Acetic Acid → HCID 86650654, compound

Participants

Reaction Conditions

Reaction Steps

Add HOAc (2.1 mL, 36.5 mmol), 2,5-dimethoxytetrahydrofuran (1.8 mL, 13.7 mmol), water (10 mL), and trifluoroacetic acid (1.4 mL, 18.3 mmol) sequentially to a solution of (±)-5-(2-fluoro-phenyl)-1-(4-difluoromethoxy-phenyl)-3-(4-difluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (4.35 g, 9.13 mmol) in THF (38 mL). Heat the reaction mixture to 35° C. for 22 hours. Observe significant formation of (±)-1-(4-difluoromethoxy-phenyl)-5-(2-fluoro-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 336 (M+H)+, Tr=3.38 min., method 1). Cool the reaction mixture to room temperature and add toluene (100 mL) in a single portion. Wash the mixture with water and then pH 7 buffer. Separate layers and observe that the aqueous layer is pH=7. Filter through sodium sulfate and add HOAc (1.05 mL, 18.3 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (2.24 g, 11.0 mmol) to the toluene solution containing 1-(4-difluoromethoxy-phenyl)-5-(2-fluoro-phenyl)-pyrrolidine-2,3-dione. Heat to 55° C. for 18 hours. Concentrate the reaction mixture and purify by silica gel chromatography (5-25% EtOAc-hexane) to yield the title compound (2.36 g, 50%) as an oil, LC-MS ESI m/z: 522 (M+H)+, Tr=5.15 min., method 1.

Provenance & Evidence