bottle, cool down the 60mL ethyl acetate solution to 10°C, add 6.0g (29mmoL) of S-benzylsuccinic acid, keep the reaction at low temperature for 4 hours after the addition, add dropwise 4.8g (29mmoL) of cis-perhydroisoindole hydrochloride in 40mL ethyl acetate solution, react at 10°C, spot on TLC until the reaction is complete, drop 6N HCl into the reaction bottle to adjust the pH to 1~2, and stir for 1 hour , separated the organic phase, and washed the organic phase with distilled water to obtain a dichloromethane solution of (2S)-2-benzyl-3-(cis-hexahydroisoindole-2-carbonyl)propionic acid.

[0052] Step (2)-step (5) adopts the ratio of raw materials, process conditions and steps described in Example 1.

[0053] After r...

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Abstract

The invention discloses a high purity mitiglinide calcium preparation method including the following steps: synthesis of (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) propionic acid; synthesis of (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) benzyl propionate; hydrolysis of the (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) benzyl propionate; and synthesis of mitiglinide calcium. The method simplifies synthetic route, and has the characteristics of convenient operation, low cost of raw materials, low equipment requirement, economy, environmental protection and simple technology. According to the method, the (2S)-2-benzyl-3-(cis-hexahydro isoindole-2-carbonyl) propionic acid can be crystallized after esterification, and is easy for purification and preservation and easy for realization of industrialized production. Tests confirm that the preparation method is easy in postprocessing, good in reaction area selectivity, high in product purity and relatively low in cost, and is conducive to industrial production.

Description

technical field [0001] The invention relates to a preparation method of high-purity mitiglinide calcium. Background technique [0002] Diabetes is a common endocrine disease. It is a disease of elevated blood sugar and sugar in urine caused by insufficient insulin in the body. Diabetes patients can be divided into insulin-dependent (type 1, IDDM) and non-insulin-dependent (type 2, NIDDM). Type 2 diabetes has accounted for more than 93.7%, and it is the most challenging public in the 21st century one of the health problems. In the past 20 years, the number of diabetic patients in my country has increased by 3 to 6 times, and it has become the hardest hit area for diabetes. The number of patients is second only to India, ranking second in the world. There are currently 40 million diabetic patients in the country, and the rate of 3,000 people per day Cardiovascular disease, kidney disease and other diseases caused by diabetes are the main causes of disability and even death in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/44
CPCC07D209/44
Inventor 尚振华徐龙朋王江霞王盼齐珊
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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