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

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Reaction Steps

To a solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(1.31 g, 5.87 mmol) in anhydrous THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (6 ml, 6 mmol) at ambient temperature under nitrogen. The yellow solution was stirred for 20 min. To the solution was added a solution of 4-(bromomethyl)-3-methylphenyl phenylmethyl ether (1.72 g, 5.91 mmol) in THF (13 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 yellow oil (3.10 g). The residue was loaded in DCM and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and the solvent evaporated in vacuo to give the title compound as a yellow gum (1.9 g); LCMS: (System 4) MH+=434, tRET=3.14 min.

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