Publication Date: 2014-May-23
The IP.com Prior Art Database
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Compound 1 - N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide
N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide is prepared in three synthetic steps. The nosyl protection of benzyl amine followed by Michael addition on the vinyl ketone yields to the corresponding o-nitrophenylsulphonyl ketone after precipitation in isopropanol. The bromination of the ketone is performed with bromine in methanol which leads to a 4:1 mixture of regioisomers in favoured to the desired one. The latter is easily obtained by precipitation in methanol/water (7:3) and eventually followed by recrystallisation in methanol.
To a solution of BENZYLAMINE (150g, 153 ml, 1400 mmol) in Ethyl acetate (1500 ml) was added triethylamine (195 ml, 1400 mmol). So, the resulting solution was cooled to 5ºC (external temperature) and 2-nitrobenzene-1-sulfonyl chloride (310 g, 1400 mmol) was added keeping the internal temperature below 15ºC. The mixture was stirred for 1.5h at room temperature. HPLC showed complete conversion. The mixture was diluted with water (750 ml) and the resulting biphasic system was stirred for 10 minutes, separated. The aqueous layer was back extracted with Ethyl acetate (450 ml).The combined organic layers were washed with 0,6 N HCl
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(750 mL). The organic layer was concentrated to 5 vol by distillation under reduced pressure (jacket temperature:45ºC, 150mBar). The resulting solution was diluted with Ethyl acetate (750 ml).
To the resulting solution at 25ºC was added POTASSIUM TERT-BUTOXIDE (7,85 g, 70,0 mmol,) followed by METHYL VINYL KETONE (139 ml, 1680 mmol) addition over 30 minutes. The suspension was stirred for 1,5h at 25ºC and HPLC was performed to check conversion. No product observed. Fresh potassium tert-butoxide (6g) was added to the suspension and exothermic event was observed and the reaction mixture became slightly brown.The resulting mixture was stirred during week end at 20ºC (usual reaction 2h). The turbid solution was quenched with brine (750 ml). The biphasic system was stirred for 10 minutes then separated. The aqueous was back extracted with Ethyl acetate (300 ml). The combined organic layers were washed with 0,6 N HCl (750 ml, 5vol). Note:Slow separation. The organic layer was concentrated to 3 vol by distillation under reduced pressure (jacket temp:45ºC, Presuure:150mBar). The brown solution was then diluted with IPA (1500 ml) and concentrated to 5 vol by distillation under reduced pressure (jacket temperature 45°C). The resulting slurry was then diluted with IPA (450 ml) and cooled down to 20°C. The slurry was stirred for 4h at 20°C, filtered. The off white solid was washed with IPA (2x150mL, 2x1vol), dried in a vacuum oven at 40°C overnight (LOD: 0.15% the solid melt at 120ºC). Filtration on gouch (porosity 4, diameter:12.5cm, width:5.5cm.
N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide as sugar like solid (432.7g) was obtained.
To a suspensio...