2-(difluoromethoxy)benzenesulfonyl chloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of 80.3 g of crude 2-difluoromethoxyphenylsulfonyl chloride in 50 ml of methylene chloride. After the exothermic reaction has subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yield 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C. After the exothermic reaction the reaction mixture is refluxed for 2 hours The organic phase is washed with water dried over sodium sulfate evaporated to dryness Recrystallisation from methanol yield 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.1 g (0.11 mol) of triethylamine are added dropwise at room temperature, with stirring, to a solution of 24.3 g (0.1 mol) of 2-difluoromethoxy-benzenesulfonyl chloride and 11.7 g (0.1 mol) of imidocarbonic acid diethyl ester in 70 ml of acetone. The reaction proceeds slightly exothermically. The reaction mixture is stirred for some hours at room temperature, and the triethylamine hydrochloride is then filtered off. The mother liquor is concentrated by evaporation, and the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column. After the eluate has been evaporated, there remain 23 g of the above ester, which crystallise (72% of theory), m.p. 80°-81° C. the triethylamine hydrochloride is then filtered off The mother liquor is concentrated by evaporation the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column After the eluate has been evaporated crystallise (72% of theory), m.p. 80°-81° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared starting from commercially available 2-bromo-4-nitrophenol, which was reacted with 2-chloro-2,2-difluoroacetophenone (J. Hu et al., J. Org. Chem., 2006, 71, 9845) to yield 2-bromo-1-difluoromethoxy-4-nitro-benzene. Subsequent Buchwald-Hartwig coupling of 2-bromo-1-difluoromethoxy-4-nitro-benzene with tert.butyloxycarbonyl-piperazine by analogy to preparation example 3.1, reduction of the nitro group to the corresponding aniline by analogy to preparation example 3.2, subsequent coupling with commercially available 2-difluoromethoxybenzene-sulfonylchloride by analogy to preparation example 1.4, and final deprotection under acidic conditions by analogy to example 1 yielded the title compound. to preparation example 1.4

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of 80.3 g of crude 2-difluoromethoxyphenylsulfonyl chloride in 50 ml of methylene chloride. After the exothermic reaction had subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yielded 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C. After the exothermic reaction the reaction mixture is refluxed for 2 hours The organic phase is washed with water dried over sodium sulfate evaporated to dryness Recrystallisation from methanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.1 g (0.11 mol) of triethylamine are added dropwise at room temperature, with stirring, to a solution of 24.3 g (0.1 mol) of 2-difluoromethoxy-benzenesulfonyl chloride and 11.7 g (0.1 mol) of imidocarbonic acid diethyl ester in 70 ml of acetone. The reaction proceeds slightly exothermically. The reaction mixture is stirred for some hours at room temperature, and the triethylamine hydrochloride is then filtered off. The mother liquor is concentrated by evaporation, and the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column. After the eluate has been evaporated, there remain 23 g of the above ester, which crystallise (72% of theory), m.p. 80°-81° C. the triethylamine hydrochloride is then filtered off The mother liquor is concentrated by evaporation the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column After the eluate has been evaporated crystallise (72% of theory), m.p. 80°-81° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 11.1 g (0.11 mol) of triethylamine are added dropwise at room temperature, with stirring, to a solution of 24.3 g (0.1 mol) of 2-difluoromethoxy-benzenesulfonyl chloride and 11.7 g (0.1 mol) of imidocarbonic acid diethyl ester in 70 ml of acetone. The reaction proceeds slightly exothermically. The reaction mixture is stirred for some hours at room temperature, and the triethylamine hydrochloride is then filtered off. The mother liquor is concentrated by evaporation, and the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column. After the eluate has been evaporated, there remain 23 g of the above ester, which crystallise (72% of theory), m.p. 80°-81° C. the triethylamine hydrochloride is then filtered off The mother liquor is concentrated by evaporation the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column After the eluate has been evaporated crystallise (72% of theory), m.p. 80°-81° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of 80.3 g of crude 2-difluoromethoxyphenylsulfonyl chloride in 50 ml of methylene chloride. After the exothermic reaction has subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yield 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C. After the exothermic reaction the reaction mixture is refluxed for 2 hours The organic phase is washed with water dried over sodium sulfate evaporated to dryness Recrystallisation from methanol yield 40.5 g of 2-difluoromethoxyphenylsulfonamide with a melting point of 128°-130° C.