Manufacture of Asymmetric Hydrogenation Catalysts

Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis.
Aug 31, 2007

Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis. Asymmetric hydrogenation is an atom economical and scaleable method for the manufacture of commercial chiral compounds. Developing efficient methods to produce the chiral ligands and catalysts on a large scale is essential to effectively commercialize this technology. The authors examine methods to manufacture select catalyst systems and their application in commercial-scale asymmetric hydrogenation.

Single-enantiomer compounds accounted for 75% of the new small molecule pharmaceuticals approved by the US Food and Drug Administration in 2006. Half of these products are made by purely synthetic means, and asymmetric chemocatalytic methods such as asymmetric hydrogenation are being used more frequently to synthesize single-enantiomer compounds.

Evolution of the technology

Figure 1
Asymmetric hydrogenation was first demonstrated almost 40 years ago, with the landmark literature reports published independently by the groups of Knowles and Horner in 1968. Both groups indicated that a rhodium catalyst, modified with a chiral phosphine ligand, was capable of inducing asymmetric hydrogenation in a suitable prochiral substrate. While working for Monsanto, Knowles developed the first commercial application for the manufacture of L-DOPA (see Figure 1), a drug used for treating Parkinson's disease (1). This pioneering work led to Knowles sharing the 2001 Nobel Prize for Chemistry with Noyori and Sharpless.

During the 1970s, there were no more than a handful of chiral ligands reported, and none of these were commercially available on large scale. The ligand system and synthesis for any given application had to be developed de novo, thereby creating significant barriers in using asymmetric hydrogenation. Most systems also were neither modular nor widely applicable over a broad range of substrates, making systematic selection of a suitable catalytic system difficult to predict. Noyori introduced the BINAP catalysts in the 1980s, and these catalysts led to Takasago developing many commercial processes for manufacturing β-hydroxy esters [used in the Lipitor (atorvastatin) side chain], alcohols, and carbapenem intermediates using ruthenium-BINAP systems (2).

During this period, a greater range of catalytic systems and substrates was established, so systematic employment of chiral catalytic technology was possible to a significantly greater extent. The largest-scale rhodium-BINAP process is the allylic isomerization of diethylgeranylamine to provide (R)-citronellal, an intermediate used to manufacture (–)-menthol, which is produced on a scale exceeding 1000 metric tons per year (2).

The commercial success of the BINAP technology encouraged many companies and research institutes to search for novel ligands outside the scope of the BINAP patents. Hoffmann-La Roche, for example, developed the MeO-BIPHEP ligands and catalysts and applied these ligands in the manufacture of vitamins and pharmaceutical intermediates. The side chain of tetrahydrolipstatin (orlistat) (see Figure 1) is manufactured using an asymmetric hydrogenation process, with a ruthenium MeO-BIPHEP catalyst (3).