Resolving industrial problems

Rhodia Chirex's Dr Tom Archibald, vp research and technology, and Dr Marcello DiMare discuss the practical industrial manufacture of small chiral molecules using asymmetric synthesis

About a decade ago, events surrounding the use of Thalimide, Naproxen and several other drugs caused the realisation that it was too dangerous to sell racemic drugs when single enantiomer drugs could be produced.The customer requirement for cost-competitive processes to make single enantiomer drugs drove the development of asymmetric synthesis and catalysis and Simulated Moving Bed (SMB) chromatography. These technologies are now reaching commercialisation because they solve problems for which traditional chemical resolution was ineffective. The market has continued to grow to the point where chiral medicines now represent more than a third of all global pharmaceutical sales (C&EN News, 2002). This market demand has driven new technologies as demonstrated by the thousands of articles, papers and patents written each year. The ability to scale up new chiral technologies from laboratory scale to provide safe, economical, good quality and environmentally acceptable process technology is the prime need of pharmaceutical companies. The possession of suitable technology, or the access to that technology, is often the deciding factor in determining which company will manufacture their new product. The successful scale-up of a chiral process is often quite difficult, and what works well in the lab may not give satisfactory results at industrial scale. One of the leading chiral technologies is the Hydrolytic Kinetic Resolution (HKR) technology discovered by Professor Eric Jacobsen of Harvard University. This technology has been licensed by Rhodia ChiRex and has now been developed into a robust industrial process providing a variety of chiral intermediates with high enantioselectivities. Several improvements have been made to the process recently. Eric Jacobsen's HKR technology, discovered in his laboratories at Harvard University,¹ is a powerful and practical means of accessing highly enantiomerically enriched terminal epoxides and their corresponding diols. A racemic terminal epoxide (a 1:1 mixture of enantiomers) is reacted with water in the presence of an optically pure Co(salen) catalyst (Figure 1). The catalyst accelerates the addition of water to one epoxide enantiomer more than the other. The net result is that one epoxide enantiomer remains unaffected while the other is converted to its corresponding diol. The epoxide and diol products differ greatly in their physical characteristics (e.g. boiling point, solubility). Consequently, a very difficult separation of enantiomers has been converted to a ready separation of chemically different species – a separation of enantiomers (resolution) has been effected. The enantiomerically pure epoxide or diol produced depends on the chiral Co(salen) catalyst. The Jacobsen HKR technology is unusual in its generality and selectivity. Rhodia ChiRex and Prof Jacobsen's group have successfully subjected more than 50 terminal epoxides bearing a wide range of functional groups to HKR reaction. The chirality of the Co(salen) framework routinely affords epoxides with enantiomeric excesses (ee) greater than 99% (a 99.5:0.5 mixture of desired and undesired enantiomers). This is a consequence of over-resolving, reducing the yield of epoxide somewhat and degrading the ee of the diol product to afford exceptionally high ee epoxide. This technique cannot be applied to accessing diols, but despite this, diols are typically afforded with enantiomeric excesses ranging from 97 to 99%. Often laboratory processes fail to give the required enantiomeric purity on scale-up. As a result, three chiral building blocks that appeared to have the greatest commercial interest, as well as their corresponding diols, were investigated: propylene oxide, methyl glycidate and epichlorohydrin. Although difficulties were encountered at first particularly in isolation of the products, all are now available at multiple metric tons. By fine-tuning the reaction conditions, Rhodia ChiRex now typically runs HKR reactions without solvent, leading to excellent volumetric productivity and low costs. In addition, the Co(salen) catalyst is very stable, surviving extended heating at elevated temperatures with no ill effects, and can be reused with the same yield and selectivity as observed with first use. Two recent improvements have been made to the commercial catalyst system. The first is to develop a practical synthesis of an oligometric version of the cobalt catalyst in which several Co(salen) groups are closely aligned. This allows one cobalt to activate the epoxide and a second to deliver the water molecule. As a result, the catalyst is 50-100x as active as the monomeric form. An additional benefit of the increased reactivity was that disubstituted epoxides, such as cyclohexene oxide, became viable substrates, and alcohols viable nucleophiles as well (Figure 2). Yields and ee values are similar to the monomeric Co(salen) systems. complex preparation The second area of improvement relates to the preparation and isolation of a stable Co(III)salen complex. Previously, activation by air was required to convert the monomeric Co(II) complex to its active form. Although this presents no issues in laboratory scale preparations, in the plant the sparging of air through organic solvents can present a safety issue. The possibility of incomplete oxidation can also occur. The current technology allows for the activation and isolation of the Co(III) complex that is stable and can be stored indefinitely. When it is time to run the reaction, the active catalyst can be used directly. The Jacobsen HKR technology has made the transition from the academic laboratory to a commercial process and can be used to give highly enantiomeric pure epoxides and diols. Rhodia ChiRex continues to work to improve the technology and expand the chiral pool available from these interesting chiral molecules for use as intermediates in the pharma industry.