Dichloromethane → Methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(methylsulfonyl)-4-isothiazolecarboxylate

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Reaction Conditions

Reaction Steps

In a separate vessel, 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 18.5 g) was taken up in dimethylsulfoxide (185 mL, 10 volumes) and potassium carbonate (1.0 equiv, 10.8 g) was added. The toluene-4-sulfonic acid 4-bromo-2,6-difluoro-benzyl ester/dichloromethane solution from Example 6 was added to the 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl/potassium carbonate/dimethylsulfoxide slurry dropwise over 1 hour. The mixture was stirred at 25° C. for 16.5 hours. Dichloromethane (185 mL, 10 volumes) then water (185 mL, 10 volumes) were added and the layers were separated. The organic layer was dried over magnesium sulfate and filtered. The dichloromethane was removed under vacuum to leave an orange paste. The orange paste was diluted with 10 volumes of 1:1 EtOAc:Hexanes (v/v) and slurried at 25° C. for 16 hours. The mixture was filtered and the filter cake washed with 55-60 mL of 1:1 EtOAc:Hexanes (v/v) and dried to give 24.22 g of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (70% yield). 1H NMR: (DMSO-d6) δ 7.57 (m, 2H); 5.46 (s, 2H); 3.80 (s, 3H); 3.57 (s, 3H). MS (API-ES pos): 442/444 (M+H)+; 205/207 (1,5-difluoro-3-bromotropylium ion), base.

Provenance & Evidence