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

Chem Pharm Bull (Tokyo). 2011;59(5):574-8. doi: 10.1248/cpb.59.574.

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.

MeSH terms

  • Amides / chemistry
  • Anti-Asthmatic Agents / chemical synthesis
  • Anti-Asthmatic Agents / chemistry
  • Anti-Asthmatic Agents / pharmacology*
  • Cyclization
  • Cyclohexanecarboxylic Acids / chemical synthesis
  • Cyclohexanecarboxylic Acids / chemistry
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Ethers / chemistry
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Magnetic Resonance Spectroscopy
  • Models, Chemical
  • Pyrrolidines / chemistry
  • Spectrophotometry, Infrared
  • Stereoisomerism

Substances

  • Amides
  • Anti-Asthmatic Agents
  • Cyclohexanecarboxylic Acids
  • Ethers
  • Integrin alpha4beta1
  • Pyrrolidines
  • 4-hydroxycyclohexanecarboxylic acid
  • cyclohexanecarboxylic acid
  • pyrrolidine