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Stage #1: tretazicar With potassium carbonate In methanol at 60℃;
Stage #2: With dihydroxyacetone In methanol at 60℃; for 0.25h; |
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A solution of 5-(aziridin-l-yl)-254-dinitrobenzamide ("CB 1954", 1.00 g, 3.97 mmol) in methanol ('AnalaR'-grade, 40 mL) was treated with excess powdered anhydrous K2CO3 (10.0 g, 72 mmol; aprox. 18 equiv.) and the mixture was heated to 6O0C with stirring. The suspension was stirred at 600C beneath a N2 blanket stream atmosphere. A solution of 1,3-dihydroxyacetone (1.50 g as DHA dimer, 8.33 mmol; 2.1 mol equiv) in methanol ('AαalaR'-grade, 40 mL), previously deaerated by flushing with N2 gas, was then added during 15 min to the reaction mixture with rapid stirring while maintaining the temperature at 60°C. A fast reaction is observed with a colour change from pale yellow-orange to brown. Thin-layer chromatography (TLC; Merck silica gel 60 GF254 on aluminium sheets, 9:1 v/v CH2Cl2 : MeOH) showed quantitative removal of the CB 1954 starting material (Rf 0.73) and formation of two polar products at Rf 0.53 and Rf 0.47. The two products showed identical TLC behaviour to authentic 5-(aziridin- 1 -yl)-2-hydroxylarnmo-4-nitrobenzamide and 5-(aziridin- 1 -yl)-4-hydroxylamino- 2-nitrobenzamide samples, respectively, prepared by published methods [Knox, RJ., Friedlos, F., Jarman, M., Roberts, JJ. Biochemical Pharmacology 37, 4661- 4669 (1988); Knox, RJ., Friedlos, F., Biggs, PJ., Flitter, W.D. Gaskell, M., Goddard, P., Davies, L., Jarman, M. Biochemical Pharmacology 46, 797-803 (1993)].The reaction mixture was filtered while hot and the insoluble material was washed with cold methanol (10 mL). The combined filtrate was cooled and rotary evaporated (3O0C, high-vacuum) to give a viscous yellow-brown oil (1.02 g, >100%). TLC examination confirmed that two major products were present. Minor spots (2 gas to prevent oxidation of the hydroxylamines to nitroso products and unwanted coloured by-products). The 2- hydroxylamine (Rf 0.53) and 4-hydroxylamine (Rf 0.47) reaction products were judged to be formed in ~40:60 ratio. Chromatographic separation of the isomers is hampered by their close elution properties using available solvent systems. However, flash chromatographic separation of a crude mixture sample (100 mg) (Merck silica gel, 60-200 mesh, 9:1 v/v CH2Cl2-MeOH) gave 5-(aziridin-l-yl)-2- hydroxylamino-4-nitrobenzamide (31 mg) and 5-(aziridin-l-yl)-4-hydroxylamino- 2-nitrobenzamide (49 mg) after solvent removal from fractions. Both products gave NMR spectra consistent with the reported properties for the isomeric hydroxylamines and TLC behaviour that was indistinguishable with the authentic compounds [Knox, RJ., Friedlos, F., Jarman, M., Roberts, JJ. Biochemical Pharmacology 37, 4661-4669 (1988)].Notes: (1) The preferred reaction solvent is methanol. 1,3-Dihydroxyacetone (DHA) dimer has limited solubility in many common solvents, including acetone and higher alcohols.(2) Reaction is almost instantaneous at 600C but is slower at lower temperatures. The use of higher temperature reaction systems may have an adverse effect on relative product yield.The product hydroxylamines show greater sensitivity to air oxidation in the presence of alkali, hence it is recommended that the K2CO3 reagent is removed from the reaction mixture as soon as possible. Chromatographic separation of the mixture containing the 2- and 4-hydroxylamine products requires minimisation of any exposure for dissolved material to O2 (air) during handling. |
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