Pictet-Spengler route to Praziquantel

 

START: 17/05/12
FINISH:

Reducing catalyst load.




Hazard and Risk Assessment
As for KAB26-4


Previous Experiments
Yb(OTf)₃ catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-4)
AuCl₃/AgOTf catalysed acyl-PS reaction to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-3)

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 (KAB26-7) - 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
All glassware was ovendried overnight prior to use. The acetonitrile used was dried over activated 3Å (30 %(w/v)) for >72 hours prior. 2,6-Lutidine was dried over activated 3Å MS for >48 hours.
17/05/12. Acetonitrile (50 mL) was added to a solid mixture of KAB23-2 (394 mg, 1.253 mmol, 1 equiv.) and 3Å powdered MS. The mixture was cooled to -40 °C in an acetonitrile/N₂ bath before the slow, dropwise addition of acetyl chloride (0.09 mL, 1.3 mmol, 1 equiv.) followed by 2,6-lutidine (0.15 mL, 1.3 mmol, 1 equiv.). The reaction mixture was left to stir at -40 °C from 15:30. After 1 hour, the mixture was allowed to gradually warm to -2 °C over ~1 hour. The reaction mixture was then left to stir at room temperature (~10-15 °C) overnight.
18/05/12. At 10:00 the reaction mixture was transferred to a separating funnel (~20 hours), before the addition of citric acid solution (pH 3-4, 30 mL) and ethyl acetate (40 mL). The organic fraction was separated and the acidic aqueous layer extracted with ethyl acetate (3 × 40 mL). The organic fractions were combined then quenched with saturated sodium bicarbonate solution (30 mL). The organic layer was isolated before the aqueous layer was extracted with ethyl acetate (4 × 40 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB26-7 as a yellow oil which solidified on standing (475 mg).
Yield calculated from HNMR.

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.


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NOTES 15/05/12

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