Study on the synthesis process of naphazoline hydrochloride

Abstract

In order to solve the problems of out-of-date synthesis process and lag-behind quality control standards of naphazoline hydrochloride,the synthesis process of aimed product was studied.According to the relevant regulation of ICH Q11 on the development and manufacture of drug substances,the modified synthesis route was designed to control the generation of impurities based on the concept of quality by design.Using 1-naphthylacetic acid as the starting material,the target compound was obtained through amidation reaction,amide dehydration reaction,catalytic addition-cyclization reaction and salt formation reaction.The results show as follows:In the amidation reaction,using dichloromethane as the solvent,n[KG-*4](1-naphthylacetic acid[BF])[BFQ]∶n[KG-*4](di-tert-butyl dicarbonate[BF])[BFQ]∶n[KG-*4](ammonia)[KG-*4]=1∶12∶12,the yield is 886％;In the dehydration reaction and the addition-cyclization reaction,N,N-dimethylformamide is used as the solvent,the workup procedure is simple and the intermediate purity is high;In the salt formation reaction,n[KG-*4](naphazoline free base[BF])[BFQ]∶n[KG-*4](36％ hydrochloric acid)[KG-*3]=1∶148,the yield is 901％.The overall yield of the four-step reaction after optimization of the reaction conditions was 5083%.The four impurities listed in the European Pharmacopoeia were not detected in the product,and no new impurities were produced.The synthesis process have advantages of mild reaction condition and operational simplicity,so the result provide a theoretical basis for the industrial production of naphazoline hydrochloride.

Keywords

• organic synthesis chemistry; naphazoline hydrochloride; synthesis process; quality by design; 1-naphthylacetic acid