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

Participants

Reaction Conditions

Reaction Steps

A 3 L 4-necked round-bottomed flask equipped with addition funnel, mechanical stirrer, nitrogen inlet, heating mantle and thermocouple was charged with [carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (10.5 g, 0.03 mol), K2CO3 (8.0 g, 0.03 mol), N,N-dimethylacetamide (DMA) (40 mL, anhydrous 99.8%), N,N′-dimethyl-ethylenediamine (1.6 g, 0.018 mol) and copper (I) iodide (1.14 g, 0.006 mol) and the resulting mixture heated to about 80° C. under nitrogen. To the resulting mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (7.9 g, 0.036 mol) slowly, over a about 20 minutes, at 80° C. and the resulting mixture stirred at this temperature for about 5 hours. The resulting mixture was then quenched while hot with H2O (60 mL), and diluted with EtOAc (70 mL), added slowly through an addition funnel. The resulting biphasic mixture was cooled to 50-55° C. and at this temperature the layers were separated. The organic layer was washed with H2O (50 mL), 0.5N HCl aq. solution (50 mL) and brine (50 mL), then filtered and concentrated under reduced pressure to about half the original volume (35-40 mL). The concentrated solution was heated to slow reflux and then heptane (25 mL) was added slowly at this temperature. The resulting suspension was cooled to 5-10° C. over a period of 1 hr, diluted with additional heptane (10 mL) and aged at this temperature for about 2 hrs. The resulting solid precipitate was filtered, rinsed with cold heptane/EtOAc (4/1) solvent mixture (10 ml), and dried 55° C. in a vacuum oven overnight, to yield the title compound as a white solid.

Provenance & Evidence