Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
AssigneeBristol-Myers Squibb Company
InventorsMichael Politino, Matthew M. Cadin, Paul M. Skonezny, Jason G. Chen
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Abstract
A process for production of cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV is provided which employs a BOC-protected amine of the structure prepared by subjecting an acid of the structure to reduce amination by treating the acid with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified phenylalanine dehydrogenase/formate dehydrogenase enzyme concentrate (PDH/FDH) and without isolating treating the resulting amine of the structure 2 with di-tert-butyl dicarbonate to form the BOC-protected amine.
Claims16
A method for forming a free base compound of the structure M′
- the method comprising:
- (I.) providing a BOC-protected compound of structure (3)
- (II.) treating the BOC-protected compound with mesyl chloride, Hünig's base, a compound of structure J
- and 1-hydroxybenzotriazole (HOBT) to form a BOC-protected intermediate compound of structure K
- (III.) dehydrating said intermediate K in the presence of pyridine and trifluoroacetic anhydride to obtain a dehydrated reaction product;
- (IV.) hydrolyzing the dehydrated reaction product in the presence of strong base to form a compound of structure L
- (V.) treating the compound of structure L with hydrochloric acid to form the corresponding hydrochloric acid salt of structure L′
- (VI.) treating the compound of structure L′ with hydrochloric acid and sodium hydroxide to form the free base compound M′.
Dependencies are inferred from the claim text.