No abstract

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.

Amination of C-H bonds activated by ether oxygen atoms is facile with chloramine-T as nitrene source and copper(I) chloride in acetonitrile as catalyst. For cyclic ethers the hemiaminal products are generally stable and can be isolated pure. For acyclic ethers, the hemiaminal products, as expected, fragment with elimination of alcohol to yield imines. When activation of benzylic positions is remote through a conjugated system, stable benzylamine derivatives are isolated. Mechanistic studies are consistent with concerted insertion of an electrophilic nitrenoid into the C-H bond in the rate-determining step, though in an asynchronous manner with a more activated substrate.

No abstract

The development and implementation of a robust process for the manufacture of metric ton quantities of the R2δ ligand imagabalin hydrochloride 4 is described. Key aspects of the synthesis include a chromatography-free, two-step telescoped process to prepare a mixture of Z:E-enamides 7 followed by a robust asymmetric hydrogenation with the rhodium-trichickenfootphos catalyst 8 to install the (3S)-stereocentre. Hydrolysis of the acetamide and ester protecting groups in the final step followed by isolation and recrystallisation of the hydrochloride salt gave high purity 4 in 40À50% overall yields.