The Synaptic Leap

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'm now happy with the data for TCMDC-123812 and TCMDC-123794. A bit of usual practical annoynce with TCMDC-123794 caused some trivial issues, namely a bit of repurification and acetone in the final spectra. These have now been taken care of and the compounds are ready for testing!
I've summarised the various intermediates and other compounds that are in the works on OpenWetWare. Please get in touch if you're interested in testing them.

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.

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

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.

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! 

PZQ can’t be resolved as-is (unless anyone has any bright ideas how to resolve amides). One of the most promising strategies to prepare enantiopure praziquantel (using a strategy that starts from the racemate) is a classical resolution of praziquanamine (1, "PZQamine"). This molecule can either be made from scratch (it’s an intermediate in the current PZQ synthesis) or can be obtained in high yield from PZQ itself.
 
 

 
The synthesis of rac-PZQ via the Pictet-Spengler route was developed by the Korean Shin Poong Pharmaceutical Company and obtains very low production costs of US¢7 per 600 mg tablet of the drug.

First step (amide bond formation to give 3)
Second step (attachment of acetal to give 4) - there's also a one-pot procedure to combine the first 2 steps
Third step (cyclization to praziquanamine to give 5)
Fourth step...

Project A: Development of a low-cost enantioselective synthesis of PZQ. It's an open project, like everything on TSL.
Meaning?: contributors can change anything they wish on these pages.
If you wish to contribute: please don't leave comments here. Instead, edit the pages below directly or leave comments.
Other ways to interact: The Friendfeed page and the Lab Book Blog (for the Pictet-Spengler approach)