To a solution of methyl 3-fluoro-5-iodo-4-methylbenzoate (115.5 g, 392.8 mmol) in toluene (˜1600 mL) at ambient temperature was charged benzophenone imine (67.6 g, 373.0 mmol), 1,1′-bis(diphenylphosphino)ferrocene (9.80 g, 17.68 mmol) and cesium carbonate (179.2 g, 550.0 mmol). The reaction vessel was vacuum purged with nitrogen three times. Tris(dibenzylideneacetone)dipalladium(0) (5.34 g, 6.05 mmol) was added before the vessel was again vacuum purged with nitrogen three times. The reaction mixture was then stirred and heated to reflux for 4 d before being cooled to ambient temperature and filtered through GF/F filter paper under a nitrogen atmosphere. The filter cake was washed with toluene (230 mL) and the filtrates combined and washed with aq. sodium sulfite (5% w/w, 580 mL). The phases were separated and the aq. phase re-extracted with toluene (580 mL). The organic fractions were combined and washed with water (580 mL), dried over sodium sulfate and filtered through GF/F filter paper. The filter cake was washed with toluene (230 mL) and the combined filtrates concentrated to ˜1000 mL in vacuo. After cooling the solution to ambient temperature, TBME (1040 mL) was charged followed by decolourising charcoal (60 g). The slurry was heated to 45-50° C. and then cooled to ambient temperature over 1 h and filtered through GF/F filter paper. The filter cake was washed with TBME/toluene (1:1 v/v, 2×230 mL). The filtrates were combined to afford a solution of methyl 3-[(diphenylmethylene)amino]-5-fluoro-4-methylbenzoate to which methanol (127 mL, 3135.4 mmol) was added. Sulfuric acid (21 mL, 394.0 mmol) was then charged over at least 1 h ensuring that the temperature was maintained in the range 18-23° C. The resulting slurry was filtered through 100 μm cloth. The filter cake was washed with TBME (580 mL) and dried on the filter under a flow of nitrogen for at least 2 h. The isolated solid was then slurried in acetonitrile (500 mL) at ambient temperature for 4-5 h before being filtered through 100 μm cloth. The filter cake was washed with acetonitrile (1×300 mL, 1×115 mL) and dried on the filter at up to 45° C. to afford methyl 3-amino-5-fluoro-4-methylbenzoate sulfuric acid salt (92.2 g, 94.5% w/w).
