Lithium Hexamethyldisilazide → 2,6-Difluoro-N-(1-{[4-[(phenylmethyl)oxy]-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide

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Reaction Steps

To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.05 g, 4.70 mmol) in anhydrous THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (4.7 ml, 4.70 mmol) at ambient temperature under nitrogen. The solution was stirred at ambient temperature for 20 min. To the solution was added a solution of 4-(bromomethyl)-3-(trifluoromethyl)phenyl phenylmethyl ether (1.47 g, 4.26 mmol) in THF (15 ml). The mixture was stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (120 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The phases were separated and the aqueous phase washed with ethyl acetate (30 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a pale yellow oil (˜2.5 g). The residue was loaded in dichloromethane and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.61 g); LCMS: (System 4) MH+=488, tRET=3.37 min.

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