The Synaptic Leap

 

 
The next step in the PZQ synthesis via the Pictet-Spengler route is an aminoalkylation of the chloroacetamide 2 with aminoacetaldehyde dimethyl acetal 3. The aminoacetal also acted as a base to trap the HCl which was generated during the reaction and therefore 2.1 equivalents were used. The aminoacetal could be easily recovered by basic liberation of its HCl-salt which precipitated from the cold toluene solution. The crude product was obtained as a brown oil and was isolated by forming the HCl-salt 4 in an overall yield of 79%. (lit.[1] 67%)
 

 

 
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]
 

 
General procedure
 

 
The first large scale synthesis of rac-PZQ was developed by the Merck KG and Bayer AG (Merck process).[1,2]  Isoquinoline as a cheap starting material was transformed by the Reissert reaction with cyanide and cyclohexanoyl chloride 2 to the cyano amide 3.
 

 
In the literature to this reaction only a few patent procedures are known, which are not very detailed in description.[3]  To understand the Reissert reaction we start a screening approach under various conditions.

I've been working on the sulfur melt reaction, trying to optimize the reaction yield of the singly dehydrogenated product (DHP below).  Many studies have been conducted, and here I'll discuss some of what I've found out.
 

Glaxo allows access to 1000s of in house chemical to the public domain
 
http://www.guardian.co.uk/science/2010/jan/20/glaxo-malaria-drugs-public...