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Racemization of PZQ and PZQamine
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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
Na naphthalide 10 min.jpg
Na naphthalide 1 h.jpg
HPLC MW55-5.jpg
HPLC MW55-6 + rac-PZQ.jpg
1H NMR MW50-10.pdf
1H NMR MW55-6.pdf
HPLC MW55-6.jpg