反应详情

温度

40 °C

6-{[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, N-(2,2-dimethoxyethyl)-N-methylsulfamide (2 eq, Example 1, Step 1) and DMAP (5 eq) were dissolved in DCM (0.06M) and EDC (3 eq) was added. The mixture was warmed to 40° C. Within 5 min the clear yellow solution turned dark brown. The mixture was stirred overnight. After dilution with DCM the solution was extracted with 1N HCl, sat. aq. NaHCO3 and brine. After drying the organic phase over Na2SO4 the solution was discoloured with activated charcoal. All volatiles were evaporated in vacuo leaving tert-butyl {2-[({13-cyclohexyl-10-[({[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-amino)carbonyl]-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-6-yl}methyl)(methyl)amino]ethyl}methylcarbamate as a glassy brownish solid (MS (ES+) m/z 755 (m+H)+). The material was dissolved in DCM (0.03M) and water was added. To the biphasic system TFA was added and then the vigorously stirred mixture was warmed to 40° C. After 2 h the acetal was completely cleaved, while some N-Boc-protected material was still around. More TFA was added until a monophasic system was obtained. Heating was continued for 3 h. Then all volatiles were evaporated in vacuo and the residual material was coevaporated three times with toluene. The residual sticky material was digested with Et2O leaving a dark red powder. This material was used without further purification in the next reaction. (ES+) m/z 609 (M+H)+.

1. extractionAfter dilution with DCM the solution was extracted with 1N HCl, sat. aq. NaHCO3 and brine
2. dry with materialAfter drying the organic phase over Na2SO4 the solution
3. customAll volatiles were evaporated in vacuo