Practical syntheses of a CXCR3 antagonist

J Org Chem. 2011 Mar 18;76(6):1767-74. doi: 10.1021/jo102399a. Epub 2011 Feb 7.

Abstract

Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Alanine / chemistry
  • Aldehydes / chemistry
  • Amines / chemistry
  • Hydrocarbons, Fluorinated / chemical synthesis*
  • Hydrocarbons, Fluorinated / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Receptors, CXCR3 / antagonists & inhibitors*
  • Stereoisomerism
  • Tartrates / chemistry

Substances

  • Acetamides
  • Aldehydes
  • Amines
  • Hydrocarbons, Fluorinated
  • Pyrimidines
  • Receptors, CXCR3
  • Tartrates
  • Alanine
  • tartaric acid