Acetic Acid → HCID 24809626, compound

Participants

Reaction Conditions

Reaction Steps

Separate the aqueous layer and wash the toluene layer with water, pH 7 buffer and saturated sodium chloride solution. Add acetic acid (26.2 mL, 456 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (23.3 g, 114 mmol) to the toluene solution containing (R)-5-[3-trifluoromethoxy-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Heat to 55° C. for 18 hours. Observe significant formation of (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (LC MS 100%, Ret. time=5.59 minutes, Method D, MS (m/z): 590 (M+1). Concentrate under reduced pressure. Dissolve the crude (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one in acetic acid (285 mL) and add sodium cyanoborohydride (7.2 g. 114 mmol). Stir 1.75 hours at ambient temperature and concentrate under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Dry the solution over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (10-30% ethyl acetate-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-2-one (18.0 g, 53%) as a yellow oil and (3S,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-2-one (0.92 g, 2.7%) as an oil.

Provenance & Evidence