Manufacture of Asymmetric Hydrogenation Catalysts - Pharmaceutical Technology

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Manufacture of Asymmetric Hydrogenation Catalysts
Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis.

Pharmaceutical Technology

Figure 11
Regarding asymmetric ketone hydrogenation, the technology in-licensed from the JST is a valuable method for producing chiral alcohols on an industrial scale. These catalyst systems were originally based on the BINAP ligand with an extremely expensive non-C2 symmetric diamine, DAIPEN (1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine). As there are several patents covering the use of ruthenium-BINAP complexes, especially for the more relevant precatalysts employing Xyl-and Tolyl-BINAP ligands, our strategy was to develop novel systems, leading to the development of the HexaPHEMP RuCl2 Diamine and the PhanePhos RuCl2 Diamine systems, both of which are highly active and selective catalysts. Both systems use readily available and relatively inexpensive diamines, and are an alternative to BINAP-based systems. The PhanePhos precatalyst systems have been used to manufacture many 1-phenylethanols on multi-100 kg scales. For example, 4'-fluoroacetophenone is hydrogenated at a molar substrate-to-catalyst ratio of 100,000/1, equivalent to a weight/weight ratio of 13,000/1 (or 1 kg of catalyst for 13 metric tons of product) (see Figure 11) (21). To achieve the high substrate-to-catalyst ratios, the substrate was purified using short-path distillation. A further distillation of the product afforded pure material and completely removed the catalyst complex.

The number of large-scale applications for the in-licensed JST technology necessitated the ability to manufacture the precatalysts efficiently. We originally prepared these complexes using the procedures of Noyori (22), whereby the ligand was reacted with an [(arene)RuCl2]2 species in dimethylformamide at 100 C, followed by treatment with a suitable diamine, typically DPEN (1,2-diphenylethanediamine), DACH (1,2-diaminocyclohexane) or DAIPEN to provide the desired product. When this methodology was applied for the larger scale manufacture of these catalyst systems, significant byproduct formation and yields lower than desired for precatalyst manufacture were observed.

Figure 12
As these complexes contain valuable chiral phosphines, chiral diamines, and metal precursors, we sought a more efficient synthetic method. Quite surprisingly, we found that an isolated [diphosphine(arene)RuCl]Cl complex could be reacted with a diamine at moderate temperatures in ethereal solvents, routinely leading to >95% yield of the desired complexes in excellent purity (see Figure 12) (23).

Figure 13
Although the JST technology works well with aryl ketones or enones, it is of little utility for the asymmetric hydrogenation of alkyl-alkyl systems. Professor Reetz recently published an asymmetric transfer hydrogenation (ATH) catalyst that gives excellent results for a range of alkyl-alkyl ketones, thus making these alcohols more readily available (24). The catalyst consists of a xanthyl-based chiral diphosphonite and a [RuCl2(p-cymene)] complex. Dowpharma recently obtained a license to this technology for the manufacture of chiral alcohols using ATH, which complements the JST technology (see Figure 13).


Asymmetric hydrogenation is a fully accepted method for the manufacture of a wide range of chiral compounds in the pharmaceutical, agrochemical, fragrance, and fine-chemical industries. The design of an effective catalyst system relies on manufacturing metal precatalysts and ligands.With effective design, a range of catalytic systems and substrates may be developed to allow for the systematic use of chiral catalytic technology.


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