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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.
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Attached Files
20th April 2011 @ 07:25
Synthesis of PZQ enamide by oxidation of PZQ with molten sulfur. Repetition of Oxidation of PZQ with sulfur (MW60-4)

Scheme MW60.png


Hazard and Risk Assessment:
HRAF MW57.pdf


Optimization of the reaction time:
Start time: 1:30 PM 20/04/2011

rac-benzoyl-PZQ (2.00 g, 6.41 mmol, M.W. 312 g/mol) and sulfur (412 mg, 12.8 mmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 2 h under argon atmosphere.
- dark brown solid after mixture cooled down, red-brown solution in ethyl acetate
Work-up:
- dissolved in ethyl acetate and evaporated with silica gel
- column chromatography (hexane:ethyl acetate, 1:1)
- still starting material left -> higher reaction temperature ?

Yield: 861 mg (2.77 mmol, 43%) yellow-orange solid -> product still contains sulfur
[M.W. 310.4 g/mol]

- recrystallization from toluene: orange solid - no change in colour
- 2. column of the combined products of MW60-4 and MW60-5 (hexane:ethyl acetate:DCM, 10:5:1)

Yield: 1.25 g pale yellow solid

Analytical data: see Characterization of PZQ-enamide
m.p. = 142-143°C (after recrystallization from toluene).
1H NMR (CDCl3, 200 MHz): δ = 1.26-1.82 (m, 10H), 2.59-2.70 (m, 1H), 2.92 (t, J=5 Hz, 2H), 3.91 (t, J=6 Hz, 2H), 4.43 (s, 2H), 6.76 (s, 1H), 7.22-7.53 (m, 4H).
Data: 1H NMR MW60-5.pdf compare with H1NMR-enamide
IR (neat): nu = 2923 cm-1, 2852, 1663, 1634, 1403, 1297, 1278, 1250, 977, 750.
Data: IR MW60-5.pdf



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
19th April 2011 @ 01:57
Synthesis of PZQ enamide by oxidation of PZQ with molten sulfur. See related experiments on rac-PZQ: Sulfur melt data smogasbord

Scheme MW60.png


Hazard and Risk Assessment:
HRAF MW57.pdf


Optimization of the reaction time:
Start time: 9:50 AM 19/04/2011

MW60-1:
rac-benzoyl-PZQ (40 mg, 128 µmol, M.W. 312 g/mol) and sulfur (7.9 mg, 256 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 10 min.
- yellow coloured solution in ethyl acetate

MW60-2:
rac-benzoyl-PZQ (40 mg, 128 µmol, M.W. 312 g/mol) and sulfur (7.9 mg, 256 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 20 min.
- orange coloured solution in ethyl acetate

MW60-3:
rac-benzoyl-PZQ (40 mg, 128 µmol, M.W. 312 g/mol) and sulfur (7.9 mg, 256 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 40 min.
- dark red coloured solution in ethyl acetate

TLC (ethyl acetate, stain: Ceric ammonium molybdate, KMnO4)
TLC MW60.jpg


-> best result for a reaction time between 20 and 40 min: 30 min - good conversion , less starting material


Scale-up:
Start time: 1:15 PM 19/04/2011

MW60-4:
rac-benzoyl-PZQ (2.00 g, 6.41 mmol, M.W. 312 g/mol) and sulfur (412 mg, 12.8 mmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 45 min under argon atmosphere.
- yellow solid after mixture cooled down, orange solution in ethyl acetate
Work-up:
- dissolved in ethyl acetate and evaporated with silica gel
- column chromatography (hexane:ethyl acetate, 3:1)
Rf = 0.18

Yield: 600 mg (1.94 mmol, 30%) [M.W. 310.4 g/mol]
Reisolated PZQ: 1.22 g (61%)

1H NMR MW60-1-1.pdf
1H NMR MW60-1-2.pdf


-> Reaction wasn't completed after 45 min at 180°C

see Repetition: Oxidation of PZQ with sulfur (MW60-5)

Analytical data: see Characterization of PZQ-enamide

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
18th April 2011 @ 05:51
Experiments on the oxidation of N-benzoyl-PZQ to the enamide by molten sulfur.
See related experiments on rac-PZQ: Sulfur melt data smogasbord

Scheme MW59.png


Hazard and Risk Assessment:
HRAF MW57.pdf


Start time: 5:15 PM 18/04/2011

MW59-1:
N-benzoyl-PZQ (40 mg, 131 µmol, M.W. 306.4 g/mol) and sulfur (8.4 mg, 262 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 5 min.

MW59-2:
N-benzoyl-PZQ (40 mg, 131 µmol, M.W. 306.4 g/mol) and sulfur (8.4 mg, 262 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 15 min.

MW59-3:
N-benzoyl-PZQ (40 mg, 131 µmol, M.W. 306.4 g/mol) and sulfur (8.4 mg, 262 µmol, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 30 min.

MW59-4:
N-benzoyl-PZQ (40 mg, 131 µmol, M.W. 306.4 g/mol) and sulfur (16.8 mg, 524 µmol, 4 eq., M.W. 32.1 g/mol) were heated at 180°C for 5 min.

MW59-5:
N-benzoyl-PZQ (40 mg, 131 µmol, M.W. 306.4 g/mol) and sulfur (16.8 mg, 524 µmol, 4 eq., M.W. 32.1 g/mol) were heated at 180°C for 15 min.

MW59-6:
N-benzoyl-PZQ (40 mg, 131 µmol, M.W. 306.4 g/mol) and sulfur (16.8 mg, 524 µmol, 4 eq., M.W. 32.1 g/mol) were heated at 180°C for 30 min.

TLC (ethyl acetate, stain: ninhydrin, Ceric ammonium molybdate, Ceric ammonium molybdate, KMnO4)
TLC MW59.jpg
TLC MW59a.jpg


Results:
All experiments showed left-over starting material -> reaction time has to be extended, see related reactions:
Scale-up: Oxidation of N-benzoyl-PZQ by sulfur (MW59-7)
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.
Attached Files
14th April 2011 @ 08:12
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