The Synaptic Leap

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.
 

Last week I was talking with Lei Liu from Tsinghua University, who was visiting Sydney to give a talk on his synthetic methodology research. I showed him the compounds that are the starting point of the open source drug discovery project for malaria, the arylpyrrole set. He said he'd seen these compounds before, in a different context, and after a little searching around we found the relevant paper here.

Ok now I'm getting close to TCMDC-123812/123794. A slight change of tack for the alternative core synthesis seems to have paid off. First alkylation of ethyl acetoacetate with chloroacetone and then condensation with 4-fluoroaniline appears to have given the pyrrole with an ester on the 3-position quite nicely in 61% yield over the two steps after recrystallisation (PMY 8-1). Sometimes it just pays to change the plan completely when you feel like progress is slow.

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.

Saw this very interesting article/development. Intel sponsoring research at top universities, but heavily encouraging the projects to be open source and the universities not to take out patents. A bold step, very counter to the philosophy that is so familiar to any current academic. From the website:
 

 We have looked at an alternative process to generate the diamine precursor to PZQ, whose resolution is documented. The process involves reduction of the cyano-imine derived from the published reaction of THIQ with peroxide/tungstate/cyanide. Having been able to reduce 1-cyanoisoquinoline very cleanly using Pd/C we anticipated that it would be possible to do the same here. It would be important, however, to maintain acidic conditions to prevent the retro-addition of the cyanide (well documented for the 1-cyano and 1-(nitromethyl)isoquinolines with a free N-H).
 

 
 

Now that both racemic and single enantiomer PZQAmine are available, it is possible to determine phase diagrams - either binary, based on MPt, or ternary based upon solubility.  But why do this ?

There may be members of this community who do not yet have direct experience of developing a new medicine from concept to pharmacy shelf.  Be assured, there is a lot more to it than "just" the synthesis of the API.  Why not take advantage of a Free ACS Webcast on May 6, 2010 Thurs 2:00-3:00 PM ET
From a Beaker to a Bottle: Overview of the Drug Discovery and Development Process for Small Molecule Therapeutics
A free webcast from the American Chemical Society as part of their Professional Growth and Development Series. Learn about the drug development process and find out how long it takes, how much it costs, and the odds of getting a new drug approved.