Ethyl chloroformate → 2-(4-Bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine

Temperature

0 °C

At 0° C. to a solution of 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoic acid (1.59 g, 2.64 mmol) in acetone (30 mL) was added TEA (442 μL, 3.17 mmol) followed by ethyl chloroformate (303 μL, 3.17 mmol). The reaction mixture was stirred at 0° C. for 45 min and NaN3 (343 mg, 5.28 mmol) was added. The reaction was stirred at 0° C. for 1 h, quenched by the addition of water and the aqueous layer was extracted with toluene (3×30 mL). The combined organic layers were washed with sat. NaCl, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was diluted with toluene (10 mL) and heated at 90° C. for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in t-BuOH/THF (1:1, 20 mL) and treated with t-BuOK/t-BuOH (1 N, 13.2 mL, 13.2 mmol). The reaction mixture was stirred at rt overnight, then heated at 85° C. for 3 h. The reaction mixture was quenched by the addition of water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. NaCl, dried over magnesium sulfate, filtered and concentrated. The residue was purified by ISCO (40 g siligel column, 0-40% EtOAc/hexane over 40 min to yield 2-(4-bromophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine as a colorless oil (1.2 g, 82% yield). LCMS: RT=1.82 min [M+H] 556.8 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (1H, d, J=6.15 Hz), 7.48-7.53 (1H, m), 7.30 (1H, d, J=7.91 Hz), 7.15 (1H, t, J=9.23 Hz), 6.96-7.00 (2H, m), 6.89 (1H, d, J=8.79 Hz), 6.61 (2H, d, J=7.91 Hz), 5.89 (1H, t, J=53 Hz), 3.49 (1H, d, J=13.6 Hz), 3.43 (1H, d, J=13.6 Hz), 1.50-1.65 (2H, m).

1. stirringThe reaction was stirred at 0° C. for 1 h
2. customquenched by the addition of water
3. extractionthe aqueous layer was extracted with toluene (3×30 mL)
4. washThe combined organic layers were washed with sat. NaCl
5. dry with materialdried over magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. additionThe resulting residue was diluted with toluene (10 mL)
9. temperatureheated at 90° C. for 6 h
10. concentrationThe reaction mixture was concentrated under reduced pressure
11. dissolutionthe residue was dissolved in t-BuOH/THF (1:1, 20 mL)
12. stirringThe reaction mixture was stirred at rt overnight
13. temperatureheated at 85° C. for 3 h
14. customThe reaction mixture was quenched by the addition of water
15. extractionthe aqueous layer was extracted with EtOAc
16. washThe combined organic layers were washed with sat. NaCl
17. dry with materialdried over magnesium sulfate
18. filtrationfiltered
19. concentrationconcentrated
20. customThe residue was purified by ISCO (40 g siligel column, 0-40% EtOAc/hexane over 40 min

ORD record

ord-87a27d871b744469bd899ae5b8ef8923

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08642576B2