以ICH Q11對化學藥品研發與生產的相關規定為指導,通過分析已報道的鹽酸萘甲唑啉合成方法的優缺點及歐洲藥典中該品種雜質的產生來源,設計一條從源頭控制雜質產生的合成路線。以1-萘乙酸為起始原料,依次經過酰胺化、酰胺脫水、催化加成環合和成鹽等四步反應得到目標化合物,并對各步驟進行工藝參數優化。結果表明：酰胺化反應中,以二氯甲烷為溶劑,n(1-萘乙酸)﹕n(二碳酸二叔丁酯)﹕n(氨水)= 1﹕1.2﹕1.2時,收率為88.6％；脫水反應和加成環合反應中,以N, N-二甲基甲酰胺為溶劑,后處理易操作且獲得的中間體純度高；成鹽反應中,n(萘甲唑啉游離堿)﹕n(36％鹽酸)= 1﹕1.48時,收率為90.1％。經工藝參數優化后的四步反應的總收率為50.83％,產品中未檢出歐洲藥典所列的四種雜質,也沒有產生新的雜質。該合成工藝反應條件溫和,適合工業化生產。
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.