title: Synthesis of 3-aminopyrazinone mediated by 2-pyridylthioimidate-ZnCl2 complexes. Development of an efficient route to a thrombin inhibitor.
abstract: A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47% overall yield is described. The problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 was overcome with the use of pyridinylthioimidate 27 in the presence of ZnCl(2) to afford adduct 3 in high yield. Several zinc complexes were characterized by solution and solid-state NMR and X-ray crystallographic analyses, and provided insight into the reaction mechanism. Preparation of pyridine N-oxide amine 4 was accomplished via a selective oxidation of the corresponding pyridinylamine 6. Pyridinylthioimidate 27 was prepared from pyrazinone 7 via a two-step one-pot process in near quantitative yield. Chlorination of the pyrazinone ring in 3 followed by hydrolysis and amide coupling completed the synthesis of 1. This chromatography-free synthesis was used successfully to prepare multikilogram quantities of the drug with reproducibility and high purity.
authors: Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. john_chung@merck.com
authors: John Y L
authors: JY
authors: Chung
authors: Raymond J
authors: RJ
authors: Cvetovich
authors: Fuh-Rong
authors: FR
authors: Tsay
authors: Peter G
authors: PG
authors: Dormer
authors: Lisa
authors: L
authors: DiMichele
authors: David J
authors: DJ
authors: Mathre
authors: Jennifer R
authors: JR
authors: Chilenski
authors: Bing
authors: B
authors: Mao
authors: Robert
authors: R
authors: Wenslow
mesh_terms: D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry*; D007096:Imidoesters / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry*; D017967:Zinc Compounds / Q000737:chemistry*
chemical_list: C482961:2-pyridylthioimidate; C482960:3-aminopyrazinone; D000991:Antithrombins; D002712:Chlorides; D007096:Imidoesters; D011719:Pyrazines; D011725:Pyridines; D017967:Zinc Compounds; C016837:zinc chloride