Pictet-Spengler route to Praziquantel

 

START: 22/03/12
FINISH: 22/03/12

Background
See synaptic leap post: here.



Hazard and Risk Assessment


Previous Experiments
Synthesis of N-(4-nitrobenzylidene)-2-phenylethanamine (KAB22-1)
Synthesis of N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (KAB19-2)
Synthesis of N-benzylidene-N-phenethylamine (KAB18-2)

Following Experiments

Chemical Information
3,4-Dimethoxyphenethylamine (1) - SMILES: O(c1ccc(cc1OC)CCN)C, InChI: InChI=1S/C10H15NO2/c1-12-9-4-3-8(5-6-11)7-10(9)13-2/h3-4,7H,5-6,11H2,1-2H3, InChIKey: ANOUKFYBOAKOIR-UHFFFAOYSA-N.

4-Nitrobenzaldehyde (2)- SMILES: O=C([H])C1=CC=C([N+]([O-])=O)C=C1, InChI: InChI=1S/C7H5NO3/c9-5-6-1-3-7(4-2-6)8(10)11/h1-5H, InChIKey: BXRFQSNOROATLV-UHFFFAOYSA-N.
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (3, KAB23-1) - SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC(OC)=C(OC)C=C2)C=C1, InChI: InChI=1S/C17H18N2O4/c1-22-16-8-5-13(11-17(16)23-2)9-10-18-12-14-3-6-15(7-4-14)19(20)21/h3-8,11-12H,9-10H2,1-2H3/b18-12-, InChIKey: LMBMXYXQVBPKHJ-PDGQHHTCSA-N.

Procedure
4-Nitrobenzaldehyde (4.6 g, 30.4 mmol, 1 eq) was suspended in diethyl ether (40 mL). 3,4-dimethoxyphenethylamine (5 mL, 30.3 mmol, 1 eq) was added, dropwise, to the stirring mixture, after which the solution went a clear dark orange colour. The reaction mixture was left to stir at rt from 13:30.
At 4:30 (+3 hours), a fine yellow precipitate had formed and in the now colourless solution. The solvent was removed under reduced pressure to give crude KAB23-1 as a fine yellow powder (10.0 g, 105%).

¹H-NMR (300 MHz; CDCl3).

Imine proton: δ 8.21 (s, 1H).

¹H-NMR shows presence of the dimethoxyphenethylamine and trace amounts of the aldehyde.

Purification
27/03/12. A test recrystallisation from hot ethanol was performed according to the literature.^[1] Start: 779 mg. ReXST: 610 mg. Yield: 78%.
Fine yellow needles were formed. The crystals were filtered and washed with EtOH, then dried under a high vacuum.
The remainder of the sample was recrystallised from hot EtOH. The flask was left to stand at rt overnight before the crystals were filtered, then washed with EtOH and dried under a high vacuum for 6 hours. Start: 9.1 g. reXST: 7.9 g. Yield 87%.



¹H-NMR (200 MHz; CDCl₃): δ 8.30 (d, J = 8.8 Hz, 2H), 8.23 (s, 1H), 7.93-7.88 (m, 2H), 6.86-6.77 (m, 3H), 3.95 (td, J = 7.1, 1.1 Hz, 2H), 3.87 (d, J = 7.7 Hz, 6H), 3.03 (t, J = 7.1 Hz, 2H).


Summary and Conclusion
Isolated yield after recrystallisation was 87%. Pure product confirmed by H-NMR.

References
[1] R. Gitto, M. L. Barreca, L. De Luca, G. De Sarro, G. Ferreri, S. Quartarone, E. Russo, A. Constanti, A. Chimirri, Journal of Medicinal Chemistry 2003, 46, 197.


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NOTES 24/03/12
- Add yield
- NMR sample

NOTES 26/03/12
- NMR settings may not be quite right for this compound - integration slightly "off." for the imine and aromatic protons.

NOTES 28/03/12
- Need to NMR reXST product.
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