Diisopropylamine → (S)-5,5,5-trifluoro-4-hydroxy-2,2-bis(3-(trifluoromethoxy)phenyl)pentanenitrile

To a solution of diisopropyl amine (0.305 mL, 2.16 mmol) in THF (6 mL) at −78° C. was added dropwise a 1.6 M solution of n-BuLi in hexane (1.35 mL, 2.16 mmol) and the mixture was stirred for 5 min. To this mixture was added a solution of 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (600 mg, 1.7 mmol), prepared as described in Example 10 (Procedure 13 and 14). The reaction mixture was stirred at −78° C. for 1 h and then (S)-2-(trifluoromethyl)oxirane (2.8 g, 25.0 mmol, 70% ee, purchased from TCI America) was added dropwise to the mixture. The cooling bath was removed and the reaction mixture was stirred at rt for 1 h. Additional (S)-2-(trifluoromethyl)oxirane (0.12 g, 1.1 mmol, 70% ee, purchased from TCI America) was added and the reaction mixture was stirred for an additional 1 h then poured into H2O and extracted with EtOAc (50 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (RT=23.65 min, YMC Sunfire 5μ column, 30×100 mm eluting with 20-100% MeOH/H2O over 25 minutes containing 0.1% TFA; 30 mL/min, monitoring at 220 nm) to give (S)-5,5,5-trifluoro-4-hydroxy-2,2-bis(3-(trifluoromethoxy)phenyl)pentanenitrile (280 mg, 36% yield, 70% ee) as a clear colorless oil. LCMS: RT=3.898 min [M+H] 474.0 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 10 mM NH4OAc; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1 H(CDCl3) ppm 2.55-2.64 (m, 1 H) 2.66-2.78 (m, 2 H) 3.87-3.95 (m, 1 H) 7.10-7.21 (m, 4 H) 7.23-7.27 (m, 1 H) 7.30-7.42 (m, 3 H).

1. customprepared
2. stirringThe reaction mixture was stirred at −78° C. for 1 h
3. customThe cooling bath was removed
4. stirringthe reaction mixture was stirred at rt for 1 h
5. stirringthe reaction mixture was stirred for an additional 1 h
6. extractionextracted with EtOAc (50 mL)
7. dry with materialThe combined organic portions were dried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. customto yield a residue
11. customThe residue was purified by preparative HPLC (RT=23.65 min, YMC Sunfire 5μ column, 30×100 mm eluting with 20-100% MeOH/H2O over 25 minutes containing 0.1% TFA; 30 mL/min, monitoring at 220 nm)

ORD record

ord-bae2a4ef5bf642bc93c8a9f12440f6bc

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09102599B2