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An efficient one-pot construction of substituted pyrimidinones |
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| Authors: | Yuelie Lu Tingjian Xiang Charles Bernard Liang Huang Aaron Siegmund Gary Guo Wanda Tormos Kevin Koch Laurence E. Burgess Prabha Ibrahim |
| Affiliation: | a Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA b Chemical Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA c Molecular Structure and Design, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA d Analytical Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA e Array BioPharma Inc., Boulder, CO 80301, USA |
| Abstract: | 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. |
| Keywords: | Pyrimidinone Methylisothiocyanate cyclization Chlorination Nucleophilic displacement Inhibitors of p38 MAP kinase |
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