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

doi:10.6023/cjoc202011021

摘要/Abstract

(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]⁺ $\mathrm{BF}_{4}^{-}$/(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.

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

(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]⁺ $\mathrm{BF}_{4}^{-}$/(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 ofN-acetylenamine ester, reaching 99% ee. 2,4,5-Trifluorophenylacetic acid (1) was used as starting material, with Mildrum?s 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.

Key words: diabetes mellitus, dipeptidyl peptidse 4 (DPP-4) inhibitor, β-amino acid, chiral phosphorus ligand, asymmetric hydrogenation, synthesis

引用此文

盛力, 高浩凌, 吴旭锋, 范钢, 刘鹏程. 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[J]. 有机化学, 2021, 41(5): 2105-2111.

Li Sheng, Haoling Gao, Xufeng Wu, Gang Fan, Pengcheng Liu. 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[J]. Chinese Journal of Organic Chemistry, 2021, 41(5): 2105-2111.

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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”的文章，特向您推荐。请打开下面的网址：https://sioc-journal.cn/Jwk_yjhx/CN/abstract/abstract348304.shtml' name="neirong"> 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'>

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