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

Chem Pharm Bull (Tokyo). 2012;60(7):882-6. doi: 10.1248/cpb.c12-00023.

Abstract

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.

MeSH terms

  • Cyclohexanecarboxylic Acids / chemical synthesis*
  • Cyclohexanecarboxylic Acids / chemistry*
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Integrin alpha4beta1 / metabolism
  • Ketones / chemistry
  • Oxidation-Reduction
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry*
  • Stereoisomerism

Substances

  • Cyclohexanecarboxylic Acids
  • Integrin alpha4beta1
  • Ketones
  • Pyrrolidines
  • trans-4-(1-((2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl)acetyl)-(4S)-methoxy-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylic acid
  • cyclohexanecarboxylic acid