Synthesis of 3-aminopyrazinone mediated by 2-pyridylthioimidate-ZnCl2 complexes. Development of an efficient route to a thrombin inhibitor.
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.
Chung
John Y L
JY
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. john_chung@merck.com
Cvetovich
Raymond J
RJ
Tsay
Fuh-Rong
FR
Dormer
Peter G
PG
DiMichele
Lisa
L
Mathre
David J
DJ
Chilenski
Jennifer R
JR
Mao
Bing
B
Wenslow
Robert
R
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*
C482961:2-pyridylthioimidate; C482960:3-aminopyrazinone; D000991:Antithrombins; D002712:Chlorides; D007096:Imidoesters; D011719:Pyrazines; D011725:Pyridines; D017967:Zinc Compounds; C016837:zinc chloride