The Synaptic Leap

 

 
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 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...

Recent work has been towards developing a GC assay to quickly monitor the sulfur melt reactions.
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In order to optimize the sulfur melt reaction, we've been trying to develop a solid set of GC conditions that'll let us quantitate the reaction progress quickly and accurately (which precludes running a column every time I try the reaction with different conditions).  Initially, PZQ and the dehydrogenated product were found to come off the column at different times, although high temperatures around 320ºC are needed.  A small blip in the PZQ-only sample's chromatogram unfortunately lines up with the product peak.
 

Dear All,
I am a PI at the Stanford University School of Medicine (med.stanford.edu/labs/michael-hsieh) who's seeking a postdoctoral fellow to help develop novel models of urinary schistosomiasis, which, as many of you know, is a "doubly neglected" tropical disease, in part because of difficulties with existing models. Interested candidates may contact me at: mhhsieh@stanford.edu. Please feel free to share this announcement with others who may be potentially interested. Looking forward to working with everyone on collaborative projects in the near future.
Sincerely,
Mike Hsieh

InChI is great and all, but today while exploring, I found two issues that bugged me.  The first arose from my simple double-checking exercise: I drew praziquantel at http://pubchem.ncbi.nlm.nih.gov/edit/ then took the InChI returned and plugged it into chemspider.com to see if it would bring up the appropriate page for PZQ (which I already knew existed).  I made the mistake of leaving one of the amide nitrogens as a carbon, so my search on chemspider returned that there were no hits at all.  Now, in this case that's fine, cause I messed up and I could ammend my structure, get the appropriate InChI, and have chemspider return the proper page, but it made me think about the fact that I don't know if anyone has a search which also returns similar structures in

The sulfur melt dehydrogenation,

was carried out, with 9.5% isolated yield of the desired product and 69.3% recovered starting material.  Other products (observed by TLC) were not found after the column.
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