Trifluoroacetic acid → HCID 86650665, compound

Participants

Reaction Steps

Add trifluoroacetic acid (1.88 mL, 24.9 mmol) to a biphasic mixture of 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(R)-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (2.60 g, 4.98 mmol) in toluene (13 mL) and water (5 mL). Stir at ambient temperature for 60 min. Observe significant formation of 5-(R)-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 420 (M+H)+, Tr=4.19 min., method 1). Wash the reaction mixture with water and pH 7 buffer. Filter through sodium sulfate and add HOAc (2.28 mL, 39.8 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (1.02 g, 4.98 mmol) to this toluene solution containing 5-(R)-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione. Heat to 55° C. for 18 hours. Concentrate reaction mixture to give a red oil. Observe significant formation of (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (LC-MS ESI m/z: 606 (M+H)+, 604 (M−H)−, Tr=5.70 min., method 1). Dissolve the crude (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one in HOAc (107 mL) and add sodium cyanoborohydride (2.68 g. 42.6 mmol). Stir 30 min. at ambient temperature. Concentrate under reduced pressure. Dissolve the residue in EtOAc and wash with 1N sodium hydroxide solution, water and saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (5-40% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-2-one (796 mg, 26%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=7.9 Hz, 1H), 8.01 (dd, J=7.8 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.39-7.34 (m, 3H), 7.28 (d, J=7.9 Hz, 1H), 7.24-7.17 (m, 3H), 7.14 (d, J=7.9 Hz, 1H), 5.24 (dd, J=9.4, 6.4 Hz, 1H), 3.43 (dd, J=10.1, 8.4 Hz, 1H), 2.98 (br s, 1H), 2.77-2.69 (m, 1H), 1.64 (dd, J=21.8, 10.3 Hz, 1H), 1.47 (s, 3H), 1.42 (s, 3H). LC-MS ESI m/z: 608 (M+H)+, Tr=3.88 min., method 1.

Provenance & Evidence