To prepare chiral molecules, asymmetric synthesis is, in principle, the best way forward, according to Joel M. Hawkins, a research adviser at Pfizer Global Research & Development. He spoke last March on the use of asymmetric catalysis in the pharmaceutical industry at an American Chemical Society ProSpectives meeting held in Boston. But the bottom line is always economics, he emphasized, as he described efforts to manufacture candoxatril, a drug Pfizer had been developing to treat congestive heart failure.

A key building block is a chiral glutarate derivative. Initially, the required S enantiomer was obtained through classical resolution of the racemate using pseudoephedrine. As candoxatril progressed through the pipeline, more efficient asymmetric syntheses were explored.

Asymmetric hydrogenation of the alkene precursor with ruthenium-BINAP gives the required product in up to 94% enantiomeric excess (ee), but in low yield. Up to 30% of the substrate is isomerized to enol by-products. A rhodium-MeDuPHOS system yields the desired enantiomer in 95% yield and greater than 99% ee [J. Org. Chem., 64, 3290 (1999)].

But when it came to prepare two tons of the the drug for Phase III clinical trials, Pfizer switched to a ruthenium-MeOBIPHEP system. With lower yields because of isomerization and with lower enantiomeric excess, this system was inferior to rhodium-MeDuPHOS. However, the catalyst availability and licensing agreement were more favorable with ruthenium-MeOBIPHEP. "The business aspect and the chemical aspect were in competition, and the business aspect won," Hawkins said. Process improvements by researchers at PPG-Sipsy decreased the isomerization to tolerable levels and made the reaction reasonable on a large scale [Org. Process Res. Dev., 5, 438 (2001).]

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