High purity mitiglinide calcium preparation method

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...

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.

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