Trifluoroacetic acid → HCID 86650657, compound

Participants

Reaction Steps

Add trifluoroacetic acid (5.5 mL, 72.9 mmol) to a mixture of 1-(4-trifluoromethyl-phenyl)-3-((R)-1-phenyl-ethylamino)-5(R)-(3-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one (6.6 g, 14.6 mmol) in HOAc (81 mL) and water (3.7 mL). Stir at ambient temperature for 3 hours. Observe significant formation of (R)-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 350.2 (M+H)+, Tr=3.71 min., method 1). Dilute the reaction mixture with toluene (100 mL) and wash the organic with water and pH 7 buffer. Filter through sodium sulfate and add HOAc (6.7 mL, 116.8 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (3.6 g, 17.5 mmol) to this toluene solution containing (R)-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Heat to 50° C. for 18 hours. Concentrate reaction mixture to give a purple oil. Observe significant formation of 3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5(R)-(3-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one (LC-MS ESI m/z: 536.2 (M+H)+, Tr=5.31 min., method 1). Dissolve the crude 3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5(R)-(3-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one in HOAc (73 mL) and add sodium cyanoborohydride (2.8 g. 43.8 mmol). Stir 3 hours at ambient temperature. Concentrate under reduced pressure. Partition the residue between dichloromethane and 1N sodium hydroxide solution. Extract the aqueous with dichloromethane. Dry the organic over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (25% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (3.55 g, 45%) as a brown oil. LC-MS ESI m/z: 538.2 (M+H)+, Tr=3.35 min., method 1.

Provenance & Evidence