Method for improving preparation technology of 3-(2,2-dimethylhydrazino)methyl propionate and 3-(2,2,2-trimethylhydrazino)methyl propionate

Abstract

The invention discloses a method for improving the preparation technology of 3-(2,2-dimethylhydrazino)methyl propionate and 3-(2,2,2-trimethylhydrazino)methyl propionate. The 3-(2,2-dimethylhydrazino)methyl propionate and 3-(2,2,2-trimethylhydrazino)methyl propionate are intermediates of a mildronate bulk drug. In the prior art, the intermediates are prepared by the following steps: making 1,1-dimehtylhydrazine carry out reactions with methyl acrylate, and then subjecting the reaction products to methylation reactions so as to obtain the target products; but the conventional technology has the disadvantages that the quality and stability of the obtain products are bad, thus the technology for producing the mildronate bulk drug becomes more complicated, and the synthesis cost is increased. The provided method separates two reactions in the synthesis route, exothermic reaction material feeding automatic control of each reaction is realized under mild conditions, the final products are subjected to a primary cooling precipitation and a secondary special purifying technology so as to obtain high purity products without complicated steps like recrystallization and washing, moreover the stability and yield of the products are both improved, the treatment time is shortened, the shelf life of the products is prolonged from two years to four years, and the method can be applied to commercial massive production.

Description

technical field [0001] The invention relates to an improved method for the preparation of methyl 3-(2,2,-dimethylhydrazino)propionate and methyl 3-(2,2,2-trimethylhydrazino)propionate, belonging to The field of chemical synthesis technology. Background technique [0002] The international nonproprietary name is Meldonium, and the chemical name is 3-(2,2,2-trimethylhydrazine) propionate dihydrate, which is famous for its cardioprotective effect. [0003] Various methods are known for the preparation of 3-(2,2,2-trimethylhydrazine)propionate dihydrate, generally comprising: [0004] 1,1-Dimethylhydrazine reacts with methyl acrylate to form 3-(2,2-dimethylhydrazino)propionic acid methyl ester, further generates corresponding 3-(2, 2,2-Trimethylhydrazine) methyl propionate halide or methyl sulfate, which is then hydrolyzed and deionized, separated with a saturated solution of carbon dioxide or sulfur dioxide, and crystallized in ethanol to obtain the dihydrate internal Salt. ...

AI Technical Summary

Problems solved by technology

[0004] 1,1-Dimethylhydrazine reacts with methyl acrylate to form 3-(2,2-dimethylhydrazino)propionic acid methyl ester, further generates corresponding 3-(2, 2,2-Trimethylhydrazine) methyl propionate halide or methyl sulfate, which is then hydrolyzed and deionized, separated with a saturated solution of carbon dioxide or sulfur dioxide, and crystallized in ethanol to obtain the dihydrate internal Salt. This conventional method avoids the use of electrodialysis and has many disadvantages: strong base ion exchange resins are unstable and decomposed or oxidized during processing; strong base ion exchange resins can only withstand a limited number of regeneration cycles; resin regeneration Large amounts of solvent, acid and base, and deionized water are required; and the ion exchange capacity is low, so the production cost of 3-(2,2,2-trimethylhydrazine)propionate dihydrate using this method is generally high

The conventional method for producing this intermediate is to make 1,1-dimethylhydrazine react with methyl acrylate and then react with methylating reagent halide to obtain the target product. This conventional continuous reaction method has many disadvantages: 1) The by-products and oxide impurities generated in the first step reaction are directly brought into the second step reaction. On the one hand, many by-products are also methylated by methylating reagents to form secondary, tertiary or quaternary ammonium salts, which lead to the target crude product Impurity content and kind complicate, and the color of the 3-(2,2,2-trimethylhydrazine) methyl propionate salt that finally obtains is very dark, causes certain difficulty to aftertreatment purification, increases production cost, more importantly It directly affects the yield and the quality and stability of the product, such as the current international quality standard for 3-(2,2,2-trimethylhydrazine) methyl propionate bromide: the appearance is white, light yellow or pink crystal Non-toxic powder, with a melting point of 118-135°C, a main content of 99.5-105%, and a validity period of two years

2) This continuous reaction is difficult to predict the correct reaction ratio relationship of each reactant and intermediate, so that the product quality, output and production process cannot be stabilized

3) The raw materials used in the reaction are easy to polymerize or oxidize at a certain temperature. Although the method of insulating the air with nitrogen is used to prevent the oxidation of raw materials and intermediates according to conventional methods, the reaction temperature and pressure involved can accelerate the alkylation reaction. , will still lead to the generation of a large number of by-products

4) The patent application publication number CN102036949A invented by Daina Chicane and Maris Tilkes has publicly mentioned the method of adding antioxidants to the reactants. Although this method suppresses the production of some by-products, it has not yet Thoroughly solve the complete optimization and stability of the final product process, the added antioxidant residue has a certain impact on the raw material drug, so this method has not yet been approved by the Pharmacopoeia in industrial production

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