Pharmaceutical applications of Jacobsen HKR technology

Transcription

1 Pharmaceutical applications of Jacobsen HKR technology Recent advances in Hydrolytic Kinetic Resolution (HKR) technology have extended its potential application in pharmaceutical syntheses. Dr Marcello DiMare, Rhodia ChiRex... it is estimated that the use of chiral technology will increase at more than 10% per annum through to It is widely recognised that single-isomer drugs are generally safer, exhibit fewer side effects and are more potent than their racemic counterparts. Chiral medicines now represent one-third of all global pharmaceutical sales (1), and it is estimated that the use of chiral technology will increase at more than 10% per annum through to 2007 to support growth in the area (2). This market demand is supported by literally thousands of articles, papers and patents which have been written describing various chiral technologies. One of the leading chiral technologies is the Hydrolytic Kinetic Resolution (HKR) technology discovered by Professor Eric Jacobsen of Harvard University and successfully commercialised by Rhodia ChiRex. This article discusses several aspects of HKR and related Co(salen)-based technologies, and their application to pharmaceuticals. Emphasis is given to the future of these technologies and, in particular, their potential for increased breadth of application and their cost effectiveness. Background Discovered in Professor Jacobsen s laboratories at Harvard University (3), the Jacobsen HKR technology is a powerful and practical means of accessing highly enantiomerically enriched terminal epoxides and their corresponding diols. The technology is not difficult to understand. A racemic terminal epoxide (a one-to-one mixture of enantiomers) is combined with approximately half an equivalent of water in the presence of an optically pure Co(salen) catalyst (Figure 1). The catalyst accelerates the addition of water to one epoxide enantiomer much 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 (for example, 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. Changing the enantiomer of Co(salen) catalyst used changes the epoxide enantiomer (diol) produced. The power of the Jacobsen HKR technology lies in its generality and selectivity. Rhodia ChiRex and Jacobsen s group have successfully subjected over 50 terminal epoxides bearing a wide range of functional groups to the HKR reaction. The chirality of the Co(salen) framework routinely 116 Innovations in Pharmaceutical Technology

2 Figure 1. Jacobsen HKR of propylene oxide. These core building blocks have all been produced in metric ton quantities, as well as the two enantiomeric Co(salen) catalysts needed to access them affords epoxides with enantiomeric excesses (ee) greater than 99% (a 99.5 to 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 an 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%. It is worth noting that Jacobsen has described a variant to the HKR reaction using the same Figure 2. Epichlorohydrin reaction starburst and building block application. Co(salen) catalyst system in which phenols take the place of water as the nucleophile (4). This has been dubbed the Jacobsen Phenolic Kinetic Resolution (PKR) reaction, and parallels its HKR cousin in affording high enantiomeric excess products in a practical manner (see below). Applications Some companies take a more reactive approach to developing and scaling their chiral technologies; this results in an unfocused technology 118 Innovations in Pharmaceutical Technology

3 development effort, targeting dozens or hundreds of potential targets and with no basic way to produce them. For a pharmaceutical organisation, this translates into expensive materials and long lead-times. Rhodia ChiRex has chosen to focus on a few widely applicable chiral building blocks using the following selection criteria: inexpensive and readily-available starting material, broad-based application and HKR as the best method of access. The three chiral building blocks that have generated the greatest interest and that form the core of the building blocks are propylene oxide, methyl glycidate and epichlorohydrin, and their corresponding diols. These core building blocks have all been produced in metric ton quantities, as well as the two enantiomeric Co(salen) catalysts needed to access them. This has been accomplished rapidly. Hundreds of kilograms of propylene oxide were produced within nine months of Jacobsen s initial report on HKR in With every carbon of epichlorohydrin (and its corresponding diol chloropropanediol) functionalised in a useful manner, the synthetic power of the building block approach is exemplified by the wide array of materials which are potentially accessible using this material (Figure 2). Possible pharmaceutical applications include but are not limited to beta-blockers, cough sedatives, cytostatics, antiarrhythmics, anorectics, antidepressants and ophthalmologicals. One such application is also shown in Figure 2: the use of the building block, propylene glycol, for the commercial manufacture of the anti-aids drug, tenoforvir (Viread TM ). Finally, the Jacobsen HKR system is practical. HKR reactions are typically run without solvent or, at most, with 10% volume co-solvent (relative to epoxide), 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 re-used with the same yield and selectivity as observed with first use. Ongoing research and development The Jacobsen HKR system does have its limitations. Catalyst loadings are relatively high (0.2 to 0.7 mol % is typical). This is a consequence of the cooperative nature of the reaction whereby one molecule of catalyst activates the epoxide and another activates the water or phenol nucleophile (reaction is second order in catalyst). As already mentioned, only the combinations of water and phenols with terminal epoxides have proven suitable. Finally, as a homogeneous catalytic system, high-volume applications suffer from the need to isolate/recycle the Co(salen) catalyst.... the Co(salen) catalyst is very stable... and can be re-used with the same yield and selectivity as observed with first use a member of the Solvay group PEPTISYNTHA s activities focus on the production of large volumes of therapeutic peptides (peptide APIs). Our experts have decades of experience in producing c-gmp peptides in accordance with the most stringent FDA and EMEA requirements. Both solution phase and solid phase technologies are available. Applying a proprietary solution phase technology, PEPTISYNTHA is able to scale up the production of peptides up to hundreds of kilograms, including HPLC purification and lyophilisation. PEPTISYNTHA : the right solution for bulk peptides! Peptisyntha S.A. 310 rue de Ransbeek - B-1120 Brussels, Belgium Tel. : Fax. : pierre.barthelemy@solvay.com Peptisyntha Inc. Higgins Court Torrance, California Tel. : Fax. : satish.joshi@solvay.com Innovations in Pharmaceutical Technology 119

4 A breakthrough arrived with the recently reported oligomeric Co(salen) catalyst system Efforts to decrease catalyst loadings by holding two (or more) Co(salen) units in proximity to each other have led to a series of publications from Jacobsen, starting in 1998 and carrying on to the present. These all succeeded in decreasing the molar quantity of Co(salen) units needed to effect HKR reactions, but were impractical due to difficult syntheses. A breakthrough arrived with the recently reported oligomeric Co(salen) catalyst system (5) (Figure 3). This system is much easier to synthesise due to the locally symmetric Co(salen) unit, and displays the expected increase in reactivity. On a per cobalt basis, a 10- to 50-fold decrease in catalyst still nets a shorter reaction time in headto-head comparisons with the normal Co(salen) system using a typical epoxide. Extrapolating from laboratory experiments, 1 kg of oligomeric catalyst can be expected to provide 460 kg of highly enantiomerically enriched epichlorohydrin. A pleasant surprise was also noted with the oligomeric catalyst system. Disubstituted epoxides, such as cyclohexene oxide, became viable substrates, and alcohols viable nucleophiles (Figure 4). Yields and ee values fully met the expectations of previous Co(salen) systems. Initial development efforts involving oligomeric catalyst 1 have now been redirected to 2, which is more stable and easier to access. Three of the four Rhodia ChiRex sites that conduct development work are involved in examining this new class of Co(salen) catalysts. Finally, Rhodia ChiRex has been collaborating with Synetix, an ICI subsidiary, since June 2001 to develop and commercialise an immobilised Co(salen) catalyst system. This has the potential to further decrease production costs for high volume applications, as a result of the facile isolation of the desired epoxide and enabling continuous processing methods to be used. Conclusion Although discovered only a short time ago, the Jacobsen HKR technology has already made the transition from the academic laboratory to a commercial tool. With the recent advances in this technology reviewed in this article, and the expanding need for chiral solutions, Rhodia ChiRex is excited at the prospect of continuing its development of this important chiral technology to meet current and future pharmaceutical needs. Dr Marcello DiMare is a member of Rhodia ChiRex Development Group where he is currently Associate Director of Process Chemistry. He works with a group of chemists on meeting the outsourcing needs of customers, and draws upon his experience as an academic within the University of California and Ligand Pharmaceuticals. Figure 3. Oligomeric Co(salen) catalyst systems. 120 Innovations in Pharmaceutical Technology

5 Figure 4. Two applications of oligomeric Co(salen) catalyst 1. Note: Rhodia ChiRex serves the outsourcing needs of some of the largest pharmaceutical and life-science companies in the world. The company s contract manufacturing services include process research and development, hazard evaluation, analytical methods development, and pilot- and commercial-scale cgmp manufacturing at its facilities in Boston (MA, USA), Malvern (PA, USA), Dudley (England), Annan (Scotland), Holmes Chapel (England) and Lyon (France). References 1. C&EN News (2000). 2. An Assessment of the Global Chiral Technology Market, Frost and Sullivan. 3. Tokunaga et al. (1997). Science, 277, Ready et al. (1999). JACS, 121, Ready et al. (2001). JACS, 123, Innovations in Pharmaceutical Technology 121