Cleavage of the Cyclohexanoyl group of rac-PZQ

01 Feb
Published by Michael Wolfle

 
reaction
 
rac-PZQ 1 (1.00 g, 3.20 mmol) was solved in EtOH (25 mL) and 12 N HCl (75 mL) and heated to reflux. After 4 h a reaction control by TLC of a worked-up sample showed a complete consumption of the starting material. The ice cooled solution was made basic to pH 12 by adding cooled 5 N NaOH and extracted with DCM. Then the combined layers were washed with basified brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product 2 was yielded as a light yellow solid (204 mg, 1.01 mmol, 32%). [1,2]
 
TLC
Reaction contol by TLC (hexane:EA = 1:1; stain: KMnO4).
 
 
 
1H NMR Praziquanamin
1H NMR of rac-Praziquanamine 2.
 
See also:
Optimizing the acidic cleavage conditions of the cyclohexanoyl group of (rac)-PZQ and
Optimizing the acid cleavage conditions II and analytical data of PZQamine
 
 
[1]    We thank the lab of Professor Thomas R. Webb, Director of High
Throughput Chemistry at St. Jude Children's Research Hospital in Memphis, TN for sharing unpublished data with us on this reaction. T. Webb, T. Goronga, personal note, 27/01/2010.
[2]    "Formation of Pyrazinoisoquinoline Ring System by the Tandem
Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis
of Praziquantel", J. H. Kim, Y. S. Lee, H. Park and C. S. Rim, Tetrahedron 1998, 54, 7395-7400.

 

Comments

In case if you isolate your product 2 as a HCl salt, i think there are chances of improving the yield.
And what if, if you use 1:1 EtOH/H2O mixture as solvent instead of EtOH alone?

Michael Wolfle's picture

Thanks for your suggestions Ahamed - The isolation of the product is not the problem of this procedure and the amine 2 can be well extracted from the basic water phase. A further purification of the amine by forming the HCl salt would be an option, but the solid product itself can be recrystallized as the free amine from toluene or ethyl acetate/hexane. Apart from this is the purity of the isolated crude product so high that no further work-up is required.
And your right, a polar solvents mixture of ethanol/water improves the solubility of the reaction intermediates and the product; therefore I used aqueous HCl solution.