Ethyl Acetate → {(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-methyl}-methyl-phosphinic acid ethyl ester

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Reaction Steps

[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (60.0 g, 181 mmol) was placed in a reactor under nitrogen, followed by addition of cesium carbonate (35.3 g, 108 mmol) and copper iodide (6.90 g, 36.2 mmol) and the resulting mixture was stirred at ambient temperature. DMA (123 g) and N,N′-dimethylethylenediame (6.36 g, 72.1 mmol) (with the addition flask washed with DMA (30 g)) were added and the resulting mixture heated to 70-75° C. with about 30-60 minutes, over which time a thin blue suspension was observed to form. To the resulting mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (47.6 g, 217 mmol) over about 10-30 minutes (with the addition flask washed with DMA (30 g)), then stirred for 5 to 7 hours at 75-85° C., with the progress of the reaction monitored by HPLC. When the reaction was deemed complete, the reaction mixture was cooled to 60-78° C., ethyl acetate (345 g) was added followed by addition of water (303 g), and the mixture stirred for 10-30 minutes. The resulting phases were separated. To the organic phase was added a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, to the organic phase was added again a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated and treated a third time with addition of a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, the organic phase heated to distill off 107-139 g of solvent (at 50-65° C.). To the resulting residue, cyclohexane (280 g) was added over 20-40 minutes and the resulting mixture cooled to 10-15° C., then stirred at this temperature for 2-3 hours, over which time a thick suspension was observed to form. The resulting suspension was filtered, the filtercake washed with a mixture of cyclohexane (135 g) and ethyl acetate (45 g), then dried at 55-60° C., under vacuum to yield the title compound as a solid.

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