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16th January 2012 @ 06:00
Experiment concluded on 18/01/12

Replication of experiment MNR7-1.

Background
Synthesis of enantiomers for the PZQ analogues.

Scheme
Scheme%20KAB10-1.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB10-1


Following Experiments

Procedure

Start: 16/01/12
Finish: 18/01/12

Ethanol (77 mL) was added to a solution of HCl (1 M, 423 mL), which was prepared by diluting HCl (36%, 13 mL) in water (410 mL). Racemic praziquantel (13 g) was weighed out and added to the solution. The white reaction mixture was heated to 96 oC overnight. When the temperature had reached ~50 oC, the solution had turned slightly foamy.

Started heating 17:30, 16/01/12.
Taken off Heat 08:07, 17/01/12

Before the addition of PZQ
After the addition of PZQ; starting the reflux


After ~14 hours, the reaction mixture had turned yellowish-brown. The solution was allowed to cool, during which, a white solid precipitated out.
The pale yellowish solution was then placed in a brine ice bath and basified with NaOH pellets (~20 g) to pH 14, turning the colour of the mixture slightly pink.

Reaction mixture (14 h)
Precipitation on cooling
Cooling reaction mixture
Adding NaOH pellets
Basified reaction mixture


The aqueous mixture was then extracted with dichloromethane (DCM, 4 x 150 mL). The precipitate readily dissolved in the DCM, turning the organic fraction orange. The DCM layers were combined, dried over magnesium sulfate, and filtered. The orange solution was concentrated under reduced pressure to give a dark orange oil, which was placed under a high-vacuum for 5 hours, to give crude KAB10-1 as a sticky orange solid (9.9 g, 118%).

First extraction with DCM
Second extraction with DCM
Third extraction with DCM
Fourth extraction with DCM
Filtering dried solution

Drying under high vacuum


RECRYSTALLISATION: The crude product was then dissolved in hot toluene (10 mL), before hexane (40 mL) was added slowly, keeping the reaction warm to hot. A white solid began to precipitate after ~15 mL of hexane had been added. The reaction mixture was allowed to cool to room temperature before placed in the freezer overnight.

Adding hexane to the hot KAB10-1/toluene solution
Cooled to room temperature


The recrystallised product was removed from the freezer and allowed to warm to rt. The crystals were filtered then washed with hexane to give a pale orange solid and a yellow filtrate.

An attempt to re-recrystallise* from hot toluene and hexane resulted in formation of a two phase mixture consisting of an orange oil bottom layer and a clear pale yellow top layer. Extensive heating and stirring, then cooling resulted in re-formation of the pale orange solid, which was then filtered, washed with hexane, then placed under high vacuum to give a KAB10-1 pale pink solid (8.1 g).

Product after removal from the freezer
Filtering out the crystals
The yellow-green filtrate
Re-recrystallisation from hot toluene (1)
Re-recrystallisation from hot toluene (2)
Filtering the solid (again)
Final KAB10-1, a mixture of PZQ and PZQamine


H-NMR of the solid suggested the reaction had not gone to completion, and the product contained a mixture of PZQ and PZQamine.

The product was taken no further, and another hydrolysis reaction was set up: see MNR7-5.

Related Experiments
Hydrolysis of rac-PZQ (MNR7-1)
Hydrolysis of rac-PZQ (MNR7-5)


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NOTES 16/01/12
- Weighed out 13.0 g of praziquantel, but probably only managed to transfer ~12.5 g.

NOTES 17/01/12
- Had to wait a bit until we acquired NaOH pellets from the store, so the reaction mixture remained acidic, though at room temperature, for an additional hour or so.
- Crude flask weight: 94.350 g

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Attached Files
Scheme KAB10-1
Hazard and Risk Assessment KAB10-1
Cooling reaction mixture
Adding NaOH pellets
Before the addition of PZQ
After the addition of PZQ; starting the reflux
Reaction mixture (14 h)
Precipitation on cooling
Basified reaction mixture
First extraction with DCM
Second extraction with DCM
Third extraction with DCM
Fourth extraction with DCM
Filtering dried solution
Drying under high vacuum
Adding hexane to the hot KAB10-1/toluene solution
Cooled to room temperature
Product after removal from the freezer
Filtering out the crystals
The yellow-green filtrate
Re-recrystallisation from hot toluene (1)
Re-recrystallisation from hot toluene (2)
Filtering the solid (again)
Final KAB10-1, a mixture of PZQ and PZQamine