Efficient and Straightforward Syntheses of Two United States Pharmacopeia Sitagliptin Impurities: 3-Desamino-2,3-dehydrositagliptin and 3-Desamino-3,4-dehydrositagliptin

[Image: see text] Various organic impurities (starting materials, reagents, intermediates, degradation products, by-products, and side products) could be present in active pharmaceutical ingredients affecting their qualities, safeties, and efficacies. Herein, we present the efficient syntheses of two United States Pharmacopeia impurities of an antidiabetic drug sitagliptin, a potent and orally active dipeptidyl peptidase IV inhibitor: 3-desamino-2,3-dehydrositagliptin and 3-desamino-3,4-dehydrositagliptin. Our three-step synthetic approach is based on the efficient cobalt-catalyzed cross-coupling reaction of 1-bromo-2,4,5-trifluorobenzene and methyl 4-bromocrotonate in the first step, followed by hydrolysis of corresponding ester with 3 M HCl to (E)-(2,4,5-trifluorophenyl)but-2-enoic acid in high overall yield, whereas the reaction with 3 M NaOH resulted in the carbon–carbon double bond regio-isomerization and hydrolysis to give the (E)-(2,4,5-trifluorophenyl)but-3-enoic acid in 92% yield. Both acid derivatives were converted to title compounds via the amide bond formation with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine. Extensive screening of coupling/activation reagents, bases, and solvents reviled that the amide bond is formed the most efficiently using the (COCl)(2)/Et(3)N in THF or alternatively EDC/NMM/(DMAP or HOBt) in DMF obtaining the title compounds in 68–76% yields and providing the overall yields for the three-step process in the range of 57–64% on a gram scale. The presented study also demonstrates the importance of a proper selection of solvent, base, and coupling/activating reagent for amide bond formation using Michael acceptor-type allylbenzene derivatives as coupling partners to minimize the carbon–carbon double bond regio-isomerization.