title: Unusual pyrimidine participation: efficient stereoselective synthesis of potent dual orexin receptor antagonist MK-6096.
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.
authors.affiliation: Process Chemistry, Merck Research Laboratories , P.O. Box 2000, Rahway, New Jersey 07065, United States and.
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chung
authors.forename: Yong-Li
authors.initials: YL
authors.lastname: Zhong
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Maloney
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reamer
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Moore
authors.forename: Hallena
authors.initials: H
authors.lastname: Strotman
authors.forename: Alexei
authors.initials: A
authors.lastname: Kalinin
authors.forename: Ronnie
authors.initials: R
authors.lastname: Feng
authors.forename: Neil A
authors.initials: NA
authors.lastname: Strotman
authors.forename: Bangping
authors.initials: B
authors.lastname: Xiang
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Yasuda
mesh_terms: D002384:Catalysis; D015394:Molecular Structure; D000068796:Orexin Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C573816:MK-6096; D000068796:Orexin Receptor Antagonists; D010880:Piperidines; D011743:Pyrimidines; C030986:pyrimidine