methyl 2,2-dimethyl-3-piperazin-1-ylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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). add the methanolic solution to an SCX-2 column (10 g) wash with methanol elute with 2.5M ammonia in methanol solution evaporate the methanol ammonia fraction

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 568 (1.137 g, 3.79 mmol) and TFA (15 ml) in DCM (30 ml) was stirred at rt for 2.5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 1 h, and the pH was adjusted to around 9-10 with 1N NaOH. The alkaline solution was extracted with DCM. The extract was dried over anhydrous magnesium sulfate, filtered, concentrated and dried under high vacuum to afford the desired product 569 (667 mg, 3.33 mmol, 88% yield) as a pale-yellow viscous liquid. The crude material was used in the next step without any further purification. MS (z): 201.1 (M+H). The reaction mixture was concentrated (azeotropes with DCM) diluted with water The alkaline solution was extracted with DCM The extract was dried over anhydrous magnesium sulfate filtered concentrated dried under high vacuum