Mildronate dihydrate preparation method

Abstract

The invention provides a preparation method of Meldonium dihydrate. In the method, a strong basic anion resin is used to hydrolyze and remove methyl ester groups, so as to avoid generating redundant anions or other impurities as far as possible, and the product has high quality, good clarity and high yield, and can be used for injection grade.

Description

Technical field [0001] The present invention involves the field of drug synthesis technology, and specifically involves a method of preparation of a rice flexion. Background technique [0002] Mi Quyu (also known as THP, MET-88 and Mildronate) is a new type of heart protection medicine.It was developed by Latvia Organic Synthetic. In 1989, GRINDEKS was sold for the first time in the former Soviet Union. It is Cunatin's structural analogy. The chemical name is 3- (2, 2, 2, and triterlagia).Propyate two aquatic compounds.Later, it has been registered to be listed in more than 20 countries including Russia, Turkey, India, and Romania.The part of Mi Quya is mitochondrial, which improves myocardial energy metabolism at the cell level.In view of the obvious difference between such drugs and other antibuchia ischemia, it is also called cell antimedia.Michalin is a structural analog of botulinum alkali. It can compete to inhibit the chlorine alkalinase, thereby inhibiting the biological ...

AI Technical Summary

Problems solved by technology

This method is a conventional method for synthesizing Meldonium, but in terms of the separation of Meldonium dihydrate and the inorganic salts produced in the post-treatment process, the current method has different difficulties and cannot be well realized in production.

[0004] Such a method is adopted in WO 2009 / 103772, after dissolving potassium hydroxide in ethanol, alkaline hydrolyzing the sulfate of methyl 3-(2,2,2-trimethylhydrazino) propionate, and filtering after reaction Remove insolubles, and the filtrate uses cationic resin to adsorb cations again, so that the resulting Meldonium has the problems of high pH and incomplete removal of sulfate radicals; such a method is adopted in EP 2128126, which uses calcium hydroxide to alkaline hydrolyze 3- (2,2,2-trimethylhydrazino) sulfate of methyl propionate, the resulting Meldonium also has the problems of high pH and incomplete removal of sulfate radicals; sodium hydroxide base is used in US2009 / 0318731 Alkaline hydrolysis of the chloride salt of 3-(2,2,2-trimethylhydrazino)propionate methyl ester, and then passing carbon dioxide to saturation at low temperature, and then filtering to remove inorganic salts, the resulting midge Hydrazine has the problem of incomplete removal of chloride and high residue on ignition of the product; in WO2008 / 28514, sodium ethoxide and iodide salt of ethyl (2,2,2-trimethylhydrazino)propionate are used to carry out The method of reaction, this method also cannot remove the inorganic salt brought in during the alkaline hydrolysis process

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