治疗银屑病药物SYL927原料药中有关物质的合成  

Synthesis of related substances of SYL927 used for treatment of psoriasis

作　　者：肖琼[1] 李彤[1] 汪小涧[1] 张蕾磊[1] 张婷婷[1] 马辰[1] 尹大力[1] 

机构地区：[1]中国医学科学院北京协和医学院药物研究所,活性物质发现与适药化北京市重点实验室,北京100050

出　　处：《中国新药杂志》2016年第15期1708-1715,共8页Chinese Journal of New Drugs

基　　金：国家“重大新药创制”科技重大专项资助项目(2012ZX09301002-001)

摘　　要：目的:SYL927是一种新型的选择性S1P_1受体激动剂。目前,作为治疗银屑病药物处于临床前研究阶段。为了对原料药中有关物质进行定量控制,本实验合成了存在于原料药中的3个有关物质。方法:以合成中间体2-(2-([1,1'-联苯]-4-基)乙基)-2-乙酰氨基丙二酸二乙酯为起始原料,经付克酰化后分别与羟基乙酸和乙酸成酯再经过环合、还原、水解、成盐等方法,得到有关物质1和2,收率分别为22%和35%。以合成中间体2-乙酰氨基-2-(2-(4'-(2-乙基噁唑-4-基)-[1,1'-联苯]-4-基)乙基)丙二酸二乙酯为起始原料,经过水解、脱羧、还原等方法,得到有关物质3,收率81%。结果:化合物的结构均经NMR和MS确证。结论:采用HPLC以及LC-MS比对的方法,确定了原料药中的有关物质为化合物1,2和3。Objective： To synthesize three related substances of SYL927,a novel selective S1P_1 receptor agonist used for treatment of psoriasis which is currently in the preclinical development,for the quality control.Methods： The ralated substances 1 and 2 were synthesized from diethyl 2-（ 2-（ [1,1＇-biphenyl]-4-yl） ethyl）-2-acetamidomalonate via multiple reaction steps including Friedel-Crafts acylation,esterification with hydroxy acetic acid or acetic acid,cyclization,reduction,hydrolysis,and salt forming reaction with an overall yields of 22% and35% respectively. The related substance 3 was obtained from diethyl 2-acetamido-2-（ 2-（ 4＇-（ 2-ethyloxazol-4-yl）-[1,1＇-biphenyl]-4-yl） ethyl） malonate by three-step reactions of hydrolysis,decarboxylation,and reduction with an overall yield of 81%. Results： The structures of the synthesized substances were confirmed by NMR and MS.Conclusion： The three related substances of SYL927 are confirmed as compounds 1,2,and 3 by the HPLC and LC-MS method.

关 键 词：SYL927 S1P1受体激动剂 有关物质 合成 

分 类 号：R914.5[医药卫生—药物化学]