Acetic Acid → HCID 86650661, compound

Add HOAc (464 mL, 8.09 mol), 2,5-dimethoxytetrahydrofuran (393 mL, 3.03 mol), water (2.27 L), and trifluoroacetic acid (153 mL, 2.02 mol) sequentially to a solution of (±)-5-phenyl-1-(4-trifluoromethoxy-phenyl)-3-(4-trifluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (1000 g, 2.02 mol) in THF (8.43 L). Stir the reaction mixture at ambient temperature for 18 hours. Add toluene (4.0 L) and isopropyl acetate (2.0 L). Wash the mixture with water (8.0 L) and saturated sodium hydrogencarbonate solution (6.0 L). Discard the aqueous layer. To the organic layer, add (R)-(+)-α-methyl benzylamine (390 mL, 3.03 mol). Stir the solution at ambient temperature for 3 hours. Concentrate the reaction mixture to obtain a mixture of 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(S)-phenyl-1,5-dihydro-pyrrol-2-one and 1-(4-trifluoromethoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-5(R)-phenyl-1,5-dihydro-pyrrol-2-one as a black oil. Dissolve the mixture (888 g, 2.02 mol) in isopropanol (2.0 L) and cool to −7° C. Filter the precipitate and wash with cold isopropanol. Dry under vacuum for 12 hours to give 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(R)-phenyl-1,5-dihydro-pyrrol-2-one (130 g, 29%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 7.24 (m, 4H), 7.11 (m, 4H), 6.98 (d, J=4 Hz, 2H), 5.78 (m, 2H), 5.13 (s, 1H), 4.30 (m, 1H), 1.44 (d, J=4 Hz 3H). LC-MS ESI m/z: 439 (M+H)+, Tr=6.30 min., method 1.

1. washWash the mixture with water (8.0 L) and saturated sodium hydrogencarbonate solution (6.0 L)
2. stirringStir the solution at ambient temperature for 3 hours
3. concentrationConcentrate the reaction mixture
4. customto obtain
5. temperaturecool to −7° C
6. filtrationFilter the precipitate
7. washwash with cold isopropanol
8. customDry under vacuum for 12 hours

ORD record

ord-935d57c188604bc2b88befb9551136e8

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08426448B2