Phosphorus oxychloride → HCID 68155996, compound

Participants

Reaction Conditions

Reaction Steps

Add phosphoryl chloride (5 equiv; 4.36 mL, 7.19 g, 46.89 mmoles) to 2,7-dichloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (1 equiv; 2.505 g, 9.38 mmoles) in chloroform (80 mL) and heat and stir at 50° C. overnight. Decant the reaction solution and evaporate in vacuo to an oil. Dissolve the oil in DCM, wash with saturated aqueous sodium hydrogen carbonate solution. Dry the DCM solution over Na2SO4, filter and concentrate to dryness to give 2,7,11-trichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as a cream colored solid. In parallel desalt methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate hydrochloride (0.837 g, 3.54 mmoles) by dissolving in methanol, add the methanolic solution to an SCX-2 column (10 g) wash with methanol and then elute with 2.5M ammonia in methanol solution, evaporate the methanol ammonia fraction to give methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate (0.665 g) as an oil. Mix this oil with 2,7,11-trichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.505 g 1.77 mmoles), potassium carbonate (0.733 g, 5.31 mmoles) and acetonitrile (20 mL) and heat at reflux overnight. Cool the reaction mixture to room temperature and filter, washing the sinter with EtOAc, then evaporate the filtrate in vacuo to a solid. Chromatograph on silica eluting with methanol/DCM (gradient elution 2:98 to 8:92). Evaporate the fractions containing product to give methyl 3-[4-(2,7-dichloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (0.69 g). MS (m/z): 449.13/451.07 (M+1).

Provenance & Evidence