Improvement method for preparation technology of 3-(2-ethyl-2,2-dimethyl hydrazinyl) ethyl propionate iodate bulk drug

Abstract

The invention relates to an improvement method for a preparation technology of a 3-(2-ethyl-2,2-dimethyl hydrazinyl) ethyl propionate iodate bulk drug being an important antiarrhythmic drug. In orderto overcome the defects of raw material and intermediate instability, many reaction by-products and the like of a 1,1-dimethylhydrazine and ethyl acrylate addition reaction, in a process from the addition reaction to an alkylation reaction, special measures for treating impurities, controlling the impurities, passivating the impurities and the like are adopted for obtaining a high-purity 3-(2-ethyl-2,2-dimethyl hydrazinyl) ethyl propionate iodate bulk drug crystal; various impurity residue varieties of a final target compound and the step of macroporous resin purification in industrial production are avoided; all impurity sources are controlled and eliminated; and the advantages of commercial scale production, cost reduction, equipment simplicity and the like are realized.

Description

technical field [0001] The invention relates to the field of organic chemistry and pharmaceutical research, in particular to an improved preparation method technology and purification technology of 3-(2-ethyl-2,2-dimethylhydrazino) ethyl iodide iodide raw material drug . Background technique [0002] 3-(2-Ethyl-2,2-dimethylhydrazino) ethyl iodide salt belongs to an anti-arrhythmic drug used for the treatment of cardiac rhythm disorders. With the understanding of the electrophysiological properties of the heart and the mechanism of action of antiarrhythmic drugs, the drug treatment of arrhythmias has made great progress. [0003] A variety of methods are known to prepare 3-(2-ethyl-2,2-dimethylhydrazino) ethyl propionate iodide salt, usually including: 1,1-dimethylhydrazine reacts with ethyl acrylate to form 3-(2,2-dimethylhydrazino) ethyl propionate, further alkylated with ethyl iodide to generate the corresponding 3-(2-ethyl-2,2-dimethylhydrazino) ethyl propionate Ester ...

AI Technical Summary

Problems solved by technology

[0004] Obtain the raw material drug of 3-(2-ethyl-2,2-dimethylhydrazino) ethyl propionate iodine salt which is used to produce high-purity side reaction residues, and the key is to prepare 3-(2,2- Dimethylhydrazino) ethyl propionate intermediate quality directly affects the purity of bulk drug, the first step addition reaction intermediate product 3-(2,2-dimethylhydrazino) ethyl propionate in synthetic steps Ester is a water-soluble thick liquid with a high boiling point, which is easy to oxidize and has poor thermal stability. Therefore, after the addition reaction, the intermediate is purified by simple vacuum distillation, which is far from reaching the purpose of purification. In the viscous addition product solution It is difficult to separate the unreacted 1,1-dimethylhydrazine and its oxidation and derivative impurities, they still remain in the first target product, so the intermediate purified by distillation method also contains various hydrazines, Organic and inorganic ammonia, these nitrogen-containing impurities are also alkylated to form secondary, tertiary or quaternary ammonium salts during the second step of the alkylation operation, resulting in an increase in the impurity content and complexity of the impurity types in the second target crude product , finally these impurities are basically similar to the physical and chemical properties of the obtained water-soluble 3-(2-ethyl-2,2-dimethylhydrazino) ethyl propionate iodide salt, the water-soluble impurities formed by the alkylation above Salt purification and separation cause great difficulty, increase production cost, and more importantly, directly affect the yield. The final API product still contains these water-soluble impurities