摘要
卡非佐米(Carfilzomib)是一种α,β-环氧酮类蛋白酶体抑制剂,适用于多发性骨髓瘤的治疗。以L-苯丙氨酸苄酯为原料,经多步反应合成得到中间体2-吗啉乙酰-L-高苯丙氨酰-L-亮氨酰-L-苯丙氨酸。另以叔丁氧羰基(Boc)保护的L-亮氨酸为原料,经Weinreb酰胺化、格氏加成、环氧化及脱保护得到中间体S-2-氨基-4-甲基-1-(2S-环氧丙基)-1-戊酮三氟乙酸盐,上述两种中间体最终经缩合得到目标产物。关键中间体及产物经1HNMR和HR-MS确证结构。该合成方法反应条件温和、纯化简便、收率较高,适合大规模生产。
Cafilzomib,a kind of proteasome inhibitor characterized by α,β-epoxyketone,is clinically used in the treatment of multiple myeloma. In this work,（（ S）-2-（ 2-morpholinoacetamido）-4-phenylbutanoyl）-L-leucyl-L-phenylalanine（ MA）,the key intermediate of cafilzomib,was prepared from L-phenylalanine benzyl ester in several steps. The other intermediate（ S）-2-amino-4-methyl-1-（（ S）-2-methyloxiran-2-yl） pentan-1-one（ MB） was synthesized from Boc-L-leucine via Weinreb amidation,Grignard reagent addition,epoxidation and deprotection. The titled carfilzomib was formed via condensation of MA and MB. The structure of the intermediates and products was confirmed by1 HNMR and HRMS. The method is suitable for large-scale production due to the mild reaction conditions,convenient purification methods and good yields.
出处
《化学试剂》
CAS
北大核心
2016年第12期1219-1223,共5页
Chemical Reagents
基金
江苏省自然科学基金青年项目(BK20140425)
南通大学引进人才科研启动资助项目(03080694)
