以ICH Q11对化学药品研发与生产的相关规定为指导,通过分析已报道的盐酸萘甲唑啉合成方法的优缺点及欧洲药典中该品种杂质的产生来源,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四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四步反应的总收率为50.83％,产品中未检出欧洲药典所列的四种杂质,也没有产生新的杂质。该合成工艺反应条件温和,适合工业化生产。
According to the relevant regulation of ICH Q11 on the development and manufacture of drug substances, the advantages and shortcomings of reported synthetic methods of Naphazoline Hydrochloride and the possible origination of it’s impurities specified in the European Pharmacopoeia were analyzed, and then 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％. After optimizing the process parameters, the total yield is 50.83％ with four successive steps, and the four impurities listed in the European Pharmacopoeia are not detected. The synthesis process has advantage of mild reaction conditions, which is suitable for industrial application.