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Pictet-Spengler route to Praziquantel
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6th August 2012 @ 00:52
Monitoring reaction at -5 °C with the idea that maybe complexes will be more stable at these temperatures and catalyse the reaction ahead of free Yb(OTf)3.

MNR41-4%20scheme.png
mnr41-8%20table.PNG

To a solution of MNR42-1 (0.2 g, 0.64 mmol) in dry acetonitrile (20 mL, HPLC grade stored over 3 Å molecular sieves for 24 hours) and 3 Å molecular sieves (3 g, dried in microwave) under argon at -5 °C, was added was added acetyl chloride (0.08 mL, 1.15 mmol), 2,6-lutidine (0.10 mL, 0.89 mmol, stored over 3 Å molecular sieves) and PZQ (0.02 g, 0.06 mmol). Yb(OTf)3 solution (0.128 g, in THF (15 mL)) (2.3 mL, 0.02 g, 0.03 mmol) was added and the reaction was stirred at -5 °C and followed by LCMS analysis.

The reaction was monitored by LCMS by taking samples carrying out the following procedure.

0.1 ml was removed from the reaction mixture using a disposable syringe and transferred to a vial. EtOAc (0.4 mL) and sodium hydrogen carbonate saturated solution (0.2 mL) was added and the vial capped and shaken. The layers were allowed to separate and the organic layer was carefully removed by pipette and transferred to another vial and concentrated to dryness under reduced pressure.

Acetonitrile (1.8 mL) was added and the mixture shaken, 0.06 mL was transferred to a LCMS vial and acetonitrile 0.3 mL).

Reaction on at 915am

Samples taken at

1015 - 1 hour
1215 - 3 hours
1415 - 5 hours
1615 - 7 hours
1815 - 9 hours
1915 - 10 hours
0915 - 24 hours

mnr41-9_plot.PNG

Plotting the data shows that the reaction is done to <95% after 9 hours but slight improvements in conversion are still observed after 10 hours. It would therefore be recommended if carrying out futures reactions at this temperature then they should be left for a minimum of 12 hours.

See Quantifying MNR41 and PZQ as a standard in LCMS analysis - MNR41-7
Attached Files
mnr41-9_plot.PNG
mnr41-9_3hours.pdf
mnr41-9_9hours.pdf
mnr41-9_10hours.pdf
mnr41-9_5hours.pdf
mnr41-9_7hours.pdf
mnr41-9_24hours.pdf
mnr41-9_1hour.pdf