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J Org Chem. 2009 Jun 19;74(12):4547-53. doi: 10.1021/jo802772d.

Practical synthesis of a potent bradykinin B(1) antagonist via enantioselective hydrogenation of a pyridyl N-acyl enamide.

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Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-DorVal, Qu├ębec H9R 4P8, Canada.


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.

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