An Automated Intermittent Flow Approach to Continuous Suzuki Coupling

Abstract

A fully automated fill/empty reactor system for liquid–liquid biphasic Suzuki couplings is described. The system was capable of charging reactant and catalyst solutions to a heated vessel, heating reagent solutions by flow heat exchanger on the way into the reactor, allowing the reaction to occur, monitoring reaction completion, discharge of the product solution, and initiation of another cycle in a repeating fashion. A unique noncontact colorimetric method was used to monitor reaction completion. The reactor system exhibits many of the characteristics of a fully continuous reactor such as (1) high productivity from a small process footprint, (2) a large number of volume turnovers each day, (3) higher heat transfer area per unit volume compared to batch because the reactor is 50× smaller, and (4) rapid heat up and cool down of process streams enabled by heat exchangers. Downstream unit operations that are intended for eventual integrated end-to-end continuous production included a batch metal removal step and a continuous antisolvent crystallization to isolate the product in high yield and purity.

Rapid Suzuki-Miyaura Couplings with ppm Level of Palladium Catalyst in a High-Pressure and High-Temperature Water System

“…Scheme 1 shows a model representation of Suzuki-Miyaura couplings (SMCs) between organoboron and organic halide substrates, catalyzed by homogeneous Palladium complexes and a base, for production of the corresponding cross-coupling compounds [30]. SMCs have already been found not only in the academic area [31] but also in diverse industrial applications such as in agrochemicals [32], pharmaceuticals [33], functional materials [34], and several kinds of intermediates [35][36][37][38]. The process involves various intrinsic characteristics; thus, reaction parameters are critical and highly relevant for extending the practical applicability; for instance: (1) optimum reagent compositions; the amount of substrates, equivalent base and amounts of catalysts, whose variation could directly affect material costs of procurement; (2) formation of undesired homo-coupled by-products, and residual of the catalyst and base after reaction completion, along with the desired cross-coupled compound, is problematic in terms of separation and purification to achieve a higher grade of purity; (3) the co-existence of both organics and inorganics during processing, which might cause solidification and thus clogging in the flow channels because of the huge difference in their polarity [37].…”

Small-Volume Continuous Manufacturing of Merestinib. Part 1. Process Development and Demonstration

“…Importantly, the optimized hydrogenolysis reaction afforded high conversion to 3 and minimized debromination, defluorination, and detectable amounts of process intermediates such as the hydroxylamine with the use of a sulfided Pt/C catalyst in the presence of ZnBr 2 . The aniline was acylated to provide amide 5 , and Suzuki–Miyaura cross-coupling gave pyrazole 7 . Finally, the penultimate compound was deprotected using a continuous flow reactor to afford the DS ( 1 ) …”

“…Development and use of an intermittent-flow stirred tank in an initial 1 kg demonstration of step 1 to produce 8 has been disclosed previously. , Due to the mixing sensitivity of the Suzuki–Miyaura coupling, it was decided that the most rapid scale-up of this reaction in an SVC-amenable platform would employ the automated, refilling stirred tank reactor. This ensured adequate liquid–liquid mass transfer independent of the reaction time, which was designed through catalyst selection and preliminary optimization activities to be approximately 15 min.…”

Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling in Continuous Flow

“…The authors have reported the detection of little leaching (<1 ppm). Application to continuous flow process on a large scale was reported recently and could open new way for industrial use [95,96].…”