Pictet-Spengler route to Praziquantel

 

PS = Pictet-Spengler

START: 20/02/12
FINISH: 02/03/12

Background
Continuation of the series of TfOH (10 mol%) catalysed Pictet-Spengler reactions to give PZQ and its analogues.




Hazard and Risk Assessment


Previous Related Experiments
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-4)

Following Experiments
TfOH catalysed PS* reaction to give PZQ (KAB3-17)
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)

Procedure
KAB6-1 (400 mg, 1.00 mmol) was dissolved in toluene (44 mL) before the addition of TfOH (8.90 μL, 0.10 mmol, 10 mol%) at rt. The mixture was immediately put in a pre-heated oil bath at 90 °C and refluxed from 10:35.


Monitoring the Reaction Progress by TLC
All TLCs were eluted with EtOAc/hexane, 5:3, v/v and stained with KMnO₄. The time noted is from the addition of the acid.


After 2 hours, the reaction mixture was removed from heat and allowed to cool. The solution was diluted with EtOAc (50 mL), then quenched with saturated sodium bicarbonate solution (50 mL).

The organic layer was separated and the aqueous fraction extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate, then passed through a silica pad.


The filtrate was collected and concentrated under reduced pressure to give crude KAB7-3 as a yellowish semi-solid (297 mg, 96%).

The crude sample was put under high vacuum for >2 hours before it was sealed and stored in the freezer overnight.

28/02/12
Attempt at recrystallisation from EtOAc/hexane.
Start: 295.4 mg
02/03/12
Recrystallisation failed. Product is a gel.



Summary and Conclusion
Triflic acid (10 mol%) catalyses partial Pictet-Spengler reaction to give the enamide intermediate. It is thought that loss of the ethoxy groups form the peptide acetal starting material results in the in situ formation of the iminium ion. Lack of electron density in the &del; aromatic group results in tautomerism of the iminium to the stable and isolatable enamide, KAB7-3.

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NOTES 20/02/12
- 15 min into the reaction and already complete consumption of the KAB6-1 starting material. Most of the product currently the enediamide intermediate (based on TLC). The enediamide spot immediately turned bright yellow on staining, with no heating required. The plate was still heated to develop the other spots.
- Flask 48.1329 g
- After standing under high vacuum, the oil showed signs of solidifying. Stored in freezer overnight.

NOTES 28/02/12
- Still not quite solid.
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