盐酸西替利嗪的合成工艺优化

Process Improvement of Cetirizine Hydrochloride

目的:对盐酸西替利嗪的合成工艺进行改进。方法:4-氯二苯甲胺与N,N-双(2-(对甲苯磺酰氧基)乙基)-对甲苯磺酰胺加成得到1-[(4-氯苯基)苯甲基]-4-(4-甲基苯基)-磺酰基哌嗪,收率90.7%;再经氢溴酸乙酸溶液脱保护,得到1-[(4-氯苯基)苯甲基]哌嗪,提高了本步反应的温度并缩短了反应时间;与2-(2-氯乙氧基)乙酰胺氮烷基化,将以正丁醇代替二甲苯做溶剂,降低反应温度以减少杂质产生。最后经水解、成盐即得目标产物。结果:目标产物纯度99.9%,总收率40.6%,已公斤级放大。结论:优化后的工艺反应温和,操作简便,适合商业化生产。

Objective:To improve synthetic process of Cetirizine hydrochloride.Methods:1-[(4-chlorophenyl)phenylmethyl]piperazine was synthesized by addition of 4-chlorodiphenylamine with N,N-bis(2-(toluenesulfonyl)ethyl)-toluenesulfonamide in a yield of 90.7%.1-[(4-chlorophenyl)phenylmethyl]piperazine was obtained by deprotection of acetic acid solution of hydrobromic acid,which increased the reaction temperature and shortened the reaction time;2-(2-chloroethoxy)acetamide was added into the product.In order to reduce impurity production,n-butanol will be used as solvent instead of xylene to reduce reaction temperature.Finally,the target product was obtained by hydrolysis and salt formation.Results:The purity of target product was 99.9%and the total yield was 40.6%,which has been scale-up kilogram.Conclusion:The optimized process has mild reaction conditions and simple operation,and is suitable for commercial manufacture.