The Synaptic Leap

This page will contain all examples of failed reactions in the attempted asymmetric hydrogenation of the PZQ enamide.
 
We are very grateful to Sigma-Aldrich for an initial donation of the catalysts employed below. Please note that we do not hold a library of other hydrogenation catalysts. Any suggestions for alternative catalysts are welcome, but in the interests of speed, the best suggestions here are catalysts + who could run the reactions (other than the Todd group) and to whom we could send PZQ enamide. This will accelerate the research.
 

The PZQ-enamide is shown below. This is an intermediate in the stereoablative route to enantiopure PZQ.

HPLC trace for PZQ-enamide (using ChiralcelOD-H, solvents: Hex:IPA:TEA 60:40:0.1, Flow Rate: 0.7 mL/min) gives retention time: 15.772 mins. Original HPLC trace attached below.
 
(Note comparison HPLC trace for PZQ itself is here.)
 

A possible solution to the large-scale preparation of enantiopure PZQ is the approach shown below, originally suggested by Craig Williams.
 

 
First step:
We have a decent approach to this involving heating in a sulfur melt. This needs improvement, but we can generate gram quantities of the intermediate PZQ-enamide easily.
 
Second step:

We started catalyst screenings for the asymmetric Pictet-Spengler reaction. So far, we have tested several achiral Brønsted-acidic catalysts to determine acid strength which is required to cyclize the open-chain praziquantel intermediate 1 to the tetrahydroisoquinoline heterocycle 2.
 

 
Catalysts:
 

 I came upon this reference:
http://www3.interscience.wiley.com/journal/123349682/abstract
which refers to masking of bitter taste of an API through formulation with a beta-cyclodextrin derivative.

Based on past experience with "Chiral Switch" projects in a commercial environment, I have drafted the attached document as a summary of my understanding of the aims of the PZQ project in the context of what would be needed (technically) to get (R)-PZQ to market in the western world.  This does not examine manufacture per se, but rather the many necessary steps to obtain permission to market.  I am sure there are some which I may have missed, but the point is that there would (in my past experience) be far more going on than focussing as at present on "manufacture" and "cost of goods", however important these will be in the long-run. 

Let's think long-term: How best to scale up production of PZQ?

This is likely most economically done in India or China (possibly Brazil or South Africa), all of which have well-established pharmaceutical manufacturing sectors.  However, building manufacturing capacity in poorer disease-endemic countries stands to have enormous benefits for economic development and potential to eventually better meet local and regional general pharmaceutical demand! 

Project to determine if it is feasible to automate / accelerate the catalyst screening project through automated software systems. 
Currently the project is in requirements initiation. We are defining top level requirements of what an automated tool will look like.  Please feel free to contribute

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

 

To host the raw data from the Pictet-Spengler approach to the enantioselective synthesis of PZQ Michael has started an Electronic Lab Notebook. We're using the open source Southampton Lab Blog interface for this, since we're collaborating with them on a couple of things related to this site.
 
Given that it's open source, the lab blog system can be changed and enhanced by anyone. This is a great chance to make the lab blog perfect for experimental organic chemistry, e.g:
 
1. How do we best report TLC data - at the moment we're taking photos, but this is cumbersome.