Studies On The Synthesis Of The Key Intermediate Of Papaverine Hydrochloride

Papaverine (English name:Papaverine Hydrochloride) is a very useful anti-spasm drugs. It is capable of inhibiting cyclic nucleotide phosphodiesterase, and then generates non-special relaxation effect on blood vessel, heart or other smooth muscle. It is mainly used for the treatment of ischemia caused by the spasm of brain, heart or outer peripHeral vascular, and spasm of internal organs such as kidney, gall bladder, gastrointestinal tract and so on.N-(3,4-dimethoxypHenethyl)-2-(3,4-dimethoxypHenyl) acetamide is the key intermediate of papaverine hydrochloride. A synthetic route of N-(3,4-dimethoxypHenethyl)-2-(3,4-dimethoxypHenyl) acetamide has been designed for industrial production based on many references. Catechol as the starting material, through methylation, chloromethylation, cyanide, amination, hydrolysis and condensation to give the desired product. Each step of the above route has been studied and optimized systematically. Furtherly, the reasearch on kilo-scale has also been completed.To synthesize the main intermediate 3,4-dimethoxyphenylacetonitrile,a "three-step one-pot" method in which 1,2-dimethoxybenzene is used as the starting material is developed. This method gets rid of the cumbersome operations of separation and purification of each intermediate in the existing literature, greatly simplifying the production process. By optimizing the feeding mode of methylation reaction, the problem that a higher reaction yield depends on the use of hydrogen chloride gas in the current process has been solved, a higher yield of hydrochloric acid solution system has been achieved, the yield of 3.4-dimethoxyphenylacetonitrile increase by 10% compared with the process in existing similar literature.N-(3.4-dimethoxypHenethyl)-2-(3.4-dimethoxypHenyl) acetamide and the intermediates have been undergone structural confirmation. The synthetic process which possesses mild reaction conditions, simple operation and competitive cost, is a suitable route for industrial production.