Phenacyl bromide → HCID 89418665, compound

Temperature

25 °C

(R)-3-[(2-aminophenyl)amino]-1,1,1-trifluoropropan-2-ol (133 mg, 0.603 mmol) was dissolved in DMF (5024 μl). 2-Bromo-1-phenylethanone (100 mg, 0.502 mmol) and Hunig's Base (88 μl, 0.502 mmol) were added and the mixture was stirred at 25° C. for 4 hours. Sodium triacetoxyborohydride was added (639 mg, 3.01 mmol), and the reaction mixture was stirred at 25° C. for 12 hours. The reaction was heated to 80° C. for 2 hours, then was cooled to 25° C., and 3-(trifluoromethoxy)benzaldehyde (144 μl, 1.005 mmol) was added. The reaction mixture was stirred at 25° C. for 2 hours, and then was heated to 50° C. for 10 hours. The reaction mixture was quenched with saturated ammonium chloride solution and then was extracted into EtOAc. The organic phase was washed four times with water, then once with brine, then was dried with MgSO4, filtered, concentrated, and purified on a 40 g silica gel column with a 0-100% DCM/Hexanes gradient. (R)-1,1,1-trifluoro-3-{2-phenyl-4-[3-(trifluoromethoxy)benzyl]-3,4-dihydroquinoxalin-1(2H)-yl}propan-2-ol was isolated as a 10:3 (R:S) mixture of diastereomers. This mixture was purified with reverse phase C18 chromatography with a 50-100% MeCN/H2O gradient with 0.1% TFA modifier. Diastereomerically pure (R)-3-((R)-4-(3-trifluoromethoxy)-2-phenyl-3,4-dihydroquinoxalin-1(2H)-yl)-1,1,1-trifluoro-propan-2-ol was isolated. 1H NMR (400 MHz, CDCl3) δ 3.28 (dd, J=9.2, 2.8 Hz, 1H), 3.39 (dd, J=12.4, 8.0 Hz, 1H), 3.63 (dd, J=8.8, 2.8 Hz, 1H), 3.83 (d, J=12.4 Hz, 1H), 4.24 (d, J=8.8 Hz, 1H), 4.37 (d, J=8.8 Hz, 1H), 4.42 (m, 1H), 4.87 (s, 1H), 6.56 (d, J=6.4 Hz, 1H), 6.70 (m, 2H), 6.82 (m, 2H), 6.93 (d, J=6 Hz, 1H), 7.04 (d, J=6.4 Hz, 2H), 7.22 (m, 3H), 7.33 (m, 3H), MS m/z=497.28.

1. stirringthe reaction mixture was stirred at 25° C. for 12 hours
2. temperatureThe reaction was heated to 80° C. for 2 hours
3. temperaturewas cooled to 25° C.
4. stirringThe reaction mixture was stirred at 25° C. for 2 hours
5. temperaturewas heated to 50° C. for 10 hours
6. customThe reaction mixture was quenched with saturated ammonium chloride solution
7. extractionwas extracted into EtOAc
8. washThe organic phase was washed four times with water
9. dry with materialonce with brine, then was dried with MgSO4
10. filtrationfiltered
11. concentrationconcentrated
12. custompurified on a 40 g silica gel column with a 0-100% DCM/Hexanes gradient

ORD record

ord-0077bac9b50c4210b0b5e17d630437cc

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09126976B2