Racemization of PZQ and PZQamine

 

Repetition of the racemization experiments on enantioenrichend (S)-(+)-PZQamine with Rhodium on charcoal to verify the results



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 Raney Nickel (MW50-6, MW50-7)
Thiyl radical-mediated racemization of S-(+)-PZQamine (MW50-8)
Racemization of S-(+)-PZQamine (MW50-9) and (R) -(-)-PZQ (MW55-5) with sodium naphthalide
Repetition: Racemization of S-(+)-PZQamine (MW50-10) and R -(-)-PZQ (MW55-6) with sodium naphthalide
Racemization of S-(+)-PZQamine with Raney Nickel under high pressure and high temperature (MW50-11)

Hazard and Risk Assessment:


Start time: 5:30 PM 13/04/2011
End time: 9:30 AM 15/04/2011

To a solution of enantioenrichend (S)-PZQamine (50 mg, 247 µmol, MW: 202.3 g/mol) in toluene (2 mL) was added Rhodium on Charcoal (50.9 mg, 49.4 µmol, 0.2 eq.; 10% Rh on C, M.W. (Rh) 102.9 g/mol) and heated to 100°C for 39 h.

TLC:

- column (silica gel; ethyl acetat, 100% then ethyl acetate, methanol, triethylamine, 10:1:0.1)
PZQamine: 13.2 mg (26%)
[α]D20 = +161° (c=1, DCM)
Data: 1H NMR MW50-13 fr_2.pdf

unpolar 'side product': 23.9 mg
Rf=0.45 (ethyl acetate, stain: potassium permanganate)
[α]D20 = +90° (c=1, DCM)
1H NMR: Data: 1H NMR MW50-13 fr_1.pdf

Synthesis of rac-PZQamine by an acidic hydrolysis of rac-PZQ



See also:
Hydrolysis of rac-PZQ (MW2-14)
Hydrolysis of rac-PZQ (MW2-13)
Optimizing the acid cleavage conditions II

Hazard and Risk Assessment:
Data: HIRAC MW2

Start time: 5:00 PM 13/04/2011
End time: 10:00 AM 14/04/2011

Procedure:
rac-PZQ (20.0 g, 64.0 mmol, M.W. 312.4 g/mol) was dissolved in a mixture of EtOH (150 mL) and 1N HCl (600 mL, 53.0 mL of 11.3 N HCl solution (35%) in 547 mL water) and heated to reflux for 17 h. Reaction monitored by TLC showed a complete consumption of PZQ (TLC, ethyl acetate, Rf ~0.5 for PZQ).

Work-up:
Solution was cooled to room temperature, washed with EtOAc (4 times 15 mL), basified with NaOH solution (5 N) to ph 12, extracted with DCM (5 x 30 mL), washed with brine, dried over NaSO4, evaporated under reduced pressure.
- the pale yellow oil became a solid after 1 h under high vac

Yield:
11.0 g (54.5 mmol, 85%) colourless solid (turning pale red/orange after a few hours at r.t.)
[M.W. = 202.1 g/mol]

Experiments on the oxidation of PZQamine to the enamide/imine by molten sulfur.
See related experiments on rac-PZQ: Sulfur melt data smogasbord



Hazard and Risk Assessment:


Start time: 11:30 AM 12/04/2011

MW57-1:
rac-PZQamine (40 mg, 198 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 5 min.

MW57-2:
rac-PZQamine (40 mg, 198 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 10 min.


MW57-3:
rac-PZQamine (40 mg, 198 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 15 min.




Start time: 11:30 AM 12/04/2011

MW57-4:
rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (6.4 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 30 min.

MW57-5:
rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (6.4 mg, 2 eq., M.W. 32.1 g/mol) were heated at 180°C for 1 h.

MW57-6:
rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 4 eq., M.W. 32.1 g/mol) were heated at 180°C for 15 min.

MW57-7:
rac-PZQamine (20 mg, 99 µmol, M.W. 202.3 g/mol) and sulfur (12.7 mg, 4 eq., M.W. 32.1 g/mol) were heated at 180°C for 30 min.


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.

Racemization experiments on (R)-(-)-PZQ with Rhodium on charcoal



See also:
Experiments on the racemization of (R)-PZQ (MW55-1 to MW55-3)
Experiments on the racemization of (R)-PZQ with Raney Nickel (MW55-4)
Racemization of S-(+)-PZQamine (MW50-9) and (R) -(-)-PZQ (MW55-5) with sodium naphthalide
Repetition: Racemization of S-(+)-PZQamine (MW50-10) and R -(-)-PZQ (MW55-6) with sodium naphthalide
Racemization of S-(+)-PZQamine with Raney Nickel under high pressure and high temperature (MW50-11)

Hazard and Risk Assessment:


Start time: 7:00 PM 7/04/2011
End time: 10:00 AM 11/04/2011

To a solution of (R)-(-)-PZQ (20.0 mg, 64.0 µmol) in toluene (2 mL) was added Rhodium/Charcoal (6.6 mg, 6.40 µmol, 0.1 eq.; 10% Rh on C, M.W. (Rh) 102.9 g/mol) and heated to 70°C for 4 d.

Chiral HPLC (Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate): RT: (R)-PZQ: 12.4 min, (S)-PZQ: 15.0 min


-> no racemization

Racemization experiments on enantioenrichend (S)-(+)-PZQamine with Rhodium on charcoal



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 Raney Nickel (MW50-6, MW50-7)
Thiyl radical-mediated racemization of S-(+)-PZQamine (MW50-8)
Racemization of S-(+)-PZQamine (MW50-9) and (R) -(-)-PZQ (MW55-5) with sodium naphthalide
Repetition: Racemization of S-(+)-PZQamine (MW50-10) and R -(-)-PZQ (MW55-6) with sodium naphthalide
Racemization of S-(+)-PZQamine with Raney Nickel under high pressure and high temperature (MW50-11)

Hazard and Risk Assessment:


Start time: 7:00 PM 7/04/2011
End time: 10:00 AM 11/04/2011

To a solution of enantioenrichend (S)-PZQamine (20 mg, 98.9 µmol, MW: 202.3 g/mol) in toluene (2 mL) was added Rhodium/Charcoal (10.2 mg, 9.89 µmol, 0.1 eq.; 10% Rh on C, M.W. (Rh) 102.9 g/mol) and heated to 70°C for 4 days.
The mixture was filtered and evaporated under reduced pressure to give 18.8 mg of PZQamine.

TLC (ethyl acetate/methanol/triethylamine, 1:1:0.02, stain: ninhydrin)


Data: 1H NMR MW50-12.pdf: PZQamine /no side products visible
[α]D20 = +98° (c=1, DCM)

-> Racemization ?! (it's not clear if the lower [α] is a result of a reacemization or lower concentration of (S)-PZQamine caused by solvent impurities/ other impurities)

-> Repeat a scaled-up reaction with an higher catalyst load, longer reaction time and higher temperature, see: Repetition: Racemization of (S)-PZQamine (MW50-13) with Rh/C