title: A novel synthetic approach to very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via tert-butyl trans-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a key intermediate.
abstract: This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1) via tert-butyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu₄NSO₃H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4-disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4-hydroxycyclohexanecarboxylic acid (9) as a commercially available starting material.
authors.affiliation: Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Tokyo, Japan. chiba.jun.mv@daiichisankyo.co.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.forename: Nobuo
authors.initials: N
authors.lastname: Machinaga
mesh_terms: D000577:Amides / Q000737:chemistry; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004987:Ethers / Q000737:chemistry; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D011759:Pyrrolidines / Q000737:chemistry; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
chemical_list: D000577:Amides; D018927:Anti-Asthmatic Agents; D003509:Cyclohexanecarboxylic Acids; D004987:Ethers; D039041:Integrin alpha4beta1; D011759:Pyrrolidines; C070042:4-hydroxycyclohexanecarboxylic acid; C044895:cyclohexanecarboxylic acid; C032519:pyrrolidine