Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 19, Issue 11, Pages 1760-1768Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.5b00267
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Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone, with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed, reactions : (1) a PKR reduction of a rac-alpha-aminoketone to set the two contiguous stereogenic Centers, (2) a cycloisomerization of bis-homopropargylic alcohol to a dihydropyran, and, finally, (3) a Ru-catalyzed oxidation of a Pyranol to the desired pyranone. The regioselective synthesis of 4 N-Boc-1-mesyl pyrazole fragment was achieved via base promoted mesyl group isomerization to afford 30:1 selectivity. A highlight, of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multikilogram deliveries and improves the overall diastereoselectivity and efficiency of the route.
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