Optimizing the acid cleavage conditions II

12 Feb
Published by Michael Wolfle

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). Finally 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
Multigram scale procedure:
rac-PZQ (20.0 g, 64.0 mmol) was dissolved in a mixture of EtOH (150 mL) and 1N HCl (600 mL) and heated to reflux for 26 h. The cooled solution was extracted with ethyl acetate (3 x 10 mL) to remove impurities and side products. The acidic aqueous solution was treated with 5 N NaOH until a pH of 12 and extracted with DCM. The combined organic layers were washed with basic brine, dried over sodium sulfate and concentrated under reduced pressure. The remaining yellow solid (12.4 g, 61.4 mol, 96%) was recrystallized from toluene and the mother liquor was concentrated and recrystallized again. The wet solid was dried in vacuum for 1 day. The purified PZQamine 2 was obtained as a pale yellow solid (11.9 g, 58.8 mmol, 92%).
1. The main side product is ethyl cyclohexanecarboxylate which as a powerful, fruity odor of pineapple
2. If necessary, PQZamine can be purified by recrystallization from toluene or a mixture of DCM/ethylacetate/hexane
Analytical data for 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).
See NMR data: Cleavage of the Cyclohexanoyl group of rac-PZQ

[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.(DOI: doi:10.1016/S0040-4020(98)00401-3)



MatTodd's picture

We've had a great offer from Jean-Paul Seerden from Syncom B.V. to search for effective conditions for the resolution of praziquanamine. Since Michael was able to produce praziquanamine so simply (above), he's shipping a few grams over to Syncom so they can investigate. Obviously we're happy to do this for anyone else who would like to research the resolution of this material. Results will be posted as soon as they come in - huge thanks to Syncom for being part of the project.