(529d) Comparison of Pd Catalyst Activation Protocols in Suzuki Coupling and Associated Impacts on in-Process Control and Process Performance

Suzuki coupling of an aryl-bromide species to boronic acid forms a pharmaceutical process intermediate. The intermediate contains an atropisomeric stereo-center that affects downstream API. To set the atropisomeric center, a ligated-Pd pre-catalyst was generated in MeTHF or THF prior to being activated with aqueous base; the Suzuki coupling reaction occurs in a biphasic mixture.

Over the course of development, two different processes were developed and implemented on pilot-plant scale: In process [A], the pre-catalyst was activated with aqueous base and subsequently charged to the starting material solution. The resulting active catalyst is a Pd(0) species that is sensitive to oxidation and exhibited degradation over time. In process [B], a small amount of the aryl-bromide starting material (10%) is charged to the pre-catalyst solution. The resulting active catalyst is a Pd(II) species that is not sensitive to oxidation (given its 2+ oxidation state) at room temperature. The two processes generated catalyst species that are different but yet still part of the same catalytic cycle.

The catalyst stability afforded by process [B] had several impacts on in-process control, processing feasibility, and reaction performance. First and foremost, an in-process check was implemented to verify whether sufficient active catalyst was generated to complete the downstream Suzuki coupling; this improvement to the control strategy was not feasible with process [A] given the time instability of the Pd(0) species. Second, the number of processing vessels was reduced from three to two. Oxygen sensitivity during the Suzuki coupling required process [A] to use three separate vessels - one each for the catalyst, base, and starting materials. With process [B], the starting materials could be charged to the catalyst vessel after generating the stable Pd(II) species. Finally, process [B] exhibited faster reaction kinetics at equivalent Pd loading. The improved kinetics allowed for process [B] to be implemented on scale at a lower reaction temperature that resulted in a minor increase in product selectivity.

In summary, the two processes showed marked differences with respect to control, feasibility, and performance. The comparison demonstrates the effects and importance of catalyst stability in a pharmaceutical manufacturing process.