Ammonium Chloride → Diethyl{2-[2,3-difluoro-4-(5-fluoropyridin-2-yl)phenyl]-1,1-difluoro-2-hydroxyethyl}phosphonate

Temperature

-78 °C

A solution of ethyl bromodifluoromethylphosphonate (3.2 g, 12.1 mmol) in tetrahydrofuran (20 mL) was added dropwise to a solution of isopropylmagnesium chloride (2 M in tetrahydrofuran) (6.1 mL, 12.1 mmol) in tetrahydrofuran (20 mL) at −78° C. After stirring at −78° C. for 5 min, a solution of 2,3-difluoro-4-(5-fluoropyridin-2-yl)benzaldehyde (1.92 g, 8.1 mmol) in tetrahydrofuran (20 mL) was added dropwise. After stirring for a further 5 min at −78° C. then a further 1 h between −78 and 0 then a further 1 h between 0 and ambient temperature. The reaction mixture was poured into saturated ammonium chloride and extracted with methylene chloride. Combined extracts were washed with saturated aqueous sodium bicarbonate, dried (sodium sulfate) and concentrated in vacuo to afford a slightly yellow oil. Chromatography over silica eluting with 0-40% acetone/methylene chloride afforded diethyl {2-[2,3-difluoro-4-(5-fluoropyridin-2-yl)phenyl]-1,1-difluoro-2-hydroxyethyl}phosphonate as an off-white solid.

1. stirringAfter stirring for a further 5 min at −78° C.
2. customa further 1 h
3. customa further 1 h between 0 and ambient temperature
4. extractionextracted with methylene chloride
5. washCombined extracts were washed with saturated aqueous sodium bicarbonate
6. dry with materialdried (sodium sulfate)
7. concentrationconcentrated in vacuo
8. customto afford a slightly yellow oil

ORD record

ord-0c6c457868c742259cdaa7875a2be4f2

Source dataset

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08193228B2