Development of a Reliable Low-Loading Palladium-Catalyzed Monoamination Process for the Large-Scale Synthesis of 3-Bromo-2,5-difluoroaniline

Abstract

The development of a manufacturing process for the multikilogram synthesis of 3-bromo-2,5-difluoroaniline required as a starting material for the anticancer KRAS^G12C inhibitor AZD4625 is described. Two potential synthetic routes to this aniline were identified involving Fe/HCl dissolving metal reduction of the nitro group of 1-bromo-2,5-difluoro-3-nitrobenzene or Pd(0)-catalyzed monoamination of 1,3-dibromo-2,5-difluorobenzene with benzophenone imine to give a haloaryl-imine intermediate that was then hydrolyzed. Optimization of the Pd(0) catalyzed C–N bond-forming step and associated mechanistic studies identified that 0.5 mol % Pd(dba)₂/Xantphos and four equivalents of K₃PO₄ in ⁱPrOAc at 80 °C could be used to produce 100 kg batches of a haloaryl-imine intermediate. Solutions of this imine in ⁱPrOAc were then hydrolyzed through treatment with aqueous HCl allowing the desired aniline 1 to be isolated as its crystalline HCl salt. Process improvements include reduction of the amount of expensive Pd(dba)₂ precatalyst used from 1.5 to 0.5 mol %, with ⁱPrOAc used as a process-friendly solvent that allowed the C–N bond formation and imine hydrolysis steps to be telescoped into a single process. Detailed mechanistic investigations identified that use of excess K₃PO₄ as a heterogeneous base was necessary to minimize catalyst deactivation and impurity formation in the low-loading Pd(0)-catalyzed C–N bond-forming step.