Acetic Acid → HCID 57951120, compound

Participants

Reaction Steps

Add trifluoroacetic acid (3.5 mL, 46.1 mmol) dropwise to a biphasic mixture of (R)-3-((R)-1-phenyl-ethylamino)-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (4.8 g, 9.22 mmol) in toluene (24 mL) and water (9.6 mL). Stir at ambient temperature for 60 min. Observe significant formation of (R)-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione (LC MS 77%, Ret. time=4.08 min., Method 3, MS (m/z): 416 (M−1). Separate the aqueous layer and wash the toluene layer with water, pH 7 buffer and saturated sodium chloride solution. Add acetic acid (4.23 mL, 73.8 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (3.77 g, 18.4 mmol) to the toluene solution containing (R)-5-[3-(2,2,2-trifluoro-ethoxy)-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-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (LC MS 100%, Ret. time=5.26 min., Method 3, MS (m/z): 604 (M+1). Dilute reaction mixture with ethyl acetate and wash with water and saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate to dryness. Dissolve the crude (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one in acetic acid (46 mL) and add sodium cyanoborohydride (1.16 g. 18.4 mmol). Stir 15 min. at ambient temperature. Concentrate under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (5-50% ethyl acetate-hexane) and purify again by silica gel chromatography (0-1% methanol-dichloromethane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (2.36 g, 42%) as a clear colorless oil. MS (m/z): 606 (M+1).

Provenance & Evidence