Trifluoroacetic acid → HCID 24984347, compound

Temperature

50 °C

Mix ethanol (120 mL), glacial acetic acid (15 mL), water (3.0 mL, 164.7 mmol), trifluoroacetic acid (6.2 mL, 82.4 mmol), (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-3-(4-trifluoromethyl-phenylamino)-1,5-dihydro-pyrrol-2-one (30.0 g, 54.9 mmol), and 2,5-dimethoxy-tetrahydrofuran (10.7 mL, 82.4 mmol). Warm the solution to 50° C. and stir the reaction mixture for 15-18 hours. Discontinue heating the solution, add water (35 mL), and cool the reaction mixture to −19° C. Filter the slurry and wash the solid with a 1:4 mixture of water-methanol (20 mL). Transfer the filtrate to a separatory funnel and wash with 6% brine (280 mL), add 6% brine (100 mL), methanol (40 mL), diethyl ether (100 mL), and saturated sodium bicarbonate solution (43 mL) to the organic phase. Separate the layers, add methanol (60 mL) to the organic phase, and concentrate the solution to approximately 1 volume containing (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Add methanol (60 mL) and (R)-4-chloro-alpha-methylbenzylamine (7.8 mL, 55.0 mmol) and stir at room temperature for 24 hours. Monitor the reaction by HPLC for completion (Method B), then cool the solution to −7° C. and continue stirring at this temperature for 72 hours. Add a pre-mixed solution of potassium hydroxide (0.69 g, 10.5 mmol) in methanol (11 mL) to the reaction mixture, warm the solution to 10° C., and stir for an additional 4 hours. Cool the solution to −7° C., filter the slurry, and rinse the resultant product with methanol (5 mL×3). Dry the solid under vacuum to obtain (R)-1-(4-trifluoromethyl-phenyl)-3-[1(R)-(4-chloro-phenyl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (12.3 g, 47.7%) as a white solid: HPLC (Method B) retention time: 4.3 minutes. MS (m/z): 539.0 (M−1). 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.38-7.36 (m, 2H), 7.30-7.27 (m, 3H), 7.10 (dd, 1H, J=8.5, 1.0 Hz), 7.05 (d, 1H, J=7.5 Hz), 6.95 (s, 1H), 6.06 (d, 1H, J=8.0 Hz), 5.96 (d, 1H, J=3.0 Hz), 5.22 (d, 1H, J=3.0 Hz), 4.35-4.32 (m, 1H), 1.43 (d, 3H, J=6.5 Hz).

1. temperatureDiscontinue heating the solution
2. temperaturecool the reaction mixture to −19° C
3. filtrationFilter the slurry
4. washwash the solid
5. additionwith a 1:4 mixture of water-methanol (20 mL)
6. washTransfer the filtrate to a separatory funnel and wash with 6% brine (280 mL)
7. additionadd 6% brine (100 mL), methanol (40 mL), diethyl ether (100 mL), and saturated sodium bicarbonate solution (43 mL) to the organic phase
8. customSeparate the layers
9. additionadd methanol (60 mL) to the organic phase
10. concentrationconcentrate the solution to approximately 1 volume
11. additioncontaining (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione
12. customMonitor the reaction by HPLC for completion (Method B)
13. temperaturecool the solution to −7° C.
14. stirringcontinue stirring at this temperature for 72 hours
15. temperaturewarm the solution to 10° C.
16. stirringstir for an additional 4 hours
17. temperatureCool the solution to −7° C.
18. filtrationfilter the slurry
19. washrinse the resultant product with methanol (5 mL×3)
20. customDry the solid under vacuum

ORD record

ord-05822f8e72bd4a83bb2a5ad8e89fc20c

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07998985B2