2,3,4-Trifluorobenzoic acid → 2-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-benzoic acid

To a stirred solution of 2,3,4-trifluorobenzoic acid (25.0 g, 142 mmol) in THF (250 mL), was added lithium bis(trimethylsilyl)amide (1M in THF, 156 mL, 156 mmol) at −78° C. under nitrogen atmosphere and the solution stirred for 45 min. To this was added a premixed solution of cis-2,6-dimethylmorpholine (17.4 mL, 142 mmol) and lithium bis(trimethylsilyl)amide (1M in THF, 156 mL, 156 mmol) (which was stirred for 45 minutes at −78° C., before the addition was made) and stirring continued for 1 h at −78° C. It was brought to room temperature and stirring continued for additional 12 hours. Solvents were evaporated and the residue dissolved in ethyl acetate, which was washed with 1N HCl, water and brine. The organic layer was dried and concentrated to give the title compound as semi-solid. Yield: 27.5 g, (72%).

1. stirringwas stirred for 45 minutes at −78° C., before the addition
2. stirringstirring
3. waitcontinued for 1 h at −78° C
4. customwas brought to room temperature
5. stirringstirring
6. waitcontinued for additional 12 hours
7. customSolvents were evaporated
8. dissolutionthe residue dissolved in ethyl acetate
9. washwhich was washed with 1N HCl, water and brine
10. customThe organic layer was dried
11. concentrationconcentrated

ORD record

ord-93723c0b72014315aaa9d2b18a5c726d

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040528B2