4-Phenylpyridine-1-oxide → N-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide

温度

0 °C

At 0° C. to a solution of (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291, 130 mg, 0.19 mmol) and 4-phenyl pyridine N-oxide (26 mg, 0.15 mmol) in acetonitrile (5 mL) was added NaOCl solution (206 μL, chlorine wt % 10-3%, 0.58 mmol). The reaction mixture was stirred at 0° C. for 10 min, then at rt for 1 h. The solvents were removed under reduced pressure and the residue was diluted with EtOAc (30 mL), washed with saturated Na2SO3 (30 mL), dried over MgSO4, filtered and concentrated. The resulting residue was right away purified by ISCO chromatography (40 g column, flow rate 25 mL/min) using hexanes/EtOAc (0-10% over 30 min) to give N—((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide as a diastereomer mixture at a retention time of 26 min (97 mg, 74% yield). The diastereomer mixture was separated by Chiral preparative HPLC chiralpak AD 20μ column, 5×50 cm, eluting with 5% IPA/Heptane with flow rate 50 mL/min.

1. waitat rt for 1 h
2. customThe solvents were removed under reduced pressure
3. additionthe residue was diluted with EtOAc (30 mL)
4. washwashed with saturated Na2SO3 (30 mL)
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated
8. customThe resulting residue was right away purified by ISCO chromatography (40 g column, flow rate 25 mL/min)
9. customhexanes/EtOAc (0-10% over 30 min)

ORDレコード

ord-67715dc56fc5493f970b6f8ac4158070

出典データセット

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08642576B2