Lithium Hexamethyldisilazide → 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

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Reaction Conditions

Reaction Steps

N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous tetrahydrofuran (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (238 mL, 238 mmol) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in tetrahydrofuran (200 mL) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracted with further ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).

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