Acetic Acid → HCID 86650652, compound

Temperature

35 °C

Add HOAc (11.5 mL, 201 mmol), 2,5-dimethoxytetrahydrofuran (9.8 mL, 75.5 mmol), water (56 mL), and trifluoroacetic acid (7.6 mL, 100.6 mmol) sequentially to a solution of (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethoxy-phenyl)-3-(4-trifluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (29.1 g, 50.3 mmol) in THF (180 mL). Heat the reaction mixture to 35° C. for 22 hours. Observe significant formation of (±)-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 420 (M+H)+, Tr=4.23 min., method 1). Cool the reaction mixture to room temperature and add toluene (200 mL) in a single portion. Wash the mixture with water and then pH 9 buffer. Separate layers and observe that the aqueous layer is pH=7. Filter through sodium sulfate and add (R)-(+)-α-methyl benzylamine (12.9 mL, 100.6 mmol). Stir the solution at ambient temperature for 18 hours. Concentrate the reaction mixture and purify by silica gel chromatography (5-15% EtOAc-hexane) to yield 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(S)-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (9.01 g, 34%) as a yellow oil, LC-MS ESI m/z: 523 (M+H)+, Tr=5.57 min., method 1 and 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(R)-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (11.1 g, 42%) as an orange solid, LC-MS ESI m/z: 523 (M+H)+, Tr=5.49 min., method 1.

1. temperatureCool the reaction mixture to room temperature
2. washWash the mixture with water
3. filtrationFilter through sodium sulfate
4. concentrationConcentrate the reaction mixture
5. custompurify by silica gel chromatography (5-15% EtOAc-hexane)

ORD record

ord-7b618f7f16b24bc29c08c3f5a3416aa0

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08426448B2