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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. 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.
Evolution of the technology
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).
By the 1990s, there were many more catalyst systems established for asymmetric hydrogenation, applying a diverse range of ligands, using rhodium, ruthenium, and iridium metals, and finding applications in pharmaceutical, agrochemicals, nutraceuticals and the flavor and fragrance industries. The two ligand systems with the greatest impact developed in the 1990s were DuPhos (1,2-bis(2,5-dialkylphospholano)benzene) by Burk (4) and Josiphos by Togni and Spindler (5). The JosiPhos ligand system is used in the largest-scale asymmetric hydrogenation process known to date: for the manufacture of the herbicide Dual Magnum[(S)-metolachlor] (see Figure 1), which is produced on a 20,000-metric-ton scale per year (6). The actual iridium Josiphos catalyst required was not known at the start of the research project, but was discovered as the development of (S)-metolachlor proceeded. Chirotech, now part of Dowpharma, obtained the exclusive license to the DuPhos, BPE (1,2-bis(2,5-diphenylphospholano)ethane) and 5-Fc (1,1'-bis (2,5-diphenyl-phospholano) ferrocene) technology for commercial pharmaceutical applications from DuPont. Chirotech subsequently developed numerous asymmetric hydrogenation processes, and the DuPhos ligands and catalysts were also offered for sale on commercially relevant scales (>100 g–multi-kilograms) (7).
Rhodium DuPhos applications and ligand synthesis
Prior to the commercialization of the DuPhos technology, Chirotech developed methods to produce the ligands and catalysts on a multigram scale, with practical but moderate yields. These methods satisfied the laboratory scale and early development needs for the compounds shown in Figure 3. As demand for these catalyst systems increased toward multi-100s grams and then to kilograms, it was clear that the initial synthetic methods were not practical in terms of yield, purity, and economics. In the first instance, Chirotech addressed the ligand synthesis and made improvements over the original routes. Hexane-2,5-diol was originally obtained using an electrochemical Kolbe coupling of single enantiomer 3-hydroxybutyric acid, but this method did not scale up well with severe fouling of the electrodes being observed (14).
Chirotech then developed an in-house method constituting a bioresolution approach starting with the 1:1 racemic/meso diol (15). Using inversion techniques on a monobutyrate derived from the meso diol, a good yield of the (R, R) enantiomer was obtained, but the yield of the (S, S) entantiomer was lower. With the introduction of highly efficient alcohol dehydrogenase enzymes and ready availability of hexane-2,5-dione, both enantiomers of hexane-2,5-diol are commercially available on the requisite scales. For security of supply reasons, Dowpharma still operates its own protected bioresolution route.
Rhodium catalyst fabrication
A further problem with this method was that the product form was variable, from robust deep red crystals to orange-yellow amorphous powders. Although all of these forms performed well in asymmetric hydrogenation reactions, the powdered materials had shorter shelf life and were prone to degrade more easily than the crystalline material. Further process development led to a scaleable process that delivers crystalline rhodium precatalysts in very high yields (91–97%) with excellent chemical purity and substantially improved chemical and physical stability.
Applications of ruthenium- based catalysts
Ruthenium catalysis is complementary to rhodium catalysis as it is effective in differing substrate classes. Dowpharma's position in this area includes ruthenium DuPhos/BPE systems and Diphosphine RuCl2 Diamine systems for asymmetric ketone hydrogenation, developed by professors Noyori and Ikariya. Chirotech in-licensed the Noyori technology from the Japan Science and Technology Corporation (JST) in December 2000.
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.
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.
Ian C. Lennon*, PhD, is a scientist and technology leader, Nicholas B. Johnson, PhD, is a business development and marketing manager, and Paul H. Moran, PhD, is a research specialist at Chirotech Technology Ltd., Dowpharma, Unit 162, Cambridge Science Park, Milton Road, Cambridge,
UK, tel. + 44 (0) 1223.728037, fax +44 (0)1223.506701 ILennon@dow.com
*To whom all correspondence should be addressed.
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