氯雷他定合成工艺优化

Optimization of synthesis process of loratadine

氯雷他定(Loratadine)在我国一直作为临床一线的抗过敏药物使用,同时也是合成第三代抗组胺药物地氯雷他定(Desloratadine)和卢帕他定(Rupatadine)的重要医药化工中间体,但目前其合成工艺存在生产成本高,毒性大,收率低等问题。本论文在调研现有文献基础上,研究了一种氯雷他定的合成工艺并对其工艺进行优化,旨在探索出一条简洁稳定,条件温和的氯雷他定合成工艺。具体方法为,以2-氰基-3-甲基吡啶为原料,经Ritter反应,碳负离子取代反应,脱保护,格氏反应,环合,氯甲酸乙酯取代后得到产品。产物经;H NMR和HPLC-MS确证,总收率达36.9%,HPLC纯度达到99.8%以上,适合工业化生产。

Loratadine, which used as a clinical anti-allergic drug, is also an important chemical industry intermediate for the syntheses of the third-generation antihistamines Desloratadine and Rupatadine.However, the existing synthesis processes suffered from some drawbacks such as high production cost, high toxicity and low yield.Based on the investigation of the previous synthesis processes, we herein reported a simple, stable, and mild synthetic method of Loratadine from 2-cyano-3-methylpyridine using Ritter reaction, carbanion substitution, deprotection, Grignard reaction, cyclization, and ethyl chloroformate substitution with the overall yield of 36.9%,LC purity was over 99.8%.The structure of the final product was confirmed by;H NMR and LC-MS.This process could be used on large scale production.