Racemic Resolution of Praziquantel and Praziquanamine

 

Enantiopure R-(-)-Praziquanamine (PZQamine) obtained from the hydrolysis of R-(-)-Praziquantel is converted back to R-(-)-Praziquantel in order to evaluate whether a racemization occurs during the reaction.





Hazard and Risk Assessment:


Start time: 12:20 PM 14/10/2010
End time: 3:15 PM 14/10/2010


To a cooled solution of R-(-)-Praziquanamine (106 mg, 524 µmol) in DCM (5 mL) at 0°C was added triethylamine (79.5 mg, 110 µL, 786 µmol, 1.5 eq.) and cyclohexanoyl chloride (84.5 mg, 77.1 µL, 84.5 µmol, 1.1 eq.). The solution was stirred for 3 h at room temperature.

- Work-up: Quenched with 0.5 N HCl, extracted with DCM, dried over Na2SO4, concentrated.

- Crude yield: 177 mg (567 µmol, 108%) yellow oil
Data: 1H NMR MW48-1 crude

TLC MWW48-1 and MW48-2 (ethyl acetate : hexane = 1:1, stain potassium permanganate)


Column (silica gel; ethyl acetate : hexane = 1:1 to ethyl acetate 100%)
Yield: 141 mg (451 µmol, 86%) colorless oil (?, lit: solid -> solvent impurities / small scale)
1H NMR: PZQ with small impurities

Reference:
1H NMR rac-Praziquanamine:Data: 1H NMR PZQ
JCAMP-DX files: see

Chiral HPLC:
Chiralcel OD-H, hexane/iso-propanol/Et3N = 60/40/0.1, 0.7 ml/min flow rate
RT (R-(-)PZQ): 10.9 min
- sideproducts (RT ~ 7.4, 7.7, 8.7 and 13.5), no S-(+)PZQ
Data: HPLC R-(-)-PZQ MW48-1.pdf

Reference: enantiopure R-(-)PZQ sample from Intervet
Data: HPLC R-(-)-PZQ reference.pdf

Results:

• Conversion of enantiopure R-(-)-PZQamine to R-(-)-PZQ could be obtained without racemization (and also the hydrolysis of R-(-)PZQ to R-(-)-PZQamine); yield of the N-cyclohexanoyl protection: 141 mg (451 µmol, 86%)
  
• Product contains impurities (determined by chiral HPLC)