Racemic Resolution of Praziquantel and Praziquanamine

 

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

See also:
From R-(-)-Praziquanamine to R-(-)-Praziquantel (MW48-1): N-Cyclohexanoyl-protection of the enantiopure PZQamine
N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine (MW48-3)
N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine in a multigram scale (MW48-4)
N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine to PZQ (MW48-5)






Hazard and Risk Assessment:


Start time: 12:20 PM 14/10/2010
End time: 3:25 PM 14/10/2010


To a cooled solution of S-(+)Praziquanamine (93.0 mg, 460 µmol) in DCM (5 mL) at 0°C was added triethylamine (69.8 mg, 96.1 µL, 690 µmol, 1.5 eq.) and cyclohexanoyl chloride (74.1 mg, 67.6 µL, 506 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: 149 mg (477 µmol, 104%) yellow oil
Data: 1H NMR MW48-2 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: 116 mg (371 µmol, 81%) colorless oil (?, lit: solid)
Data: 1H NMR MW48-2 after column
Reference:
1H NMR rac-Praziquanamine:Data: 1H NMR PZQ
JCAMP-DX files: see

Chiral HPLC:
Column: Chiralcel OD-H; hexane/iso-propanol/Et3N = 60:40:0.1, 0.7 ml/min flow rate
RT (S-(+)PZQ): 12.9 min (low concentration, traces of side products?)


Reference: enantiopure S-(+)PZQ sample from Intervet


Results:
Conversion of enantiopure S-(+)-PZQamine to S-(+)-PZQ could be obtained without racemization (and also the hydrolysis of S-(+)-PZQ to S-(+)-PZQamine); yield of the N-cyclohexanoyl protection: 116 mg (371 µmol, 81%)