铑/(2S,2'S,3S,3'S)-3,3'-二叔丁基-4,4'-二甲氧基-2,2',3,3'-四氢-2,2'-联苯并[d][1,3]草酰膦(MeO-BIBOP)催化的不对称还原烯胺合成(R)-3-叔丁氧羰基氨基-4-(2,4,5-三氟苯基)丁酸  

Rhodium/(2S,2'S,3S,3'S)-3,3'-Di-tert-butyl-4,4'-dimethoxy-2,2',3,3'-tetrahydro-2,2'-bibenzo[d][1,3]oxaphosphole(MeO-BIBOP)Catalyzed Synthesis of(R)-3-tert-Butoxy-carbonylamino-4-(2,4,5-trifluorophenyl)butyric Acid by Asymmetric Reduction of Enamines

作　　者：盛力[1] 高浩凌 吴旭锋 范钢[1] 刘鹏程 Sheng Li;Gao Haoling;Wu Xufeng;Fan Gang;Liu Pengcheng(Research&Development Center,Zhejiang Medicine Co.,Ltd.,Shaoxing,Zhejiang 312500;Changhai Biological Compamy,Zhejiang Medicine Co.,Ltd.,Shaoxing,Zhejiang 312300)

机构地区：[1]浙江医药股份有限公司研究院,浙江绍兴312500 [2]浙江医药股份有限公司昌海生物分公司,浙江绍兴312300

出　　处：《有机化学》2021年第5期2105-2111,共7页Chinese Journal of Organic Chemistry

摘　　要：(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸是重要的药物中间体,因此发展其高立体选择性的合成方法极具有实用价值.通过实验研究发现[Rh(NBD)2]+4 BF-/(2S,2'S,3S,3'S)-3,3'-二叔丁基-4,4'-二甲氧基-2,2',3,3'-四氢-2,2'-联苯并[d][1,3]草酰膦(MeO-BIBOP)催化剂对N-乙酰基烯胺酯的氢化具有较高的立体选择性,达到99%ee.反应以2,4,5-三氟苯乙酸(1)为起始原料,与米氏酸(2)经缩合、醇解、缩合、氨基乙酰化、不对称氢化、水解和氨基保护合成目标产物,总收率达到61%,纯度达到99.62%,为其放大生产提供了实用和高效的合成方法.(R)-3-Amino-4-(2,4,5-trifluorophenyl)butyric acid is an important pharmaceutical intermediate,so it is of great practical value to develop its highly stereoselective synthetic method.It is found that[Rh(NBD)2]+4 BF-/(2S,2'S,3S,3'S)-3,3'-di-tert-butyl-4,4'-dimethoxy-2,2',3,3'-tetrahydro-2,2'-bibenzo[d][1,3]oxaphosphole(MeO-BIBOP)catalyst has high stereoselectivity for the hydrogenation of N-acetylenamine ester,reaching 99%ee.2,4,5-Trifluorophenylacetic acid(1)was used as starting material,with Mildrumʼs acid(2)through condensation,alcoholysis,condensation,amino acetylation,asymmetric hydrogenation,hydrolysis and amino protection to synthesize target product with 61%yield in total and 99.62%purity.It provides a practical and efficient synthetic method for its scale-up production.

关 键 词：糖尿病 二肽基肽酶-4(DPP-4)抑制剂 Β-氨基酸 手性膦配体 不对称氢化 合成 

分 类 号：TQ460.1[化学工程—制药化工]