Scale up of a continuous slurry Suzuki coupling with Vapourtec

Green Chemistry has published the paper entlitled “Continuous slurry plug flow Fe/ppm Pd nanoparticle-catalyzed Suzuki–Miyaura couplings in water utilizing novel solid handling equipment”, in which Professor Bruce H. Lipshutz, in collaboration with Novartis, explored continuous slurry Suzuki coupling with Vapourtec equipment [1].

The paper described a novel and greener approach to perform Suzuki-Miyaura couplings in flow. The heterogeneous catalyst, suspended an aqueous micellar medium, was continuously pumped and premixed before entering a tubular reactor.

To be able to reliably do this work, Lipshutz’s team took advantage of the versatile V-3 pumps, which are not only able to pump slurries, but they can also work as dynamic backpressure regulator without clogging. This synthetic route yielded over 13 g/h of an API intermediate.

Suzuki-Miyaura coupling in flow

For most synthetic chemists, Suzuki-Miyaura coupling is perhaps the most common cross-coupling reaction used in the lab. This useful reaction, mediated by Pd(0), forms a C-C bong between an organoboron and halide compounds in presence of a base.

In continuous flow, heterogeneous catalysis is usually done by packing the catalyst in a fixed bed reactor. This simple approach has allowed most research groups to explored Suzuki couplings in flow in the past decade. The limitations of this approach are residence time restrictions and difficulty of scaling up.

Handling solids in flow is challenging without the right system. Pumping solids is near impossible for most pumps and, most back pressure regulators tend to clog when solids pass through. Vapourtec developed the V-3 pumps with the aim to overcome these issues. These peristaltic pumps are capable of working under pressure, delivering smooth flow rate of solutions, slurries and even gases, controlling a reactor’s pressure or even introducing oscillatory flow regime.

Green Suzuki-Miyaura coupling in flow

Global environmental concerns mean we need to continually strive for more sustainable solutions than current batch processes. Enabling technologies, such as continuous flow, offer a greener pathway. Good mixing, short residence times and the ability to work under pressure makes flow chemistry an accelerating technology most companies are now implementing.

In this paper, the Lipshutz group took this green approach to the next level, by using aqueous solutions and using nanoparticles that could be recovered further down the stream.

Dr Manuel Nuño commented: “this is a fantastic piece of work showing a different way of working with heterogeneous catalysis. The article very clearly explained all the issues you can expect when working with slurries and suspensions. Although you MIGHT be able to pump a fixed volume of a slurry with a syringe pump, people often forget whatever you put in the reactor, it has to come out! When we worked with continuous hydrogenation with Pd on charcoal slurries [2], [3], we learned that fixed BPRs are not suitable for these type of applications

Extracted from the article, the team said:

“While other commercial systems were considered, the Vapourtec E-Series reactor system was chosen due to its inclusion of peristaltic pumps as the primary mode of delivering reagents together with an internalized, probe-monitored heating well for the reactor coil. This instrument has been reported to accommodate light slurries in suspension while our examination of this system found that the NPs suspended in an aqueous micellar medium could be easily pumped without clogging” [1]