Me-DuPHOS-Rh-Catalyzed Asymmetric Synthesis of the Pivotal Glutarate Intermediate for Candoxatril.
A greatly improved process has been developed for synthesis of the glutarate derivative 2, a key intermediate required for Pfizer's drug candoxatril. The cationic (R,R)-Me-DuPHOS-Rh catalyst was found to allow highly efficient and enantioselective hydrogenation of a unique carboxylate substrate (5) to afford the desired product in >99% ee and high yield (95%). The robust nature of the process was validated on a 12 kg reaction scale. A novel mechanism for the hydrogenation process is proposed. Through use of a labile eta(6)-benzene-Rh-Me-DuPHOS complex, the postulated catalytic intermediates have been synthesized by independent means. Detailed spectroscopic analyses of these intermediates corroborate the mechanistic hypotheses. Interconversion of these key catalytic intermediates has been demonstrated.
Burk
Mark J.
MJ
Chirotech Technology Limited, Cambridge Science Park, Milton Road, Cambridge CB4 4WE, England, and Pfizer Limited, Process Research and Development, Sandwich, Kent CT13 9NJ, England.
Bienewald
Frank
F
Challenger
Stephen
S
Derrick
Andrew
A
Ramsden
James A.
JA