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 4
In the original synthetic protocol for the DuPhos ligands, 1,2-bis (phosphino) benzene was deprotonated with n-BuLi, followed by addition of the cyclic sulfate and then further n-BuLi (see Figure 4) (14). This approach gave the ligands in good yields and purities. Upon scaling up this process to produce kilogram amounts, yields were not reproducible, and higher levels of impurities were formed. These problems were readily solved by an inverse addition procedure, whereby n-BuLi is added to a mixture of 1, 2-bis (phosphino) benzene and the cyclic sulfate. This process is readily scaleable, giving high purity ligand in excellent yields on multikilogram scales (16). This process also has been applied to other 1,4-diols to give access to ethyl and isopropyl phospholane ligands, as well as the related 1,3-diols for the proprietary phosphetano ligands, FerroTANE (Dowpharma, Midland, MI) (17).

Rhodium catalyst fabrication

Figure 5
For some asymmetric hydrogenation catalyst systems, it is acceptable to make the precatalyst in situ from a metal complex and the ligand. We have the general approach that it is better to preform and isolate the ligand–metal catalyst complex so it can be charged to the reactor as a defined species. This approach results in more robust and reproducible reactions, with greater quantification (important for CGMP manufacture) and no debate as to whether the precatalyst complex has completely formed. Initially, standard established literature methods were used to make the Rh-DuPhos complexes: (1,5-cyclooctadiene) Rh(I) acetylacetonate] is converted into the sparingly soluble Rh bis(1,5-cyclooctadiene) tetrafluoroborate complex (18), and the ligand reacts with this intermediate to provide the precatalyst complex in solution. Addition of an antisolvent is required to precipitate the desired product (see Figure 5). This method worked well for a range of diphosphine ligands, but provided material in modest yields (~70%) and variable product form. Obviously, failing to isolate 30% of valuable ligand and metal precursor is neither desirable nor economical.

A further problem with this method was that the product form was variable, from robust deep red crystals to orange-yellow amorphous powders. Although all of these forms performed well in asymmetric hydrogenation reactions, the powdered materials had shorter shelf life and were prone to degrade more easily than the crystalline material. Further process 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.

Figure 6
The new process involves taking [(1,5-cyclooctadiene) Rh(I) acetylacetonate] in an ethereal solvent (see Figure 6a), treating it with an alcohol solution of strong acid, such as tetrafluoroboric acid, to give a soluble bis-solvato species (see Figure 6b), which is then reacted with an ethereal solution of the bisphosphine ligand (see Figure 6c). Shortly after the addition of the ligand crystallization 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 precatalyst is deposited in exceptionally high yields (19).


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