Ian Lennon and Nicholas Johnson, from CPS-Chirotech, a subsidiary of Dr Reddy's Custom Pharmaceuticals Services, discuss the production and advantages of preformed rhodium complexes for use in asymmetric hydrogenation
During the past 10 years there has been a marked increase in the proportion of single enantiomer small molecule drugs that have been approved by the FDA. Furthermore, an increasing percentage of these are being manufactured using wholly synthetic means, as opposed to being derived from natural products.
In 1998, 48% of the small molecule drugs approved by the FDA were single enantiomers, and in less than half of these the chiral motif was made by synthetic chemical methods. By 2007, the proportion of single enantiomers in small molecule drug approvals had risen to 71%, and of these products, 70% had the chirality introduced by synthetic chemical methodology.
This trend has led to an increased demand for chiral technologies, such as biocatalysis, classical resolution and asymmetric hydrogenation. For example, four drugs have recently been approved by the FDA that, reportedly, use homogeneous asymmetric hydrogenation technology in their manufacture. These drugs are Rozerem1 and Tipranavir2 launched in 2005, Sitagliptin3 in 2006 and Aliskiren4 in 2007.
Since 1995, CPS-Chirotech has been developing and applying asymmetric hydrogenation and during this time it has demonstrated an exceptional substrate scope. Specific reports on the results of collaborations with pharmaceutical customers include asymmetric hydrogenation processes for Tipranavir, Candoxatril, Pregabalin, unnatural a-amino acids, succinates and amines (Figure 1).2,5
Whether manufacturing complex chiral intermediates or using this technology to develop enabling asymmetric hydrogenation processes for customers, CPS-Chirotech’s strategy has been to produce preformed metal catalyst complexes where possible, rather than forming the precatalyst in situ from a ligand and corresponding precious metal precursor.
We consider that there are significant advantages in using preformed complexes in commercial scale manufacturing, including:
• Confidence that the metal precursor has been fully complexed to the ligand. Small amounts of uncomplexed metal precursor can lead to slower or stalled reactions and lower enantiomeric excess product, due to achiral hydrogenation.
• When using a preformed catalyst, it is simpler to optimise the catalytic reaction with respect to catalyst loading and other reaction parameters, as the exact amount of catalyst being employed is well-defined and controlled.
• The catalyst can be supplied to defined specifications and use-tested, providing assurance of consistent performance.
• Validation of cGMP manufacturing process using a preformed catalyst may be simpler than when using in situ preparation of the catalyst.
Rh catalyst fabrication
Having adopted the general approach that it is preferable to pre-form and isolate the ligand/metal catalyst complex, to facilitate robust and reproducible reactions with greater quantification, an efficient and hopefully broadly applicable method of catalyst synthesis was sought. The first ligand and catalyst systems to be investigated were the well-known DuPhos and BPE, licensed from DuPont in 1995.
Initially standard literature methods were used to make the Rh-DuPhos complexes, where [(1,5-cyclooctadiene) Rh(I) acetylacetonate] is converted into the sparingly soluble Rh bis(1,5-cyclooctadiene) tetrafluoroborate complex. The ligand reacts with this intermediate to provide the precatalyst complex in solution. Addition of an anti-solvent is then required to precipitate the desired product (Scheme 1).
This method worked well for a range of diphosphine ligands, but provided material in modest yields (~70%). Obviously, failing to isolate 30% of valuable ligand and metal precursor was neither desirable nor sustainable.
A further problem with this method was that the product form was variable, from robust deep red crystals to orange/yellow amorphous powders. While this range of forms performed well in asymmetric hydrogenation reactions, the powdered materials had limited shelflife through being more prone to degradation than the crystalline material. Further chemical 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.
The new process (Scheme 2) involves taking [(1,5-cyclooctadiene) Rh(I) acetylacetonate] in an ethereal solvent (Fig. 2a), treating it with an alcohol solution of strong acid, such as tetrafluoroboric acid to give a soluble bis-solvato species (Fig. 2b), which is then reacted with an ethereal solution of the bisphosphine ligand (Fig. 2c).
Shortly after the addition of the ligand crystallisation of the precatalyst complex is observed. This protocol controls the rate of nucleation at higher temperatures through rate of ligand addition, such that granular, free-flowing pre-catalyst is deposited in exceptionally high yields.5
The difference in quality of the precatalyst formed using this process is remarkable. The original catalyst fabrication process often provided an orange amorphous powder that had poor long-term stability. The new process consistently produces highly crystalline material, with the ability to control the crystal size (Fig. 3). This material is sufficiently stable to be readily dispensed and weighed in air, and with long-term storage under an inert atmosphere, it has a significant shelflife and consistently provides reproducible results in asymmetric hydrogenation.
As our early needs were for both enantiomers of [Me-DuPhos Rh (COD)]BF4, we applied this procedure in its manufacture first. We obtained very high yields of crystalline precatalyst (>95%) on batch sizes from 2 to 2.5kg per run, with the ability to further increase the batch size. This process is now operated routinely and consistently produces high quality product, and is a significant advance when compared with the original precatalyst synthesis.
With this process working exceptionally well for rhodium Me-DuPhos complexes, we subsequently investigated the synthesis of other related bisphosphine complexes. We found that this methodology could be applied to the manufacture of a wide range of precatalysts, all giving crystalline products in high yield and quality (Fig. 4). Not surprisingly, the crystalline form in each case is subtly different and the crystallisation protocol requires tailored optimisation for each product; however, the basic process is retained for each precatalyst produced. To date we have successfully applied this method to more than 20 bis- and mono-phosphine systems.5
In conclusion, through Chirotech, Dr Reddy’s CPS has gained specialist expertise in the area of asymmetric hydrogenation, efficiently utilising proprietary technology in the manu-facture of many chiral intermediates for the past 15 years.5 These powerful technologies are now married to the extensive manufacturing facilities of Dr Reddy’s CPS in India, Europe and Mexico. Underpinning this is the ability to manufacture ligands and the corresponding precious metal precatalysts and use them effectively at commercial scale.
We have provided an insight into our activities in Rh-based catalyst preparation, demonstrating that a range of diphosphine-rhodium complexes can be reproducibly manufactured in high purity and yield, while highlighting some of the advantages of using preformed catalysts vs in-situ formation.