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Enantioselective Hydrogenation of dehydro-PZQ and derivatives
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20th April 2011 @ 07:33
Experiments on the oxidation of N-benzoyl-PZQ to the enamide by molten sulfur. Scale-up of Oxidation of N-benzoyl-PZQ by sulfur (MW59-1 to MW59-6)
See related experiments on rac-PZQ: Sulfur melt data smogasbord

Scheme MW59.png


Hazard and Risk Assessment:
HRAF MW57.pdf


Start time: 2:15 PM 19/04/2011

N-benzoyl-PZQ (2.50 g, 8.16 mmol, M.W. 306.4 g/mol) and sulfur (524 mg, 16.3 mmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 90 min.
- first heated for 45 min at 180°C -> lots of starting material left

Yield: 987 mg (3.24 mmol, 40%) orange solid [M.W. 304.3 g/mol]
- Recrystallized from toluene: no change in colour
- 2. column of the combined products of MW59-7 and MW59-8 (hexane:ethyl acetate:DCM, 10:5:1)

Yield: Yield: 1.08 g (3.55 mmol) pale yellow solid

Analytical data:
Rf (ethyl acetate) = 0.45.
m.p. = 168-170°C (recrystallized from toluene)
1H NMR (CDCl3, 200 MHz): δ = 2.94 (t, J= , 2H), 3.96 (t, J= , 2H), 4.54 (s, 2H), 6.67 (s, 1H), 7.20 (m, 4H), 7.47-7.61 (m, 5H). (Rotemers-> broad signals)
13C NMR (DMSO-d6, 500 MHz): δ = 28.1, 37.9, 45.9 (bs), 107.7, 120.0 (bs), 122.6, 127.0, 127.6 (bs), 128.1, 128.2 (2C), 128.4 (2C), 128.6 (bs, 2C), 131.1, 133.7, 162.6, 167.7. (Rotemers-> broad signals)
IR (neat): nu = 1664 cm-1, 1628, 1408, 1375, 1296, 1253, 758, 702, 613.
MS (ESI (+)) m/z (%): 631 (100, [M2+Na]+), 327 (56, [M+Na]+).
HRMS (ESI (+)) Calcd. for [C19H16N2O2+Na]+: 327.11040, found: 327.11034.

1H NMR MW59-7.pdf
IR MW59-7.pdf
1H NMR MW59-7 (500 MHz).pdf
13C NMR MW59-7 (500 MHz).pdf


Chiral HPLC: development of a method to distinguish N-benzoyl-PZQ enamide and the enantiomers of N-benzoyl-PZQ (enantioselective hydrogenation)
Column: Chiralcel OD-H,
Method: hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate, RT: N-benzoyl-PZQ enamide: 22.3 min, N-benzoyl-PZQ enantiomers: 24.1 min, 30.4 min.
-> no base line separation of N-benzoyl-PZQ enamide and one enantiomer of N-benzoyl-PZQ
HPLC MW58_MW59 (40_60_01).jpg
HPLC MW59-7.jpg


Method: hexane/iso-propanol/Et3N = 70/30/0.1, 0.7 ml/min flow rate, RT: N-benzoyl-PZQ enamide: 26.1 min, N-benzoyl-PZQ enantiomers: 29.8 min, 37.4 min.
-> base line separation
HPLC MW58_MW59 (30_70_01).jpg


Results:
The reaction had not gone to completion after 90 min, as there was still starting material left. Purification of the product caused some difficulties due to the presence of a sulfur impurity (yellow color of the product) which couldn't be removed completely by column chromatography or recrystallization from toluene (See: Comments)

Related experiment: Repetition: Oxidation of N-benzoyl-PZQ by sulfur (MW59-8)


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.
Linked Entries
Attached Files
1H NMR MW59-7.pdf
IR MW59-7.pdf
HPLC MW59-7.jpg
HPLC MW58_MW59 (40_60_01).jpg
HPLC MW58_MW59 (30_70_01).jpg
HPLC MW58_MW59 (40_60_01).jpg
1H NMR MW59-7 (500 MHz).pdf
13C NMR MW59-7 (500 MHz).pdf
13C NMR MW59-7 (200 MHz).pdf
1H NMR MW59-7 (500 MHz) JCAMP-DX.dx
13C NMR MW59-7 (500MHz) JCAMP-DX
13C NMR MW59-7 (200 MHz) JCAMP-DX.dx