Synthesis of Boscalid via a three-step telescoped continuous flow process implemented on a MJOD reactor platform

Abstract

A three step continuous/semi-flow process leading to the fungicide Boscalid® is disclosed. The first step of the process is a Suzuki cross-coupling where 1-chloro-2-nitrobenzene is coupled with 4-chlorophenylboronic acid at a temperature of 80 °C using a solvent mixture of ethanol/water as the reaction medium with sodium carbonate as the base and tetrakis(triphenylphosphine)-palladium as the catalyst. This reaction step was developed as a batch procedure and then adapted and implemented on a multi-jet oscillating disk (MJOD) continuous flow reactor platform. The intermediate 4′-chloro-2-nitro-1,1′-biphenyl was achieved in high yield (82%). The second step which was telescoped with the first one involved a nitro group reduction of high efficacy. The reduction method was based on NaBH₄/CoSO₄·7H₂O as the reduction system. The reduction product 2-amino-4′-chloro-1,1′-biphenyl was achieved in high yield (79%) at a short reactor residence time (3 min). The final step of the process is composed of a two-step sequence where 2-amino-4′-chloro-1,1′-biphenyl is transformed into the corresponding iminosulfanone intermediate (not isolated), which immediately reacts with the 2-chloronicotinic acid present in the reaction mixture to form Boscalid® in a yield of >66%. The three-step process provided an overall yield of >42%, which corresponds to a mean step yield of ≈75%.