Trifluoroacetic acid → HCID 86650665, compound

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.

1. washWash the reaction mixture with water and pH 7 buffer
2. filtrationFilter through sodium sulfate
3. temperatureHeat to 55° C. for 18 hours
4. concentrationConcentrate
5. customreaction mixture
6. customto give a red oil
7. stirringStir 30 min. at ambient temperature
8. concentrationConcentrate under reduced pressure
9. dissolutionDissolve the residue in EtOAc
10. washwash with 1N sodium hydroxide solution, water and saturated sodium chloride solution
11. dry with materialdry over sodium sulfate
12. filtrationfilter
13. concentrationconcentrate under reduced pressure
14. customPurify the residue by silica gel chromatography (5-40% EtOAc-hexane)

ORD record

ord-ebdca5fa493c49d79413e0d243086ef1

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08426448B2