The Synaptic Leap

A new patent application using a multistep reaction (Ugi reaction) for the synthesis of Praziquantel
 

 

 

 
Here is a procedure from a German Patent Application from 1975 which uses quinic acid for the racemic resolution of praziquanamine. However, the procedure gives less information about the yield obtained.
 

 

 
The Pictet-Spengler cyclisation of the acetal 4 to the tetrahydroisoquinoline substructure 5 was conducted in concentrated sulfuric acid. The reaction showed a complete conversion to the tricycle in a very good yield and with high purity. The product was isolated by extraction from the basic aqueous solution, no further purification was needed. No side products were observed in the 1H NMR spectrum.

 

 
Here we started another synthetic approach to PZQ. The Pictet-Spengler route, used for the industrial synthesis of (rac)-PZQ, offers a straightforward way to this anthelmetic drug in 5 steps.[1]
Starting from inexpensive 2-phenylethylamine and chloroacetyl chloride the amide 2 can be obtained in a short reaction time with high yield. 
 

 

 
This experiment was conducted in order to examine whether the cyclohexanoyl amid bond could be cleaved under mild acidic conditions by using a 50 vol% TFA solution in DCM. After 48 h under refluxing temperature 99% of the starting material could be recovered.
As a result, this procedure can be used for the scission of acid-labile protecting groups of prospective derivatives of PZQ without touching the cyclohexanoyl group.
 

 

 
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.
 

 

 
rac-PZQ 1 (1.00 g, 3.20 mmol) was solved in EtOH (25 mL) and 12 N HCl (75 mL) and heated to reflux. After 4 h a reaction control by TLC of a worked-up sample showed a complete consumption of the starting material. The ice cooled solution was made basic to pH 12 by adding cooled 5 N NaOH and extracted with DCM. Then the combined layers were washed with basified brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product 2 was yielded as a light yellow solid (204 mg, 1.01 mmol, 32%). [1,2]