Industrial-scale synthesis and applications of asymmetric hydrogenation catalysts.

This Account provides an overview of our activities in the area of asymmetric hydrogenation over the last 12 years. We discuss the manufacture of metal-containing precatalysts and their use in asymmetric hydrogenation processes. Many of the metal complexes have been made on a multikilogram scale for our own use and also provided to our customers. In addition, we review some of the applications that we have developed for our asymmetric hydrogenation catalysts, many of which have been operated on commercial scales. This all underlines that asymmetric hydrogenation is a mature technology that has been adopted for use in the pharmaceutical and fine-chemical industries.

Efficient synthesis of an imidazole-substituted delta-amino acid by the integration of chiral technologies.

Two methods to produce (2S)-5-amino-2-(1-n-propyl-1H-imidazol-4-ylmethyl)-pentanoic acid were investigated. Diastereoisomeric salt resolution, using the quinidine salt, gave the desired intermediate in 98% ee and 33% yield. Asymmetric hydrogenation of various substrates gave high conversions, with up to 83% ee. Integration of these two approaches via asymmetric hydrogenation of a quinidine salt substrate followed by crystallization provided the desired intermediate in 94% ee and 76% yield.

An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation.

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.

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.