盐酸萘甲唑啉的合成工艺研究

Study on the synthesis process of naphazoline hydrochloride

为了解决盐酸萘甲唑啉现有合成工艺落后、质量控制标准低等问题,对盐酸萘甲唑啉合成工艺进行了研究。以ICH Q11对化学药品研发与生产的相关规定为指导,设计一条从源头控制杂质产生的合成路线。以1-萘乙酸为起始原料,依次经过酰胺化、酰胺脱水、催化加成环合和成盐等4步反应得到目标化合物,并对各步骤进行工艺参数优化。结果表明,酰胺化反应中,以二氯甲烷为溶剂,n(1-萘乙酸)∶n(二碳酸二叔丁酯)∶n(氨水)=1∶1.2∶1.2时,收率为88.6%;脱水反应和加成环合反应中,以N,N-二甲基甲酰胺为溶剂,后处理易操作且获得的中间体纯度高;成盐反应中,n(萘甲唑啉游离碱)∶n(36%盐酸)=1∶1.48时,收率为90.1%;经工艺参数优化后的4步反应的总收率为50.83%,产品中未检出欧洲药典所列的4种杂质,也没有产生新的杂质。合成工艺反应条件相对温和,后处理简单,可为盐酸萘甲唑啉的工业化生产提供理论基础。

In order to solve the problems of out-of-date synthesis process and lag-behind quality control standards of naphazoline hydrochloride,the synthesis process of aimed product was studied.According to the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(1-naphthylacetic acid)∶n(di-tert-butyl dicarbonate)∶n(ammonia)=1∶1.2∶1.2,the yield is 88.6%;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(naphazoline free base)∶n(36%hydrochloric acid)=1∶1.48,the yield is 90.1%.The overall yield of the four-step reaction after optimization of the reaction conditions was 50.83%.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.