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14th April 2011 @ 09:12
Preparation of N-benzoyl-PZQ as starting material for an oxidative dehydrogenation

Scheme MW58.png


Hazard and Risk Assessment:
HRAF MW57.pdf


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)
TLC MW58-1a.jpg


- 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

1H NMR MW58-1.pdf
13C NMR MW58-1 (lb_2).pdf
13C NMR MW58-1 (lb=6).pdf
IR MW58-1.pdf


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.
    Attached Files
    Scheme MW58.png
    1H MW58-1.dx
    13C NMR MW58-1 (lb_2).pdf
    1H NMR MW58-1.pdf
    TLC MW58-1a.jpg
    13C NMR MW58-1 (lb=6).pdf
    13C MW58-1.dx
    1H NMR MW58-1.pdf
    IR MW58-1.pdf
    HPLC MW58-1 (40_60_01).jpg
    HPLC MW58 (30_70_01).jpg