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Preparation of N-benzoyl-PZQ as starting material for an oxidative dehydrogenation
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Hazard and Risk Assessment:
Start time: 6:30 PM 14/04/2011
End time: 9:15 AM 15/04/2011
To an ice-cooled solution of rac-PZQamine (3.23 g, 16.0 mmol, M.W. = 202.3 g/mol) and triethylamine (2.43g, 24.0 mmol,3.35 mL, 1.5 eq., M.W. 101.2, d=0.726 g/mL) in DCM (60 mL) was added benzoyl chloride (3.38 g, 24.0 mmol, 2.80 mL, 1.5 eq., M.W. = 140.6 g/mol, d=1.21 g/mL) at 0°C and stirred at room temperature for 15 h.
The reaction was quenched with water and stirred for a further 30 min. The mixture was neutralized with sodium hydrogen carbonate solution and the layers were separated. The organic layer was washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. After evaporation of the solvent a yellow solid remained.
- crude yield: 6.42 g (21.0 mmol, 131%) [M.W. 306.4 g/mol]
TLC (ethyl acetate, stain: ninhydrin, KMnO4)
- recrystallized from toluene (70 mL), filtered, dried under vac.: yield: 4.69 g (15.3 mmol, 96%) colourless solid, still toluene impurities -> high vac
Yield: 4.10 g (13.4 mmol, 84%)
- filtrate evaporated, remaining orange solid recrystallized a second time from toluene (20 mL)
Yield: 520 mg (1.70 mmol, 11%)
Result:
Over-all yield: 4.62 g (15.1 mmol, 94%)
Analytical data:
Rf (ethyl acetate, 100%) = 0.45.
m.p. 157-158.5°C (recrystallized from toluene) (lit. 158-160°C (acetone) [1])
1H NMR (CDCl3, 200 MHz): δ = 2.74-3.10 (m, 4H), 4.02-4.10 (m, 1H), 4.40 (br m, 1H), 4.80-5.00 (m, 2H), 5.19 (br m, 1 H), 7.21 (m, 4H), 7.48 (m, 5H).
13C NMR (CDCl3, 50.3 MHz): δ = 28.8, 39.0, 45.8 (br), 51.5 (br), 54.9 (br), 125.4 (br), 127.0, 127.4 (br, 2 C), 127.5, 128.8 (2 C), 129.5, 130.7, 132.5 (br), 134.4 (br), 135.0, 164.4, 170.3.
IR (neat): nu = 1786 cm-1, 1611, 1420, 1289, 1247, 1212, 1036, 760, 718, 698, 656.
MS (ESI (+)) m/z (%): 635 (100, [M2+Na]+), 329 (28, [M+Na]+).
HRMS (ESI (+)) Calcd. for [C19H18N2O2+Na]+: 329.12605, found: 329.12619.
HPLC: Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate, RT: 24.8 min, 31.5 min.Data: HPLC MW58-1 (40_60_01).jpg
HPLC: Chiralcel OD-H, hexane/iso-propanol/Et3N = 70/30/0.1, 0.7 ml/min flow rate, RT: 30.2 min, 38.3 min. Data: HPLC MW58 (30_70_01).jpg
Starting material for:
Oxidation of N-benzoyl-PZQ by sulfur (MW59-1 to MW59-6)
Scale-up: Oxidation of N-benzoyl-PZQ by sulfur (MW59-7)
References:
[1] Spectral and Chemical Properties of Pyrazino-[2,1-a]-isoquinolin-4-one Derivatives, K. Kiec'-Kononowicz, Arch. Pharm. 1989, 322,795-799. DOI: 10.1002/ardp.19893221104.
>
Hazard and Risk Assessment:
Start time: 6:30 PM 14/04/2011
End time: 9:15 AM 15/04/2011
To an ice-cooled solution of rac-PZQamine (3.23 g, 16.0 mmol, M.W. = 202.3 g/mol) and triethylamine (2.43g, 24.0 mmol,3.35 mL, 1.5 eq., M.W. 101.2, d=0.726 g/mL) in DCM (60 mL) was added benzoyl chloride (3.38 g, 24.0 mmol, 2.80 mL, 1.5 eq., M.W. = 140.6 g/mol, d=1.21 g/mL) at 0°C and stirred at room temperature for 15 h.
The reaction was quenched with water and stirred for a further 30 min. The mixture was neutralized with sodium hydrogen carbonate solution and the layers were separated. The organic layer was washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. After evaporation of the solvent a yellow solid remained.
- crude yield: 6.42 g (21.0 mmol, 131%) [M.W. 306.4 g/mol]
TLC (ethyl acetate, stain: ninhydrin, KMnO4)
- recrystallized from toluene (70 mL), filtered, dried under vac.: yield: 4.69 g (15.3 mmol, 96%) colourless solid, still toluene impurities -> high vac
Yield: 4.10 g (13.4 mmol, 84%)
- filtrate evaporated, remaining orange solid recrystallized a second time from toluene (20 mL)
Yield: 520 mg (1.70 mmol, 11%)
Result:
Over-all yield: 4.62 g (15.1 mmol, 94%)
Analytical data:
Rf (ethyl acetate, 100%) = 0.45.
m.p. 157-158.5°C (recrystallized from toluene) (lit. 158-160°C (acetone) [1])
1H NMR (CDCl3, 200 MHz): δ = 2.74-3.10 (m, 4H), 4.02-4.10 (m, 1H), 4.40 (br m, 1H), 4.80-5.00 (m, 2H), 5.19 (br m, 1 H), 7.21 (m, 4H), 7.48 (m, 5H).
13C NMR (CDCl3, 50.3 MHz): δ = 28.8, 39.0, 45.8 (br), 51.5 (br), 54.9 (br), 125.4 (br), 127.0, 127.4 (br, 2 C), 127.5, 128.8 (2 C), 129.5, 130.7, 132.5 (br), 134.4 (br), 135.0, 164.4, 170.3.
IR (neat): nu = 1786 cm-1, 1611, 1420, 1289, 1247, 1212, 1036, 760, 718, 698, 656.
MS (ESI (+)) m/z (%): 635 (100, [M2+Na]+), 329 (28, [M+Na]+).
HRMS (ESI (+)) Calcd. for [C19H18N2O2+Na]+: 329.12605, found: 329.12619.
HPLC: Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate, RT: 24.8 min, 31.5 min.Data: HPLC MW58-1 (40_60_01).jpg
HPLC: Chiralcel OD-H, hexane/iso-propanol/Et3N = 70/30/0.1, 0.7 ml/min flow rate, RT: 30.2 min, 38.3 min. Data: HPLC MW58 (30_70_01).jpg
Starting material for:
Oxidation of N-benzoyl-PZQ by sulfur (MW59-1 to MW59-6)
Scale-up: Oxidation of N-benzoyl-PZQ by sulfur (MW59-7)
References:
[1] Spectral and Chemical Properties of Pyrazino-[2,1-a]-isoquinolin-4-one Derivatives, K. Kiec'-Kononowicz, Arch. Pharm. 1989, 322,795-799. DOI: 10.1002/ardp.19893221104.