The Synaptic Leap

 

 
Further progress of acidic hydrolysis of rac-PZQ can be reported. As we have shown, the cleavage of the cyclohexanoyl group works better under mild acidic conditions (Table 1). The best result was obtained by using an HCl concentration of 1 mol/L and a reaction time of 24 h at reflux temperature (entry 5). At least 96% of the starting material could be converted to the amine 2. The crude product could be isolated in a high purity and no further purification was required. The 1H NMR spectrum shows no impurities and the melting point of the colorless solid agrees with the literature references.[1]
 

Table 1: Reaction conditions and results
 
Analytical data of 2 (Praziquanamine, 2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one):
m.p. 117-118°C (lit.[1] 117-119°). 1H NMR (CDCl3, 200 MHz): d = 1.76 (bs, 1H), 2.64-3.02 (m, 4 H),  3.49 (d, J=17.6, 1H),  3.61 (d, J=17.4, 1H),  3.67 (ddd, J=13.2, 4.7, 1.2, 1H), 4.69-4.85 (m, 2 H), 7.04-7.20 (m, 4H). 13C NMR (CDCl3, 50.3 MHz): d = 29.4, 39.4, 50.4, 50,7, 57.5, 125.3, 127.2, 127.6, 130.0, 134.8, 135.6, 167.9. C12H14N2O (202.3).

[1]     “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.