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

Temperature

60 °C

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).

1. temperaturerefluxed for three hours
2. customThe volatiles were then removed by evaporation under reduced pressure
3. customevaporated
4. customThe crude yellow acid chloride thus obtained
5. customwas thoroughly dried under vacuum at room temperature
6. temperatureThe resulting almost clear solution was cooled to room temperature
7. customthe volatiles were removed by evaporation
8. additionThe residue was treated with tetrahydrofuran (100 mL), methanol (100 mL) and 2N NaOH (30 mL)
9. stirringAfter stirring at room temperature for two hours
10. customthe organic solvents were removed by evaporation
11. extractionextracted several times with dichloromethane
12. dissolutionA whitish solid present between the aqueous and the organic layer that could not be dissolved with dichloromethane
13. filtrationwas filtered off
14. customaffording 0.4 g of crude product
15. dry with materialThe combined organic extracts were dried over sodium sulfate
16. customevaporated
17. customgiving 4.2 g of crude product
18. customPurification of both the filtered solid
19. extractionthe organic extract by flash chromatography over silica gel (eluent: dichloromethane/methanol/33% NH4OH in 9:1:0.1 ratio)

ORD record

ord-5f90ce2cad6e4d669dedc188a7ecc341

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08114865B2