氯雷他定合成方法的改进  

Improvement of synthetic method of loratadine

作　　者：陈鹏 郑滔 屈俊杰 钟旭斌 王涛 汪华 CHEN Peng;ZHENG Tao;QU Jun-jie;ZHONG Xu-bin;WANG Tao;WANG Hua(Livzon Syntpharm Co.,Ltd.(Zhuhai FTZ),Zhuhai Guangdong 519030)

机构地区：[1]珠海保税区丽珠合成制药有限公司,广东珠海519030

出　　处：《天津化工》2023年第3期38-41,46,共5页Tianjin Chemical Industry

摘　　要：氯雷他定是第二代抗组织胺药物,是合成地氯雷他定和卢帕他定的重要中间体,在抗过敏类和抗荨麻疹类药物市场中占有较大份额,基于氯雷他定优异的临床效果和较大的市场用量,本文通过对现有主要以三环酮为原料的3种氯雷他定合成方法进行介绍,分别总结了各个合成方法在实际合成过程中存在的问题,以期对今后改进氯雷他定合成方法提供依据。我们对磷酸酯加成反应的合成方法进行了改进,主要对添加碱种类、碱当量数、正丁基锂当量数、磷酸酯当量数、反应溶剂、回流温度、回流时间进行优化,最终确定以三乙胺为添加碱,二甲苯为反应溶剂,在130℃下回流,最终得到白色固体氯雷他定,产率达87%,纯度为99.96%,较原来反应条件相比产率和纯度都有了一定的提高,该反应路线具有较高实现工业化生产的可能性。Loratadine was a second-generation antihistamine drug,an important intermediate for the synthesis of desloratadine and rupatadine,and occupies a large share in the anti-allergic and anti-urticaria drug markets.Based on the excellent clinical effect and large market dosage of loratadine,this paper introduces three reported synthetic methods of loratadine mainly using tricyclic ketone as raw materials,and summarizes the practical synthesis of each synthetic method.The problems existing in the process are expected to provide a basis for improving the synthesis method of loratadine in the future.Among them,we have improved the synthesis method of the phosphate addition reaction,mainly to improve the type of base added,the number of base equivalents,the number of n-butyllithium equivalents,the number of phosphate ester equivalents,the reaction solvent,reflux temperature,and reflux time.It was determined that triethylamine was used as an added base,and xylene is used as a reaction solvent,and refluxed at 130℃to finally obtain a white solid loratadine with a yield of 87%and a purity of 99.96%.and purity have been improved to a certain extent,and the reaction route has a high possibility of realizing industrial production.

关 键 词：氯雷他定 三环酮 抗组织药物 合成方法 

分 类 号：TQ031.2[化学工程]