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 (100 g, 0.3 mol), Cs2CO3 (58.6 g, 0.18 mol), N,N-dimethylacetamide (DMA) (300 mL, anhydrous 99.8%), N,N′-dimethyl-ethylenediamine (10.6 g, 0.12 mol) and copper (I) iodide (11.4 g, 0.06 mol) and the resulting mixture heated to about 80° C., under nitrogen. To the resulting mixture was then added a solution of 4-(2-bromo-vinyl)-1,2-difluoro-benzene (78.8 g, 0.36 mol) in DMA (30 mL), slowly over a period of about 20 min and the resulting mixture stirred at this temperature for 5 hours. The resulting mixture was then quenched while hot with H2O (600 mL), and diluted with EtOAc (700 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 (500 mL), 0.5N HCl aqueous solution (500 mL) and brine (500 mL), then filtered and concentrated under reduced pressure to approximately half the original volume (350-400 mL). The concentrated solution was heated to slow reflux. Heptane (250 mL) was then added slowly at this temperature. The resulting suspension was cooled to 5-10° C. over a period of 1 hr, diluted with additional heptane (100 mL) and aged at this temperature for a period of about 2 hrs. The resulting solid precipitate was filtered, rinsed with cold heptane/EtOAc (4/1) solvent mixture (100 ml), and dried at 55° C. in a vacuum oven overnight, to yield the title compound as a white solid.

Provenance & Evidence