Thionyl Chloride → N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide

Participants

Reaction Conditions

Reaction Steps

4-(4-Methyl-piperazin-1-yl)-2-nitro-benzoic acid (5.54 g, 18.37 mmol) in dry tetrahydrofuran (100 mL) was treated with 0.070 mL of N,N-dimethylformamide followed by neat thionyl chloride (5.5 mL, 76.43 mmol) and refluxed for three hours. The volatiles were then removed by evaporation under reduced pressure and the solid was repeatedly taken up with anhydrous toluene (100 mL×3) and evaporated. The crude yellow acid chloride thus obtained was thoroughly dried under vacuum at room temperature then suspended in dry tetrahydrofuran (100 mL) and treated with a suspension of 5-benzenesulfonyl-indazol-3-ylamine (2.11 g, 7.71 mmol) and N,N-diisopropylethylamine (6.3 mL, 36.74 mmol). The reaction mixture was stirred at 60° C. (oil bath temperature) for 22 hours. The resulting almost clear solution was cooled to room temperature and the volatiles were removed by evaporation. The residue was treated with tetrahydrofuran (100 mL), methanol (100 mL) and 2N NaOH (30 mL). After stirring at room temperature for two hours, the organic solvents were removed by evaporation. The aqueous phase was adjusted to pH 7.5 and extracted several times with dichloromethane. A whitish solid present between the aqueous and the organic layer that could not be dissolved with dichloromethane was filtered off affording 0.4 g of crude product. The combined organic extracts were dried over sodium sulfate and evaporated giving 4.2 g of crude product. Purification of both the filtered solid and the organic extract by flash chromatography over silica gel (eluent: dichloromethane/methanol/33% NH4OH in 9:1:0.1 ratio) afforded 0.9 g of recovered 5-benzenesulfonyl-indazol-3-amine and 1.71 g of title compound as a yellow solid (43% yield).

Provenance & Evidence