Practical synthesis of a potent bradykinin B(1) antagonist via enantioselective hydrogenation of a pyridyl N-acyl enamide.
A practical and efficient synthesis of bradykinin B(1) antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10. The key to the success of the synthesis was the development of a fluorodenitration step to install the fluorine in pyridine 7 and a catalytic enantioselective hydrogenation of N-acyl enamide 9 to set the stereochemistry.
O'Shea
Paul D
PD
Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-DorVal, Québec H9R 4P8, Canada. paul_oshea@merck.com
Gauvreau
Danny
D
Gosselin
Francis
F
Hughes
Greg
G
Nadeau
Christian
C
Roy
Amélie
A
Shultz
C Scott
CS
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry; D065169:Bradykinin B1 Receptor Antagonists; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry; D006865:Hydrogenation; D008745:Methylation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D000577:Amides; D000588:Amines; D001393:Azoles; D001897:Boronic Acids; D065169:Bradykinin B1 Receptor Antagonists; D006845:Hydrocarbons, Fluorinated; D011725:Pyridines