Characterisation of rac- and (R)- PZQ Amine

Published by ndt228 on 5 October 2011 - 10:06pm
AttachmentSize
PZQ Phase Diagram v1.pdf13.06 KB
PZQAmine DSC raw data.pdf219.67 KB

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.
Explanation:  Whilst the "pure" racemate and (R)- enantiomer show sharp melting point behaviour typical of pure materials, mixtures of the two exhibit melting point depression.  When this reaches a minimum the mixture is known as the eutectic.  By using DSC (differential scanning calorimetry) to observe the melting event in detail, two melting endotherms can be observed for most of the mixtures.  The onset of melting is determined graphically from the DSC, and is more informative than the temperature of the endotherm peaks.  These data can be plotted to map out the phase diagram, which is of relevance because melting point is a surrogate for solubility, and hence the behaviour of these materials during recrystallisation. 
I will next be attempting to improve the resolution of the DSC method by adjusting the scan rate, so as to better define the location of the eutectic point.  For the present it is clear that crystallisation of PZQAmine mixtures with below 50% ee will deliver racemic crystals, whereas mixtures of above 95% ee can be crystallised up to enantio-purity. 
It is therefore important at present not to convert the diastereomeric salt to free amine until confident that the salt is of at least 95% ee. 
Best regards, Nick

Comments

MatTodd's picture

Nick,
 
This is great. Particularly nice to have the raw data.
 
So your comments above refer to the crystalisation of the amine itself. In the published procedure we talk about the salt of this amine being the thing that is crystallised, rather than the liberated amine. To be honest I can't recall if Michael played around with the crystallization of the PZQamine - i.e. to determine the ease of crystallisation of the two. It'd be nice to be able to crystallise the amine directly, since then an assessment of  e.e. could be made directly without having to do a conversion from salt to amine. With your professional Process hat on, would you agree? Or are salt crystallisations preferable?
 
Your analysis puts a useful value on the e.e. needed before PZQamine crystallization is useful. I know you want to refine this, but how accurate is the number, or rather how confident are you of that value? Should we try to show this experimentally yet? e.g. crystallize 90% and 97% e.e. PZQamine to check which way it goes?
 
Craig Williams emailed me with this additional question: "I wanted to know how you think the phase diagram will help. Are you thinking of using zone refinement? This is an old technique for separating solids with different melting points."