Unusual pyrimidine participation: efficient stereoselective synthesis of potent dual orexin receptor antagonist MK-6096

Org Lett. 2014 Nov 21;16(22):5890-3. doi: 10.1021/ol5028249. Epub 2014 Nov 3.

Abstract

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.

MeSH terms

  • Catalysis
  • Molecular Structure
  • Orexin Receptor Antagonists*
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*

Substances

  • MK-6096
  • Orexin Receptor Antagonists
  • Piperidines
  • Pyrimidines
  • pyrimidine