盐酸罗沙替丁醋酸酯的合成工艺优化及初步质量研究  

Improved synthesis and quality control of roxatidine acetate hydrochloride

作　　者：周志华 雷鹏飞 许炳浩 田慧敏 许佑君[1] ZHOU Zhi-hua;LEI Peng-fei;XU Bing-hao;TIAN Hui-min;XU You-jun(School of Pharmaceutical Engineering,and Key Laboratory of Structure-Based Drug Design&Discovery(Ministry of Education),Shenyang Pharmaceutical University,Shenyang 110016)

机构地区：[1]沈阳药科大学制药工程学院基于靶点的教育部重点实验室,沈阳110016

出　　处：《中南药学》2020年第2期205-209,共5页Central South Pharmacy

摘　　要：目的优化盐酸罗沙替丁醋酸酯合成工艺,制备合成过程中有关物质及建立相应的HPLC检测方法。方法以间羟基苯甲醛为起始原料,经与哌啶还原胺化、3-氯丙胺盐酸盐成醚、氯乙酰氯酰化、醋酸盐取代成酯、成盐,得盐酸罗沙替丁醋酸酯。针对选定的特定路线,制备了4种可能的有关物质。结果目标产物结构经MS和1H-NMR确证。反应总收率为31.0%(以间羟基苯甲醛计),终产品纯度达到99.6%。结论本文还建立了涉及该合成过程中的起始原料、中间体、主要有关物质和终产品的HPLC检测方法,可以有效监控产品质量。反应路线原料廉价易得,溶剂可回收套用,操作简便稳定,适合工业化生产。Objective To improve the synthetic route of roxatidine acetate hydrochloride,prepare related compounds and establish a reliable HPLC method.Methods Roxatidine acetate hydrochloride was synthesized from 3-hydroxybenzaldehyde by successive reductive amination with piperidine,etherified with 3-chloropropylamine hydrochloride,and condensed with chloroacetyl chloride.Then the formed amide was treated with potassium acetate for the esterific roxatidine which was finally transformed to the pharmaceutical hydrochloric form.The authentic samples of 4 possible related substances were also prepared for the quality control study.Results The structure of the final product and some important intermediates were confirmed by MS and 1 H-NMR.The total yield was 31.0%based on 3-hydroxybenzaldehyde,and the purity of the final product was higher than 99.6%(HPLC).Conclusion A reliable HPLC method has been established to control the quality of the final product,the key intermediates and main related compounds.The improvement has several advantages,such as cheap raw materials,recyclable solvent,simple operation,and mass production.

关 键 词：盐酸罗沙替丁醋酸酯 抗溃疡药 合成工艺 有关物质 高效液相色谱法 

分 类 号：R971[医药卫生—药品]