Pfizer hydrogenation catalysts

The hydrogenation was carried out on 12-kg scale for Pfizer by Dow/Chirotech, using a cationic Rh-DuPhos catalyst [79] and on 250-kg scale by PPG-Sipsy with a Ru-biphep complex [80]. Both catalysts achieved very high enantioselectivities and medium activities. 

Further hydrogenations of a variety of C=C substrates depicted in Figure 37.22 range from a pilot process to several feasibility studies. Of special interest are PhanePhos, originally reported by Merck, an unsymmetrically substituted phos-pholane developed by Pfizer, and the rare case of an Ir-diphosphine complex active for the hydrogenation of a C=C bond. Nevertheless, the catalyst performances of most processes summarized in Figure 37.22 are probably not (yet) sufficient for manufacturing purposes. Indeed, several of the reports explicitly mention that further development was stopped, either because another route proved to be superior or because the compound was abandoned. 

Disodium methylsuccinate was made by hydrogenating a concentrated solution of itaconic acid supplied by Chas. Pfizer and Company in aqueous sodium hydroxide (pH. 8.7) over Raney nickel catalyst at 50 p.s.i. and 80-100°. After the catalyst was removed by filtration, the product was isolated by evaporation of the water and the residue was dried in a vacuum oven at 70-80°. 

Asymmetric hydrogenations with transition metal catalysts have been applied to single enantiomer synthesis in the pharmaceutical industry with considerable success. ChiroTech and Pfizer developed an improved synthesis of glutarate derivative (139), an intermediate required for the synthesis of Candoxatril (140) (156). The drug, a neutral endopeptidase inhib-... 

Pregabalin is an anticonvulsant produced by Pfizer and several catalysts have been developed to hydrogenate a key intermediate. First results were reported by Chirotech... 

In addition to these pilot processes, a number of apphcations on the bench scale were described (see Fig. 12). Pfizer [85] obtained good results for a Rh/ FerroTANE-catalyzed hydrogenation of a substituted itaconic acid for the synthesis of MMP-3 inhibitor UK 370,106 (ee 94%, ton 1,000) but in the end, chose a more robust Ru/binap catalyst for scale up. A similar catalyst was used by Hochst [56] for the hydrogenation of a p-ketoester for the HMG-CoA reductase inhibitor Glenvastatin HR 780 and a Ru/Josiphos catalyst was highly selective for the hydrogenation of an intermediate for an anthrax lethal factor inhibitor with a tetra substituted C=C bond reported by Merck [86]. 

A transfer hydrogenation was piloted by Avecia/Piramal ([59] and references therein) for an intermediate of diltiazem, a Ca-antagonist marketed by Pfizer (Scheme 51). The catalyst was prepared in situ from [cp IrCl2]2 and dpenCs and very high stereoselectivity was achieved. 

Rh-Catalyzed Hydrogenation of C=C (ChiroTech). This diastereoselec-tive process developed for Pharmacia Upjohn (now part of Pfizer) for an intermediate for tipranavir is being carried out on a production scale. Essential was the addition of Na2C03 as cocatalyst (66). The catalyst tolerates E/Z mixture of substrate and shows high chemoselectivity, but nitro group reduction can be a problem. 

Rh-Catalyzed Hydrogenation of C=C (ChiroTech, PPG-Sipsy). This hydrogenation process for an intermediate for candoxatril was developed and carried out for Pfizer by both by ChiroTech, using a cationic Rh/duphos catalyst (71a) and by PPG-Sipsy with a Ru-MeObiphep catalyst system (71b). 

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