Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
AssigneeAstraZeneca AB
InventorsMichael Politino, Matthew M. Cadin, 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.
Claims14
A method for making a compound of the structure
- or a salt thereof, the method comprising:
- treating (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid first with an alkyl chloroformate or mesyl chloride in the presence of a base, and then with ammonia to form (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate;
- and
- deprotecting the (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate to form the compound or salt.
A method for making a compound of the structure
- or a salt thereof, the method comprising:
- treating (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate with diethylzinc and chloroiodomethane to form (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate;
- then
- deprotecting the (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate to form the compound or salt.
An isolated compound selected from
- (S)-1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate;
- (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate;
- (1S,3S,5S)-tert-butyl 3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate;
- and
- (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid.
Dependencies are inferred from the claim text.