甲磺酸洛美他派的合成工艺改进-学兔兔 www.xuetutu.com.pdf

2015年第23卷
合成化学
第5期,445~448
Chinese Journal of Synthetic Chemistry
No.5,445~448
制药技术
甲磺酸洛美他派的合成工艺改进
张旭阳2,刘冰妮?,刘颖,刘登科2,王平保2
(1.天津医科大学研究生院,天津3000702.天津药物研究院,天津300193
摘要:以9-芴甲酸为起始原料经亲核取代反应和N-酰基化反应制得N-(2,2,2-三氟乙基)9-(4-溴丁基)9H
芴基9-甲酰胺(4);4-(三氟甲基)-[1,1'-联苯]-2羧酸与M叔丁氧羰基氨基哌啶反应制得中间体M-(1-叔
丁氧羰基哌啶4-基)4(三氟甲基)-「1,1'-联苯]-2-甲酰胺(7);7在4mol?LHC二烷溶液中脱除保护
基制得M(哌啶4-基)4-(三氟甲基)-[1,1'-联苯]-2-甲酰胺盐酸盐(8);8与4在K2CO3作用下反应制得洛
美他派(9);9与甲磺酸经成盐反应合成了甲磺酸洛美他派,总收率36.4%,其结构经HNMR,R和HR-ES
MS确证。
关键词:9-苭甲酸;洛美他派;甘油三酯转移蛋白抑制剂;合成;工艺改进
中图分类号:0621.3:R914.5文献标识码:ADOI:10.15952/.cnki.9jsc.1005-151.2015,05,.0445
Process Improvement on the Synthesis of Lomitapide Mesylate
ZHANG Xu-yang: 2, LIU Bing-ni, LIU Ying, LIU Deng-ke, WANG Ping-bao
(1. Graduate School, Tianjin Medical University, Tianjin 300070, China
2. Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
Abstract: 9-(4-bromobutyl)-/ -(2, 2, 2-trifluoroethyl)-9h-aluorene-9-carboxamide( 4)
was sy
the
sized by nucleophilic substitution and N-acylation using 9h-fluorene-9-carboxylic acid as the starting
material. -(piperidin-4- 1)4(trifluoromethyl)-[1, 1-biphenyl-2-carboxamide hydrochloride(8)
was prepared by the reaction of N-acylation and deprotection from 4-(trifluoromethyl)-[1, 1'-biphen-
yl]-2-carboxylic acid and tert-butyl 4-aminopiperidine-1-carboxylate Lomitapide mesylate in the o-
verall yield of 36.4% was synthesized by reaction of mesylate with Lomitapide which was obtained by
nucleophilic substitution of 4 with 8. The structure was confirmed by H NMR, IR and HR-ESI-MS
Keywords: 9h-fluorene-9-carboxylic acid; Lomitapide; microsomal triglyceride transfer protein in-
hibitor; synthesis; process improvement
甲磺酸洛美他派(1),商品名为 Juxtapid,化微粒体甘油三酯转移蛋白抑制剂的活性,减少乳
学名为N-(2,2,2-三氟乙基)-9(4-(4-{4-(三氟糜微粒和极低密度脂蛋白胆固醇(VLDL-C)的合成
甲基)[1,1'-联苯]-2-甲酰氨基}哌啶-1-基】丁和分泌,间接减少低密度脂蛋白胆固醇(LDL-C),
基)-9H-芴基-9-甲酰胺甲磺酸盐,是由美国Aege-从而降低患者的动脉粥样硬化风险
rion's公司开发的降血脂新药!-2。1通过抑制年12月美国食品药品管理局(FDA)批准其上市,
收稿日期:2014-11-18
甚金项目:国家重大新药创制专项(2011ZX09401-009);国家科技重大专项“重大新药创制”课题(2013ZX09102104)
作者简介:张旭阳(1989-),男,汉族,河南商丘人,硕士研究生,主要从事药物合成的研究。Tel.022-23005905,E-mai: xyol
o foxmail. com
通倌联系人:王平保,研究员,Tel,022-23006864,E-mail;wangpo@tipr.com