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

Yield:1235406-41-3 71%

Reaction Conditions:

Stage #1: N-[(2,4-dimethoxyphenyl)methyl]-1,2,4-thiadiazol-5-aminewith lithium bis(trimethylsilyl)azanide in tetrahydrofuran at -78 - 78; for 2.08333 h;Inert atmosphere;
Stage #2: 3-cyano-4-fluorobenzene-1-sulfonyl chloride in tetrahydrofuran at -78 - 20;

Steps:

1

Preparation 1N-(2,4-Dimethoxybenzyl)-1 ,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous THF (600 mL) and stirred under a nitrogen atmosphere at - 78°C. A 1 M solution of LiHMDS in THF (238 mL, 238 mmol) was added dropwise 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 TH F (200 mL) was added dropwise 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 overnight. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracting with further ethyl acetate. The combined organics were dried over MgSO₄, 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 %).¹HNMR (CDCIs): δ 3.60 (s, 3H), 3.79 (s, 3H), 5.32 (s, 2H), 6.22 (s, 1 H), 6.32-6.48 (m, 1 H), 7.05-7.09 (m, 1 H), 7.18-7.24 (m, 1 H), 7.70-7.73 (m, 1 H), 7.92-7.99 (m, 1 H), 8.22 (s, 1 H).

References:

WO2012/4714,2012,A2 Location in patent:Page/Page column 51