Racemic Resolution of Praziquantel and Praziquanamine

 

Acidic cleavage of the N-cyclohexanoyl group of S-(+)-PZQ

- optimized conditions for rac-PZQ: http://www.thesynapticleap.org/node/296



Start time: 7:05 PM 05/10/2010
End time: 1:00 PM 06/10/2010


Procedure:
S-(+)-PZQ (300 mg, 960 µmol) was dissolved in EtOH (3 mL) and 1 N HCl (12 mL) was added (cloudy solution) and heated to reflux for 18h. The yellow solution was cooled to room temperature and made basic to pH 12 by adding aq. 5 N NaOH.
- extraction with DCM (3x 5 mL), organic layer was washed with brine, dried over NaSO4, concentrated under reduced pressure

Crude yield of S-(+)-PZQamine: 203 mg (1.00 mmol, 105%) yellow solid, (strong fruity smell - from side products?)

- column (silica gel, EA:MeOH:TEA = 4:1:0.01) obtained 122 mg (603 mmol, 63%) of a pale brown solid (odorless)

Analytical data:
m.p. 117-118°C (lit.[1] 117-119°).
Rf = 0.23 (EA:MeOH:TEA = 4:1:0.01)
1H NMR (CDCl3, 200 MHz): d = 1.84 (bs, 1H), 2.71-3.06 (m, 4 H), 3.53 (d, J=17.6, 1H), 3.69 (d, J=17.4, 1H), 3.73 (ddd, J=13.2, 4.7, 1.2, 1H), 4.78-4.91 (m, 2 H), 7.12-7.29 (m, 4H).
Data: 1H NMR MW2-12
[α]D20 = 296° (c=1, DCM) ([α]D20 for R-(-)-PZQamine: -306° (c=?, solvent=?) [2])
C12H14N2O (202.3)
Note: melting point of S-(+)-PZQamine, purified by column chromatography varies from the recrystallized sample - compare analytical data with Purifying PZQamine for defining a phase diagram
see also: http://www.thesynapticleap.org/node/296

Following experiments:

Optical rotation of S-(+)-Praziquanamine

From S-(+)-Praziquanamine to S-(+)-Praziquantel (MW48-2): N-Cyclohexanoyl-protection of the enantiopure PZQamine

References:

[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)

[2] “Pyrazinoisochinolin-Derivat“, R. Polke, F. Loebich, J. Seubert, H. Thomas and P. Andrews, German Patent Application (1975) DE 2,331,713..