Phosphorus oxychloride → HCID 68155996, compound

HRID 1877801Notes

Reaction equation

HRID 1877801 reaction equation
P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[C:9]2[N:15]([CH:16]=1)[CH2:14][C:13]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=1[NH:11][C:10]2=O>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]2[N:15]([CH:16]=1)[CH2:14][C:13]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:12]=1[N:11]=[C:10]2[Cl:3]

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 68156100HCID 68156100, compound

Product 1

HCID 68155996HCID 68155996, compound

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Conditions

Temperature
50 °C

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).

Workup

  1. temperatureheat
  2. customDecant the reaction solution
  3. customevaporate in vacuo to an oil
  4. dissolutionDissolve the oil in DCM
  5. washwash with saturated aqueous sodium hydrogen carbonate solution
  6. dry with materialDry the DCM solution over Na2SO4
  7. filtrationfilter
  8. concentrationconcentrate to dryness

Sources & evidence

ORD record
ord-b372b21e76e24825b452c8c65bce2c03
Source dataset
uspto-grants-2012_11
Patent number
US08314092B2

Reaction notes

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