Manufacture of Asymmetric Hydrogenation Catalysts - Pharmaceutical Technology

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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.


Pharmaceutical Technology



Figure 7
The difference in quality of the precatalyst formed using this process is noteworthy (see Figure 7). The original catalyst fabrication process often provided an orange amorphous powder that performed well in the asymmetric hydrogenation reaction, but had poor long-term stability. This material had to be handled very carefully under rigorously inert conditions, as the larger surface area made it more prone to atmospheric oxidative decomposition. The new process provides a deep red crystalline material, and allows the crystal size and reproducibility to be controlled to produce high-quality product (see Figure 7). This material can be readily weighed in air, as long as it is stored under nitrogen, has a long shelf life (>12 months), and provides reproducible results in asymmetric hydrogenation.


Figure 8
As our early needs were for both enantiomers of [Me-DuPhos Rh (COD)]BF4, we first applied this procedure in manufacture. Very high yields of crystalline precatalyst (>95 %) on batch sizes from 2–2.5 kg per run (see Figure 8) were obtained, with the ability to increase the batch size as required. This process is operated routinely and consistently produces high-quality product, a major advance when compared with the original precatalyst synthesis.


Figure 9
With this process working well for rhodium Me-DuPhos complexes, Dowpharma investigated the synthesis of other related bisphosphine complexes. This methodology could be applied to the manufacture of a wide range of precatalysts, all giving crystalline products in high yield and quality (see Figure 9). Unsurprisingly, the crystalline form in each case is subtly different, and the crystallization protocol requires tailored optimization for each product. The basic process, however, is retained for each precatalyst produced. To date, we have applied this method to more than 20 bis-and mono-phosphine systems (19).

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.


Figure 10
Limited representatives of the DuPhos ligand family have been developed for ruthenium catalysis. Among these ligands, the i-Pr-DuPhos Ru (TFA)2 system is good for the asymmetric hydrogenation of acrylate derivatives. This catalyst outperforms other ruthenium-based catalysts, including biaryls, for the asymmetric hydrogenation of tiglic acid, a γ-amino acid derivative (20) and furoic acid (see Figure 10). The latter process to (R)-3-furoic acid was scaled up for clinical supplies.


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