Lithium Hexamethyldisilazide → Gsk-5498A

Temperature

5 °C

A solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9) (4.59 g, 20.6 mmol) in THF (45 ml) was cooled to 5° C. under nitrogen. A solution of 1.0 M lithium bis(trimethylsilyl)amide in THF (20.6 ml, 20.6 mmol) was added dropwise maintaining the temperature below 10° C. After 10 minutes a solution of 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (5.29 g, 20.6 mmol, JRD fluorochemicals Ltd) in THF (9 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched using 1 M hydrochloric acid (50 ml). The reaction mixture was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried with magnesium sulphate, filtered and solvent removed in vacuo. The crude material was dissolved in DCM and applied to a 330 g silica cartridge. The cartridge was eluted with 0-100% ethyl acetate in cyclohexane over 45 min. The required fractions were combined and evaporated in vacuo, to give the title compound as a white solid (6.75 g). The white solid (6.75 g) was dissolved in ethyl acetate (70 ml) and heated to 50° C. Cyclohexane (280 ml) was then added dropwise over 20 min.

1. temperaturemaintaining the temperature below 10° C
2. customThe reaction was quenched
3. extractionThe reaction mixture was extracted with ethyl acetate (2×50 ml)
4. washThe combined organic extracts were washed with brine (50 ml)
5. dry with materialdried with magnesium sulphate
6. filtrationfiltered
7. customsolvent removed in vacuo
8. dissolutionThe crude material was dissolved in DCM
9. washThe cartridge was eluted with 0-100% ethyl acetate in cyclohexane over 45 min
10. customevaporated in vacuo

ORD record

ord-228e70687ce84be0b62d5703c0948001

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08399436B2