Synthesis toward CRHR1 Antagonists through 2,7-Dimethylpyrazolo[1,5-α][1,3,5]triazin-4(3H)-one C-H Arylation

J Org Chem. 2015 May 1;80(9):4716-21. doi: 10.1021/jo502894r. Epub 2015 Apr 20.

Abstract

A novel synthetic protocol for 8-aryl substituted pyrazolo[1,5-α][1,3,5]triazin-4(3H)-ones was developed employing Pd-catalyzed C-H arylation. The reaction yield was influenced by the presence of a phosphine ligand, pivalic acid, and base selection. With the use of 5-10 mol % catalyst, reactions of 2 with p- or m-substituted aryl bromides proceeded in moderate to good yields. Lower yields were observed with o-substituted aryl bromides. Using this method a precursor for MJL1-109-2, a known nonpeptide CRHR-1 antagonist, was successfully synthesized.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Triazines / chemical synthesis
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • 2,7-dimethylpyrazolo(1,5-alpha)(1,3,5)triazin-4(3H)-one
  • Pyrazoles
  • Receptors, Corticotropin-Releasing Hormone
  • Triazines
  • CRF receptor type 1