A key step in the synthesis of Vaborbactam is diastereoselective chain homologation of a boronate ester to an a-chloroboronic ester using chemistry originally developed in the 1980s by Donald Matteson (Figure 1).⁵ This reaction involves generation of dichloromethyl lithium at low temperatures (typically -95° to -100°C), reaction with a boronate ester to generate a boron ‘ate’ complex and subsequent rearrangement to generate the required chain-extended building block. The homologation is carried out in the presence of zinc chloride, which both promotes high levels ofdiastereoselectivity (due to chelation control in the transition state) and suppresses epimerization of the chlorinated product.The requirement for low temperature generation and processing of the organometallic species stems from its instability at higher temperatures, resulting in decomposition via formation of a carbine through a-elimination of LiCl.⁶ This lithiation-borylation methodology has been further developed by Aggarwal and applied to a number of other complex synthetic targets.⁷

Scale-up of low-temperature organometallic chemistry in batch is intrinsically challenging for a number of reasons. The ability to remove heat from the reactor during exothermic additions at cryogenic temperatures is difficult and often very high dilutions and slow addition rates are required to maintain control. This in turn can decrease efficiency and productivity. Poor mixing, particularly at the point of addition, can also generate localized hot-spots and variable local stoichiometries resulting in formation of impurities and impacting yield and product quality. Continuous processing is frequently used to mitigate problems of this type encountered during batch processing. Flow chemistry is often the preferred approach in scaling up chemistry that utilizes highly reactive organometallic reagents such as organolithium or organomagnesium derivatives, including unstable species such as the lithium carbenoids utilized in the Matteson reaction.⁸In situ formation and extremely rapid trapping of the organometallic species before decomposition can occur is possible under flow conditions but is poorly achieved in a large batch reactor.

The Matteson homologation, used to assemble the pivotal Vaborbactam a-chloroboronic ester intermediate (Figure 1), is eminently amenable to a flow chemistry strategy. Based on early pioneering work by a team at Novartis in which millisecond generation and trapping of dichloromethyllithium at higher temperatures under flow conditions was demonstrated,⁹ Christian Schuster’s team at Patheon (Thermo Fisher Scientific), in collaboration with a wider group of industry experts,successfully utilized this technology, converting a lab-based model reaction into a continuous manufacturing process run on several-hundred-kilogram scale under full cGMP conditions in yields of 97% .¹⁰ The corresponding batch process proved unscalable under laboratory conditions. Ultimately several tonnes of Matteson product were prepared in a process validation flow campaign enabling FDA fast-track approval and facilitating rapid development of Vaborbactam.

Key to the success of this work was a detailed investigation into the zinc chloride addition and developing conditions to prevent precipitated solids clogging the system – a mainstay of flow chemistry processes. In early development work, the process flowstream was quenched into a batch vessel containing the pre-cooled zinc Lewis acid.

This quickly became a bottleneck for increasing throughput, however. Two engineering solutions to this problem were explored, a continuous loop quench (mimicking the batch process) and a continuous stirred tank (CSTR)-based cascade quench. In the loop quench, boronate adduct was fed into a circulating pre-cooled solution of zinc chloride with reaction temperature controlled by heat exchangers. The product solution was pumped out and consumed zinc salt was continuously replenished in the loop reactor to keep the molar ratio constant. In the CSTR approach, zinc chloride solution was constantly fed to the pre-cooled vessel, the product solution exiting the CSTR in a cascade system controlled by an overflow device. The loop reactor system was ultimately selected to move forward and enabled the reaction to be run at a higher temperature and with better diastereometric control.

By leveraging the advantages a continuous process can impart, including increased process control, energy efficiency and reduced processing times, Schuster’s team succeeded in taking a difficult, unscalable organometallic reaction to full-scale production. Another victory in the ongoing battle against the bacteria!

References:

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2. Meropenem/Vaborbactam: a review in complicated urinary tract infections, S. Dhillon, Drugs 2018, 78, 1259-1270. The first b-lactamase inhibitor approved for clinical use was Clavulanic acid in the 1970s.

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10. Development of a continuous flow process for a Matteson reaction: from lab to full-scale production of a pharmaceutical intermediate, C. Schuster et al, Org. Process Res. Dev.2019, 23, 1069-1077.