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Racemization of PZQ and PZQamine
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30th March 2011 @ 06:35
Racemization experiments on S-(+)-PZQamine with Raney nickel under high pressure and high temperature. Continuation of: Racemization of S-(+)-PZQamine with Raney Nickel (MW50-6, MW50-7)

Scheme MW50-6.png


See also:
Racemization of S-(+)-PZQamine with Pd/C (MW50-1 to MW50-3)
Racemization of S-(+)-PZQamine with Pd/C (MW50-4)
Racemization of S-(+)-PZQamine with Pd/BaSO4 (MW50-5)
Thiyl radical-mediated racemization of S-(+)-PZQamine (MW50-8)

Hazard and Risk Assessment:
HRAF MW50.pdf


Start time: 10:00 AM 30/03/2011
End time: 18:00 PM 30/03/2011

To a solution of S-(+)-PZQamine (50 mg, 248 µmol, MW: 202.3 g/mol) in ethanol (40 mL, minimum volume of the high pressure vessel) was added Raney nickel (29 µL suspension of Raney nickel in water (~0.1 g/mL), 2.91 mg, 49.5 µmol, 20 mol%, M.W. (Ni) 58.7 g/mol) under hydrogen pressure (10 bar, 150 psi) and heated to 100°C for 6 h.
- problem with the heating: temperature went up to 210°C and a pressure of ~ 500 psi (33 bar).

TLC (ethyl acetate, methanol, triethylamine, 1:1:0.02, stain: ninhydrin, reference: rac-PZQamine):
TLC MW50-11.JPG

TLC (ethyl acetate, methanol, triethylamine, 10:1:0.02, stain: KMnO4 / ninhydrin):
TLC MW50-10 + MW50-11.JPG
Attached Files
30th March 2011 @ 02:14
Racemization experiments on enantioenrichend S-(+)-PZQamine (MW49-13) with sodium naphthalide. Repetition of MW50-9

Scheme MW50-9.png


See also:
Racemization of S-(+)-PZQamine with Pd/C (MW50-1 to MW50-3)
Racemization of S-(+)-PZQamine with Pd/C (MW50-4)
Racemization of S-(+)-PZQamine with Pd/BaSO4 (MW50-5)
Racemization of S-(+)-PZQamine with Raney Nickel (MW50-6, MW50-7)
Thiyl radical-mediated racemization of S-(+)-PZQamine (MW50-8)
Racemization of S-(+)-PZQamine with Raney Nickel under high pressure and high temperature (MW50-11)

Hazard and Risk Assessment:
HRAF MW50-9.pdf


Start time: 12:00 pm 30/03/2011
End time: 18:00 pm 30/03/2011

Preparation of sodium naphthalide (0.5 M solution in THF):
To a solution of naphthalene (320 mg, 5.00 mmol, M.W. = 128.2 g/mol) in THF (5 mL) was added sodium (115 mg, 10.0 mmol, M.W. = 23.0 g/mol) under a argon atmosphere and stirred at r.t.
- pale green colour after 10 min, dark green after 1 h
Na naphthalide 10 min.jpg
Na naphthalide 1 h.jpg

- after the reaction was finished the remaining sodium was quenched by addition of isopropanol, then methanol

Racemization of S-(+)-PZQamine (MW50-10):
To a solution of S-(+)-PZQamine (30 mg, 148 µmol, MW: 202.3 g/mol) in THF (2 mL) was added a solution of sodium naphthalide (296 µL of a 0.5 M solution, 29.7 µmol, 148 µmol, 1.0 eq. ) and stirred for 4 h at r.t.
- the green colour of the sodium naphthalide disappeared immediately and the previous pale yellow solution of the starting material turned dark red, after 2 min the solution got a orange colour.

TLC (ethyl acetate, methanol, triethylamine, 10:1:0.02, stain: KMnO4 / ninhydrin):
TLC MW50-10 + MW50-11.JPG


1H NMR: PZQamine, naphthaline, side product
Data: 1H NMR MW50-10.pdf

-> small column to separate PZQamine from naphthaline



Racemization of R-(-)-PZQ (MW55-6):
To a solution of R-(-)-PZQ (30 mg, 96.2 µmol, MW: 312 g/mol) in THF (2 mL) was added a solution of sodium naphthalide (192 µL of a 0.5 M solution, 96.2 µmol, 1.0 eq.) and stirred for 4 h at r.t.
- the green colour of the sodium naphthalide disappeared immediately and the previous clear solution of the starting material turned yellow, after a few seconds the solution turned pale yellow.
- reaction was quenched by addition of methanol, solvent was evaporated and the remain was filtered through a mini column (silica gel, ethyl acetate 100%)
Chiral HPLC: Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate: no PZQ left (dimerization/degeneration ?)
- Reference: RT: (R-(-)PZQ): 12.3 min, S-(+)PZQ: 14.3 min.
HPLC MW55-6.jpg
HPLC MW55-6 + rac-PZQ.jpg


1H NMR: Data: 1H NMR MW55-6.pdf

-> no PZQ left...


References:
[1] Procedure for sodium naphthalide (Step C.): tert-BUTYL-tert-OCTYLAMINE, E. J. Corey and Andrew W. Gross, Organic Syntheses, Coll. Vol. 8, p.93 (1993); Vol. 65, p.166 (1987).

[2] Process for racemizing of optically active amines, T. Inoue and Y. Hirayama, United States Patent US005969186A, 1999.
Attached Files
23rd March 2011 @ 07:48
Racemization experiments on enantioenrichend S-(+)-PZQamine (MW49-13) with sodium naphthalide as a radical anion catalyst.

Scheme MW50-9.png


See also:
Racemization of S-(+)-PZQamine with Pd/C (MW50-1 to MW50-3)
Racemization of S-(+)-PZQamine with Pd/C (MW50-4)
Racemization of S-(+)-PZQamine with Pd/BaSO4 (MW50-5)
Racemization of S-(+)-PZQamine with Raney Nickel (MW50-6, MW50-7)
Thiyl radical-mediated racemization of S-(+)-PZQamine (MW50-8)

Hazard and Risk Assessment:
HRAF MW50-9.pdf


Start time: 1:00 pm 24/03/2011
End time: 6:50 pm 24/03/2011

Preparation of sodium naphthalide (0.1 M solution in THF):
To a solution of naphthalene (128 mg, 1.00 mmol, M.W. = 128.2 g/mol) in THF (10 mL) was added sodium (23 mg, 1.00 mmol, M.W. = 23.0 g/mol) under a nitrogen atmosphere and stirred at r.t. -> no reaction, color should turn green
- added more sodium (23 mg, 1.00 mmol) -> shiny metal surface turned grey, after 2 h the metal surface began to turn greenish (moist solvent ?)
- after 5 h: solution turned green/brown
[M.W. sodium naphthalide 151.2 g/mol]

Start time: 6:50 pm 24/03/2011
End time: 10:00 pm 25/03/2011

Racemization of S-(+)-PZQamine (MW50-9):
To a solution of S-(+)-PZQamine (30 mg, 148 µmol, MW: 202.3 g/mol) in THF (3 mL) was added a solution of sodium naphthalide (297 µL of a 0.1 M solution, 29.7 µmol, 20 mol%) and stirred for 15 h at r.t.

Racemization of R-(-)-PZQ (MW55-5):
To a solution of R-(-)-PZQ (30 mg, 96.2 µmol, MW: 312 g/mol) in THF (3 mL) was added a solution of sodium naphthalide (192 µL of a 0.1 M solution, 19.2 µmol, 20 mol%) and stirred for 15 h at r.t.

Chiral HPLC: Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate, RT: (R-(-)PZQ): 11.5 min, S-(+)PZQ: 13.8 min.
HPLC MW55-5.jpg

-> no racemization

Results:
- no racemization or any reaction -> Na naphthalide already quenched before a reaction happend (?)

Repetition of the experiment:
Repetition: Racemization of S-(+)-PZQamine with sodium naphthalide (MW50-10)


References:
[1] Procedure for sodium naphthalide (Step C.): tert-BUTYL-tert-OCTYLAMINE, E. J. Corey and Andrew W. Gross, Organic Syntheses, Coll. Vol. 8, p.93 (1993); Vol. 65, p.166 (1987).

[2] Process for racemizing of optically active amines, T. Inoue and Y. Hirayama, United States Patent US005969186A, 1999.
Attached Files
22nd March 2011 @ 06:53
Continuation of the racemization experiments on (R)-(-)-PZQ (MW48-5)

Scheme MW55.png


See also:
Experiments on the racemization of (R)-PZQ (MW55-1 to MW55-3)
Racemization of S-(+)-PZQamine with Raney Nickel (MW50-6, MW50-7)

Hazard and Risk Assessment:
HRAF MW50.pdf


Start time: 6:00 PM 22/03/2011
End time: 9:00 PM 25/03/2011

MW55-4 (1 atm hydrogen)
To a solution of (R)-(-)-PZQ (20.7 mg, 66.3 µmol, MW: 312.4 g/mol) in ethanol (2 mL) was added Raney nickel (778 µg, 133 µmol, 0.2 eq.; 7.8 µL suspension of Raney nickel (Suspension in water ~0.1 g/mL), M.W. (Ni) 58.7 g/mol) under a atmosphere of hydrogen and heated to 70°C for 2.5 d.
Chiral HPLC (Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate):
- no racemization of (R)-PZQ (RT: (R)-PZQ: 11.2/11.6 min, (S)-PZQ: 13.3 min)
HPLC MW55-4.jpg
HPLC MW55-4 + rac-PZQ.jpg


MW55-7 (1000 kPa hydrogen) -> moved to Racemization of (R)-PZQ with Raney Nickel under high pressure and high temperature (MW55-7)
Attached Files
3rd March 2011 @ 07:44
Racemization experiments on enantioenrichend S-(+)-PZQamine (MW49-13) with ABCN as a radical initiator and thiophenol radical as an H abstractor.

scheme.png


See also:
Racemization of S-(+)-PZQamine with Raney Nickel (MW50-6, MW50-7)
Racemization of S-(+)-PZQamine with Pd/BaSO4 (MW50-5)
Racemization of S-(+)-PZQamine with Pd/C (MW50-4)
Racemization of S-(+)-PZQamine with Pd/C (MW50-1 to MW50-3)

Hazard and Risk Assessment:
HRAF MW50-8.pdf


Start time: 10:30 AM 4/03/2011
End time: 17:00 PM 4/03/2011


To a solution of S-(+)-PZQamine (50 mg, 247 µmol, MW: 202.3 g/mol) and thiophenol (5.4 mg, 5.0 µL, 49.4 mmol, 0.2 eq., d: 1.077 g/mL, MW: 110.2 g/mol) in benzene (5 mL) was at reflux for XX h in the precence of 1,1′-Azobis(cyclohexanecarbonitrile) (ABCN) (12.1 mg, 49.4 µmol, 0.2 eq. MW: 244.3 g/mol), which was divided in three equal portions and added successively every 2 h.

Work-up: solvents evaporated, dissolved in 1 N HCl, extracted with ethyl acetate, basified with Na2CO3 solution, extracted with ethyl acetate, dried over Na2SO4, evaporated

Crude Yield 32 g red solid.


[1] Thiyl Radical Mediated Racemization of Benzylic Amines, S. Escoubet, S. Gastaldi, N. Vanthuyne, G. Gil, D. Siri and M. P. Bertrand, Eur. J Org. Chem. 2006, 3242-3250. DOI: 10.1002/ejoc.200600120
Attached Files