Optimizing the acidic cleavage conditions of the cyclohexanoyl group of (rac)-PZQ

05 Feb
Published by Michael Wolfle

 
Reaction
 
After the first test reaction of an acidic hydrolysis of PZQ with 12 N HCl the conditions for the cleavage of the cyclohexanoyl group were varied. Lower concentrations of aq. HCl were used and the reaction times for the total consumption of the starting material needed to be extended.
 
Procedure
rac-PZQ (500 mg, 1.60 mmol) was dissolved in a mixture of  EtOH (10 mL) and various concentrations of HCl (40 mL) and heated to reflux for the time given in Table 1. The cooled solution was treated with 5 N NaOH until a pH of 12, and extracted with DCM. The combined organic layers were washed with basic brine and dried over sodium sulfate. The crude product was obtained as a colorless to pale yellow solid (yields given in Table 1). The purity of the product was determined by 1H NMR.
 
Table1Table 1. Reaction conditions and results
 
The final optimized conditions and analytical data are posted here.

Comments

jcbradley's picture

In all cases you don't find any starting material in the isolated product?  Do you think the low yields are due to cleavage of the tertiary amide, which would end up in the aqueous layer?

Michael Wolfle's picture

Hi Jean-Claude,

That’s right, the starting material in this reaction was completely consumed. The few impurities found in the 1H NMR are non-specific. And there’s a high chance that under these vigorous conditions with high concentrated HCl also the tertiary amide bond will be cleaved. But even with an extensive extraction of the aqueous layer with DCM no side products could be obtained.

jcbradley's picture

Michael - that is what you would expect from the cleavage of the tertiary amide, right?  The resulting zwitterion would be hard to isolate - staying in the aqueous layer under acidic or basic conditions.  Since you're getting a high yield of the desired product that's convenient - I was just curious to see if you had investigated further.