立他司特的合成工艺优化研究

Study on Optimization for Synthetic Process of Lifitegrast

对现有的立他司特合成工艺进行优化,以2-(叔丁氧基羰基)-5,7-二氯-1,2,3,4-四氢异喹啉-6-羧酸为初始原料,在酸性条件下脱Boc后,与苯并呋喃-6-羧酸发生缩合反应,再与(S)-2-氨基-3-甲砜基-苯丙酸缩合反应后得到立他司特,总收率在45%左右。优化后的工艺极大地简化了生产操作,缩短生产时间,降低生产成本,适合工业规模化生产,精制后的纯度符合立他司特原料药的质量要求。目标产物经1 HNMR、13 CNMR和ESI-MS得到结构确证。

The synthesis process of lifitegrast was explored.Taking 2-(Boc)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid as raw material,after removed Boc under acidic conditions,reacted with 6-benzofurancarboxylic acid,and then condensed reacted with(S)-2-amino-3-methylsulfonyl-phenylpropionic acid,the target compound was synthesized.The total yield was about 45%.This process greatly simplified the production operation,reduced the cost and was suitable for industrial-scale production.The purity met the quality requirements of lifitegrast API.The targeted compound structure was confirmed by 1H NMR,13C NMR and MS.