当前位置:
首页
网刊
治疗银屑病药物SYL927原料药中有关物质的合成
治疗银屑病药物SYL927原料药中有关物质的合成
肖〓琼,李〓彤,汪小涧,张蕾磊,张婷婷,马〓辰,尹大力

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
Synthesis of related substances of SYL927 used for treatment of psoriasis
(Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica &  Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China)

摘要参考文献相关文章

起始页:1708

摘要:目的:SYL927是一种新型的选择性S1P1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。

关键词:SYL927;S1P1受体激动剂;有关物质;合成

通讯作者:尹大力,男,博士,研究员,主要从事药物分子设计与合成研究。

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

作者简介:肖琼,女,硕士,助理研究员,主要从事药物分子设计与合成研究。

Abstract:Objective: To synthesize three related substances of SYL927, a novel selective S1P1 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% and 35% 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.

Key words:SYL927; S1P1 receptor agonist; related substance; synthesis

    [1]〓韩伟娟, 张海婧, 汪小涧, 等. 胺基丙二醇类衍生物、其制备方法和其药物组合物与用途. 中国:103702973 [P]. 2014-04-02.
    [2]〓TIAN YL, JIN J, WANG XJ, et al. Design, synthesis and docking-based 3D-QSAR study of novel 2-substituted 2-aminopropane-1,3-diols as potent and selective agonists of sphingosine-1-phosphate 1 (S1P1) receptor[J]. Med Chem Commun, 2013, 4: 1267-1274.
    [3]〓PEI WW, LI SH, NIE XP, et al. Convenient syntheses of 2-alkyl(aryl)-4,5-diphenyloxazoles and 2-alkyl (aryl)-4-phenyloxa zoles[J]. Synthesis, 1998, 1998(9): 1298-1304.
    [4]〓MAIKO H, MITSUHARU N, MASATOSHI K, et al. Removal of sphingosine 1-phosphate receptor-3 (S1P3) agonism is essential, but inadequate to obtain immunomodul-ating 2-aminopropane-1,3-diol S1P1 agonists with reduced effect on heart rate[J]. J Med Chem, 2010, 53(8): 3154-3168.