An efficient one-pot construction of substituted pyrimidinones

A concise, scaleable synthesis of building block 10 for p38 kinase inhibitor B is described. The key step is the one-pot construction of 5-aryl-3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one 4 from arylacetic acid ethyl ester 1. Subsequent hydrolysis of the thiomethyl group to the hydroxy 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 the rapid evaluation of a variety of side chains at the 2-position of the pyrimidinone in SAR studies of inhibitors of p38 MAP kinase.