Pictet-Spengler route to Praziquantel

 

START: 29/05/12
FINISH: 31/05/12

Lowering catalyst load to 1 mol%. Letting reaction run for >30 min.


Hazard and Risk Assessment


Previous Experiments
Isolating byproducts in the Yb(OTf)₃ catalysed acyl Pictet-Spengler reaction (KAB26-9)
AuCl₃/AgOTf catalysed acyl-PS reaction to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-10)
Extending the Yb(OTf)₃ catalysed acyl-Pictet-Spengler reaction time at -30 °C (KAB26-8)

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-2) - 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.
1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11) - SMILES: O=[N+]([O-])C1=CC=C(C2N(C(C)=O)CCC3=CC(OC)=C(OC)C=C32)C=C1, InChI: InChI=1S/C19H20N2O5/c1-12(22)20-9-8-14-10-17(25-2)18(26-3)11-16(14)19(20)13-4-6-15(7-5-13)21(23)24/h4-7,10-11,19H,8-9H2,1-3H3, InChIKey: OIFIJKJQAGAGKY-UHFFFAOYSA-N.

Procedure
NOTE: Reaction was performed under anhydrous conditions.
29/05/12. KAB23-2 (1.50 g, 4.77 mmol, 1 equiv.) was dissolved in acetonitrile (160 mL) over 3 Å MS. Acetyl chloride (0.34 mL, 4.8 mmol, 1 equiv.) and 2,6-lutidine (0.55 mL, 4.8 mmol, 1 equiv.) were sequentially added, dropwise, at 0 °C. Yb(OTf)₃ (0.034 g, 0.048 mmol, 0.01 equiv.) was added. The mixture was allowed to warm to rt and left to stir under an argon atmosphere from 18:00.
30/05/12. After 24 hours, the molecular sieves were removed via vacuum filtration. The filtrate was diluted with EtOAc (50 mL) and washed with saturated NaHCO₃ solution (30 mL). The organic layer was isolated and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried (MgSO₄), and concentrated under reduced pressure to give crude KAB26-11 as a yellow oil (1.8 g, 106%).

31/05/12. The crude oil partially crystallised overnight. Methanol was added to the oil and solid mixture, which was heated until all the solid had dissolved. Dry silica was added and the mixture concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 70-100% EtOAc/hexane. The KAB26-11 product was collected in fractions 26-51, which were combined and concentrated in vacuo to yield a yellow powder (1.30 g, 77%).

Summary and Conclusion

References
[1] S. W. Youn, The Journal of Organic Chemistry 2006, 71, 2521-2523. DOI: 10.1021/jo0524775. Paper
[2] K. Manabe, D. Nobutou, S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158.

Abbreviations Used:
EtOAc = ethyl acetate
TLC = thin layer chromatography
RM = reaction mixture
MS = molecular sieves
Soln = solution

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