Development of an efficient one-pot construction of substituted pyrimidinones

ORGN 170

Yuelie Lu1, T. J. Xiang1, Charles Bernard1, Tracy Bostick2, Liang Huang1, Longbin Liu1, Aaron Siegmund1, Gregory Sukay1, Gary Guo1, Michael Bartberger3, Celia Dominguez1, Wanda Tormos1, Kevin Koch4, Laurence E. Burgess4, Thomas C. Basil4, Prabha Ibrahim4, and Conrad Hummel4. (1) Department of Small Molecule Drug Discovery, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320-1789, (2) Chemistry Process Research and Development, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, (3) Department of Molecular Structure, Amgen Inc, One Amgen Center Drive, Thousand Oaks, CA 91320-1789, (4) Array BioPharma Inc, 3200 Walnut Street, Boulder, CO 80301
A concise, scaleable synthesis of building block 10 for p38 kinase inhibitor is described. The key step is the one-pot construction of 5-ary-3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one 4 from aryl acetic acid ethyl ester and 4-cyanopyridine. Subsequent hydrolysis of the thiomethyl group to the hydroxyl group and chlorination provided the key intermediate, 2-chloro-3-methyl-6-pyridin-4-yl-5-aryl-3H-pyrimidin-4-one 10. This class of reactive building blocks enabled medicinal chemistry to explore a variety of side chains at the 2 position of the pyrimidinone in an effort to optimize potency and in vivo efficacy.