Resolution of PZQAmine

Published by ndt228 on 2 May 2010 - 9:34am

I'd like to suggest that this approach deserves its own thread - at present it is mentioned within the stereoselective synthesis project.  I think it is more important than that - if you agree, there is existing content that should be migrated across to here. 

Comments

ndt228's picture

As PZQAmine is the penultimate intermediate in the current racemic synthesis of PZQ, it must be (even) cheaper to make than PZQ.  (See links elsewhere on this site to the present route).  Making the leap-of-faith that a resolution can be found, the cost of conversion of (R)-PZQAmine to (R)-PZQ will be essentially the same as at present, other than changes driven by the different physical properties of the (R)- enantiomer.   This will include the cost of cyclohexanecarbonyl chloride (see discussion elsewhere), which thereby "drops out of the equation" as topic of concern.
There are two necessary steps to a successful resolution project:   (1) A viable resolution  (2) A viable recycle process for the off-isomer.   It is also important to be realistic in what can be achieved - whilst the theoretical efficiency of step (1) is 50%, you will need a 90% yield of the (R)- content to even manage 45% conversion per cycle.  To get yields this high will require process research, but this comes after you have identified a range of candidate processes and narrowed down the field.  So the message at this moment is - don't get hung up about costs.  Do the research, do it well, and don't miss anything in screening for resolving agents.
As far as the recycle is concerned, is there a possibility that re-exposure of the (S)-PZQAmine to the original cyclisation conditions could induce racemisation ?  If so, then this would probably be about as cheap as the step could possibly be made, as it would plug straight in to the existing full-scale production method. It will probably be easier to test than to argue about, as a route to the resolved amines already exists, via resolution of PZQ (see project of that name) and amide hydrolysis (conditions established in the Todd lab).
Best regards, Nick