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

I was looking at all the difficulty that is occuring with finding a cheap source of chiral catalyst for the Pictet-Splenger and mused about using Phenylglycine, as this avoids the issue due to it being part of the chiral pool.
Anyway here is my attempt at getting the key ring system together for the system. Don't think anything I used is particularly expensive. Sorry about the conditions being vague, was just a quick thought that I came up with.

Background
Relevant experiment.  Basically, the Pictet-Spengler to form 3 PZQ analogues and PZQ itself.
The mass spec is of a by-product of the acid mediated PS cyclisation of MNR10-1 to form KAB8-1, aka the dimethoxy N-benzoyl PZQ analogue.

 
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.
 

The attached file contains X-ray powder diffraction patterns (XRPDs) for racemic and (R)- PZQAmine, as well as a mixture of the two.  These confirm that (as is often the case) the racemic compound and the single enantiomer have different crystal structures.  This is consistant with the phase diagram for PZQ Amine gathered from the melting point of mixtures of the two.
Thanks to Jana Galbraith (Almac Sciences Physical Sciences Dept) for recording these patterns.

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.

The first paper arising from the open science coordinated by this site has just been published here. Though the project is very much ongoing, it's super exciting to be able to publish a paper as a milestone. i.e. one can run an open project, and once a certain point has been reached, one can submit a paper for traditional peer review to act as a reviewed summary of progress.
 
Many people are thanked in the original article, but I'd like to say thank you to everyone who helped the project on this site, particularly you industry/process guys - your advice was readily forthcoming and of a particularly high quality.

Praziquantel: Racemic Resolution

This page is intended as a place where people can discuss the student-led optimization of PZQ resolution. Relevant ELN is here, containing background here. Description of how students can help out is here (PDF). Paper will be assembled here. Blog post describing the project is here.