Preparation method of dextromethorphan

Abstract

The invention discloses a preparation method of dextromethorphan ((+)-3-methoxy-17-methyl-(9 alpha,13 alpha,14 alpha)-levorphane, I). The method comprises the following steps that a dextromethorphan intermediate (+)-1-(4-methoxy) benzyl-1,2,3,4,5,6,7,8-octahydro-isoquinoline (II) conducts N-benzylation reaction with a benzylation reagent under alkaline conditions to form (+)-1-(4-methoxy) benzyl-N-benzyl-1,2,3,4,5,6,7,8-octahydro-isoquinoline (III); the intermediate (III) is subjected to acid cyclization reaction to form (+)-3-hydroxy-17-benzyl-(9 alpha,13 alpha,14 alpha)-levorphane, (IV); the intermediate (IV) reacts with dimethyl sulfate or methine halide, and is subjected to O-methylation and N-methylation reaction to form (+)-3-methoxy group-17-benzyl-17-methyl-(9 alpha,13 alpha,14 alpha)-levorphane quaternary ammonium salt (V); (V) is subjected to catalytic hydrogenation reaction; benzyl is removed; and dextromethorphan (I) is obtained. Therefore, the preparation method can use a common and cheap methylation reagent to substitute an unusual methylation reagent such as phenyltrimethylammonium hydroxide, and the yield of reaction can be increased.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of dextromethorphan. Background technique [0002] Dextromethorphan ((+)-3-methoxy-17-methyl-(9α,13α,14α)-morphan, I) is the dextroisomer of morphine-like levomorphan methyl ether, which inhibits It is a powerful central antitussive drug whose antitussive strength is equal to or slightly stronger than that of codeine. Due to the low drug resistance and addiction of this variety, it is an antitussive drug suitable for long-term use or high-dose use. The drug has been included in the pharmacopoeia of many countries, and it is also one of the important varieties that my country needs to focus on in this field. [0003] [0004] Synthetic methods of dextromethorphan (I) have been reported, most of which are through optically pure intermediates (+)-1-(4-methoxy)benzyl-1,2,3,...

AI Technical Summary

Problems solved by technology

However, in the actual operation process, it was found that the above-mentioned common methylation reagents inevitably undergo different degrees of N-methylation reactions at the same time as O-methylation, resulting in N,N-dimethylation Quaternary ammonium salt, so that the yield of dextromethorphan is less than 20%, and the separation is very difficult

Images