Lithium Hydroxide → HCID 59606534, compound

Temperature

60 °C

A mixture of ethyl 4-fluoro-3-nitrobenzoate (Chontech 01072; 500 mg; 2.35 mmol; 1 eq.), 3,3-difluoropiperidine hydrochloride (Aldrich 665517; 554.47 mg; 3.52 mmol; 1.5 eq.) and triethylamine (712.07 mg; 7.04 mmol; 3 eq.) in DMF (3 mL) was stirred at 60° C. for 4 hours. The reaction mixture was then partitioned between ethyl acetate and aq. NH4Cl. The organic layer was washed three times with aq. NH4Cl then brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) then water (15 mL) were added. The reaction mixture was stirred at room temperature for 4 hours and the THF was evaporated under vacuum. The resulting solution was washed with Et2O, acidified with acetic acid and extracted twice with Et2O. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil which was crystallized from water. Filtration and drying under high vacuum afforded the title compound (630 mg, 94%) as a yellow solid.

1. customThe reaction mixture was then partitioned between ethyl acetate and aq. NH4Cl
2. washThe organic layer was washed three times with aq. NH4Cl
3. dry with materialbrine, dried over magnesium sulfate
4. concentrationconcentrated in vacuo
5. customto give a yellow oil
6. stirringThe reaction mixture was stirred at room temperature for 4 hours
7. customthe THF was evaporated under vacuum
8. washThe resulting solution was washed with Et2O
9. extractionextracted twice with Et2O
10. dry with materialThe combined organic layer was dried over magnesium sulfate
11. concentrationconcentrated in vacuo
12. customto give a yellow oil which
13. customwas crystallized from water
14. filtrationFiltration
15. customdrying under high vacuum

ORD record

ord-0c1c8bb9befc41cea6c7e724b5d12c2c

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08889668B2