The Synaptic Leap

January 2012, Here’s a quick update on where we are regards the Bronsted Acid catalysed Pictet-Spengler reaction.
 

It’s been too long since I’ve updated the progress of this project on here but here’s a brief summary of where we are and what’s planned for the near future.  From late November we’ve had a summer student, Kat Badiola, working on the project.  She started with preparing pure, racemic samples of the 3 PZQ analogues shown below (compounds 6-8) via the Pictet-Spengler cyc

We have received encouraging biological results for the analogues we sent for testing before Christmas. Mat has discussed this here on TSL and on G+. Our best hit came from the "near-neighbour" compound and the original GSK hits came out slightly less active than in their original high throughput screen. However, Paul Willis at MMV rates TCMDC-123794 as a better lead than PMY 14-1 (TSL post).

 
I've now reached the end of my second week in the lab working on the Pictet-Spengler route to praziquantel.
 
It's been quite a steep learning curve so far, particularly in terms of analysis and familiarizing myself with the lab.  I've had experience (if you can call it that) with NMR and MS before, but that was only in the sense that I prepared my sample in the tube/bottle and a week later, I got a spectrum on my bench.  Now I'm preparing NMR and LCMS samples on a daily basis.  I'm finding it much easier to use the LCMS (however, interpreting data is another matter), and I've been introduced to the procedure for recording NMR spectra.
 

I'm now fairly confident that I've made TCMDC-123794 and TCMDC-123812. By fairly confident I mean that I've got a reasonable looking but crude 1H NMR and low res. mass spec of both of the compounds. They are not clean by NMR after a column and the yield of the reaction was pretty bad (~20%). Still this isn't too bad for a first go, using a quick and dirty acid chloride. Most of the mass seems to go toward turning the acid into the anhydride. This is supported by NMR but mass spec hasn't given a positive result so far.

A start has finally been made on determining the phase diagram for PZQAmine from 0 to 100% ee, based upon melting point determination of known % w/w mixtures of racemicand single enantiomer PZQAmine.  Samples of the latter were provided by Michael early this year. 
The "version 1" phase diagram is attached, along with a second file containing the raw data.  Note that the data has been generated from mixtures of racemic and (R)- PZQAmine, and the data simply "mirrored" into the (S)- rich region of the diagram.  The ee of the supplied (R)- amine has been taken as stated (97% ee) and not rechecked.

In the last couple of weeks my time has mostly been spent trying to figure out whats going on in the oxidation of pyrrole-3-carbaldehyde to the corresponding acid.

Praziquantel: Racemic Resolution

This is the first biweekly-ish update on the resynthesis of TCMDC arylpyrrole series leads TCMDC-123794 and TCMDC-123812. 

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