A promising partnership

01 November 2001 00:00  [Source: APC]

Catalysts are a fast-moving industry - chemical manufacturers are constantly looking for more efficient catalysts to supersede the current generation, as well as for new applications. Alan Tyler looks at recent research focusing on the use of catalysts in another evolving sector - that of chiral chemistry

Catalysts are, by definition, substances that alter the rate of a chemical reaction without being consumed themselves. An increasing number of downstream chemical companies are looking to catalysts to increase the rate at which they generate that most precious of commodities - cash.

The catalyst business is worth over $9bn/ year, while the value of products dependent on catalysts, including petroleum products, automobiles, chemicals, pharmaceuticals, synthetic rubber and plastics, and many others, is said to be around $500bn/year. SRI Consulting, Menlo Park, California, US, said 'about 90% of chemical manufacturing processes, and more than 20% of all industrial products in the US, employ underlying catalytic steps.'

Technological advancements in catalysts are continually being introduced: the single-site catalyst market for polyolefin synthesis, valued at $1m in 1994, could be valued at $15bn in 2015; and the increase in the use of chiral catalysts has led to development of new pharmaceutical products.

Catalysts often decrease in activity or become lost through material handling and need to be regenerated or replaced, and the catalyst industry is continually striving to develop catalysts that do not lose their activity, are more efficient than the current generation catalysts, and are not lost through material handling. SRI suggests that these factors, together with economic growth and discoveries of new uses for catalysts, contribute to the continued growth of the catalyst business. SRI also said that 'development is further driven by the need for new sources of energy and chemicals, concern over environmental pollution, the desire for new types of products, and the cost of and potential restrictions on the availability of the noble metals used in many catalysts.'

The role of chirals

Catalysts play a significant role in the synthesis of pharmaceutical and agrochemical intermediates, and can lead to significantly lower production costs. The recent Frost and Sullivan report on chiral technologies suggests that the market will grow 13%/year to 2007.

A strong growth area for the catalysts in this sector is chiral chemistry - itself the fastest growing area of the fine chemicals industry, since most new drug approvals are now chiral. Central to chirality is asymmetric synthesis, which involves the use of chemical catalysts to synthesise the required isomer from the starting materials. Catalysts containing metals such as palladium and rhodium are used to introduce chiral centres into achiral molecules.

The first reported example of homogeneous asymmetric catalysis using a soluble chiral metal complex was in 1966 by Noyori and colleagues.

Thousands of examples of successful high yield, highly enantioselective, homogeneously catalysed reactions have now been reported, the vast majority of which employ platinum group metals, particularly Rh, Ru, Ir, Pd, in combination with phosphine ligands. Well over 1000 chiral phosphine ligands have been synthesized and applied to the full spectrum of organic reactions, including C=C, C=O, C=N hydrogenations, hydrosilylations, isomerizations, C-C couplings, allylic alkylations, cyclopropanations, insertions into C-hetero atom bonds, hydroformylation and carbonylation, hydrocyanation, dimerisation and oligomerisations.

The demand for chiral catalysts is expected to increase dramatically in the next few years with the use of enantiomerically pure pharmaceuticals and agrochemicals.

One company which has opted for taking the chiral route is Synetix Chiral Technologies UK, part of ICI. Product manager Fred Hancock, said that chiral technologies offer several advantages to the user. Currently, resolution of enantiomers is the dominant technology, however, at some point, half the material needs to be removed and possibly recycled or disposed of. This could be an expensive step if it comes too far along the reaction chain.

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Hancock says the range of reactions that can be carried out in an asymmetric way - using either chemo- or bio-catalysts - is expanding. Companies need to be able to get this technology working on a larger scale.

Synetix Chiral Technologies is looking at developing processes that use asymmetric catalysts. Hancock said these catalysts have been well researched at the laboratory level, and that Synetix is bringing its background in catalytic process design to create robust processes which utilise these asymmetric catalysts.

The use of homogeneous catalysts can be very effective for synthesis, however, the catalysts will need to be separated after the reaction, using techniques including biphasic separation or precipitation. The major method Synetix has chosen to utilise is immobilisation of the catalyst on a support material, which allows either slurry or fixed bed processes to be used. Hancock said the fixed bed process was amenable to scale up.

In June, Synetix and Rhodia ChiRex announced an agreement to jointly develop and manufacture immobilised catalysts for use in the manufacture of pharmaceutical intermediates and fine chemical compounds.

The Synetix Chiral Technologies team has successfully immobilised Rhodia ChiRex's proprietary cobalt-SALEN catalyst, which is used in Rhodia ChiRex's Jacobsen Hydrolytic Kinetic Resolution Technology, licensed from Harvard in 1996. Synetix will now manufacture commercial quantities of the newly immobilised catalyst for Rhodia ChiRex.

Synetix is able to design a silica surface with a pore size specific for the size of the catalyst ligand, said Hancock. The ligand is inserted into the pores in the silica and then the cobalt centre is added to the ligand.

Hancock said the immobilised catalysts offered benefits to users, increased turnover, and no product contamination. He added that Synetix is in the process of expanding its immobilisation technology to other application areas.

John Lindley, Rhodia ChiRex business development manager, said the technology was being commercialised for a range of chiral building blocks.

Synetix is able to immobilise catalysts onto a range of support materials including polymer supports and inorganic oxides. Catalysts are immobilised onto the supports using techniques including: electrostatic attachment, in which ion exchangeable acid sites are produced on the support, then, metal ions are exchanged for protons and once immobilised, the metal can be chelated to the required ligand; covalent attachment, in which inorganic oxides are prepared by the sol-gel process, creating defined pore size distributions on drying into which ligands can be attached by the introduction of Silicon-Carbon bonded organic linkers.

CATHy - a proprietary catalyst

Another major player in this sector is Avecia, whose chiral technologies allow provision of kilogramme quantities of enantiomerically pure compounds - to support early pharmaceutical development at the research and optimisation stage, right through scale up to economic production.

Avecia's Catalytic Asymmetric Transfer Hydrogenation (CATHy) is a proprietary catalyst developed to make a broad range of chiral alcohols and amines.

Technical manager John Blacker says the CATHy catalyst moves hydrogen from a cheap reagent such as isopropanol selectively to 'one face' of the substrate of interest to give a chiral product. The substrate can be a ketone, which gives an optically active alcohol, or it can be an imine, which gives an optically active amine.

The catalysts are composed of three units: the chiral ligand, the precious metal and a cyclopentadiene. Many analogies of these building blocks are commercially available, so by mixing and matching a library of CATHy catalysts can be generated and screened against the compound of interest to find the best one.

In biocatalysis, microbes or their enzymes give the options of resolving racemic mixtures or direct synthesis of homo-chiral products from achiral starting materials and are therefore highly flexible and complementary to metal-based catalysts.

While fine chemical companies are embracing catalysis as a key technology in the pharmaceutical development chain, traditional materials and catalyst companies are also looking at moving down the supply chain into the fine chemical area. UK-based Johnson Matthey moved closer to its customer base earlier this year, when it acquired Meconic of the UK for £147m ($215m) and Pharm-Eco Laboratories of the US for $9.9m, and took on Pharm-Eco's net borrowings of $37m.

These services complement Johnson Matthey's pharmaceutical materials business, based at West Deptford, New Jersey, US, which manufactures active pharmaceutical ingredients for drugs that are already approved for market, or are very near to receiving final approval.

This business is similar to that of Meconic - which trades in fine chemicals out of Edinburgh as MacFarlan Smith - in a number of ways, including complementary product ranges, and a focus on high value, low volume products, particularly controlled substances. Whereas MacFarlan Smith makes opiates and other controlled substances from natural substances, the US facility uses synthetic routes.

MacFarlan Smith also offers an attractive opportunity for the geographic expansion of Johnson Matthey's current pharmaceutical fine chemicals business into the UK and Europe. 'MacFarlan Smith has been a catalyst customer of Johnson Matthey for a number of years, and obviously we expect that relationship to continue and grow,' David Morgan, JM's group corporate development director told CMR/PCE. The company's Edinburgh facility is currently being expanded.

'The combination of MacFarlan Smith with our pharmaceutical materials business makes great commercial sense on a variety of levels,' added Morgan. 'It will expand our product portfolio while extending our geographic reach and presenting broader market opportunities, and is in line with our strategy of developing our business both organically and by targeted acquisition.' Pharm-Eco, meanwhile, based on two sites in the Boston, Massachusetts, area and employing around 120 people, provides contract research, process development and small scale synthesis services to the pharmaceutical industry. Its turnover last year was $17m. Pharm-Eco's services are primarily focused on drug development, from discovery through to Phase II clinical trials.

Growth areas

'Our pharmaceutical materials business unit sits within the catalysts and chemicals division, and one of our major growth areas in recent years has been providing catalysts to fine chemicals engaged in providing chiral technologies for pharmaceutical applications,' added Morgan. Johnson Matthey's catalysts and chemicals division has produced most of the growth in its overall business this year, and the company claims that its expanded line of homogeneous chiral catalyst precursors provides researchers with exciting new processing options. While autocatalyst sales have remained strong, benefiting from the global spread of emissions legislation and the introduction of our new process technology, demand for platinum group metal refining has also been good, which has benefited its chemicals business.

Not all companies see catalytic solutions as the preferred method of achieving the best results in chiral synthesis. The fine chemicals division of Kaneka is continuously developing novel tools for chirality, but Lieven Janssens, of Kaneka Pharma Europe in Brussels, Belgium, remains a little sceptical of the scope for asymmetric synthesis using chemical catalysts at this time. 'The pharmaceutical market is most interested in receiving a high quality product at a competitive price - not just in exotic chemistry,' he says. 'There are still not so many successful commercial applications of such technologies, and we have found that biotechnology and traditional organic chemistry can provide results that are just as good.' Nevertheless, Lieven Janssens says there is a future for asymmetric synthesis in chiral applications, and Kaneka is working to develop such solutions to add to its existing portfolio of technologies.

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