A concise synthesis of a 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 reductive etherification.
This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of 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). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.
Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co. Ltd., 1–2–58 Hiromachi, Shinagawaku, Tokyo, Japan.
Jun
J
Chiba
Fumihito
F
Muro
Masaki
M
Setoguchi
Nobuo
N
Machinaga
D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007659:Ketones / Q000737:chemistry; D010084:Oxidation-Reduction; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
D003509:Cyclohexanecarboxylic Acids; D039041:Integrin alpha4beta1; D007659:Ketones; D011759:Pyrrolidines; C576301:trans-4-(1-((2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl)acetyl)-(4S)-methoxy-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylic acid; C044895:cyclohexanecarboxylic acid