Practical asymmetric synthesis of a non-peptidic alphavbeta3 antagonist

J Org Chem. 2005 Mar 4;70(5):1771-9. doi: 10.1021/jo048082n.

Abstract

The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.

MeSH terms

  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cyclization
  • Integrin alphaVbeta3 / antagonists & inhibitors*
  • Molecular Structure
  • Pentanoic Acids / chemical synthesis*
  • Pentanoic Acids / chemistry
  • Pentanoic Acids / pharmacology*
  • Structure-Activity Relationship

Substances

  • Azepines
  • Integrin alphaVbeta3
  • Pentanoic Acids