Starting from the Racemate
There are two general ways to generate enantioenriched PZQ starting from the racemate - either by destroying the stereocentre, or not.
1. Destroying the stereocentre, then reinstating it (a "stereoablative" approach). Craig Williams suggested this interesting possibility: take rac-PZQ and oxidize to the enediamide 2. This allows a catalytic, asymmetric hydrogenation to give (R)-PZQ. This is attractive because asymmetric hydrogenations are efficient, and both enantiomers of rac-PZQ can be taken through to the enantiopure material.
Craig's Suggestion
This is a great suggestion. According to the original review of PZQ by Peter Andrews et al., a similar idea is contained in the original patent literature on PZQ. The reference is "J. Seubert, German Pat. Appl. 2,418,111". I tracked down this patent, and it's unsurprisingly in German. While I can order a beer in German and ask the way to the cinema, I can't translate this. Does anyone with some German have some time to extract relevant information from this patent and give the conditions that were used for the generation of the enediamide, and whether this was done on PZQ or an analog? I'll post it below. [update - translation now shown below]
We have started to look at the oxidation reaction to the enediamide, but need help with this reaction. The review has no experimental details - but the reaction has been published in...[need reference]
2. Resolution
According to the same review above, intermediates in the synthesis of PZQ (3 and 4 below) could be resolved. (PZQ itself presumably cannot, unless anyone has any bright ideas). Obviously this is a less attractive approach than a catalytic, asymmetric synthesis of such intermediates. However, the unwanted enantiomer, after conversion to (S)-PZQ, can be transformed to the enediamide 2 and hydrogenated to rac-PZQ. This therefore converts the inactive enantiomer of PZQ to rac-PZQ, giving another 25% yield of the desired enantiomer.
Resolvable intermediates
The review describes this process without specifiying what R is (where for PZQ it's cyclohexanoyl).
For the resolution via 4 to be effective, this molecule either needs to be synthesised from scratch, or it can be made from PZQ. For an industrial approach, it is probably best to simply make this molecule from scratch, as in the current industrial synthesis, but either way can easily be used to generate quantities of 4. What is needed now is a robust method for the resolution of amine 4. This idea now has its own page here.
Resolution of Praziquanamine
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). 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.
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Either way, it’s a secondary amine. We need a resolution that is inexpensive, and will work on a large scale. We need advice (from anyone reading):
1) Which chiral acids are good candidates for such a resolution?
2) Which solvents should we look at first?
3) Which conditions should we aim for to keep the eventual cost of the large-scale process low?
4) Are there any good guidelines for procedures to maximize the yield of crystalline salt, and the yield of the subsequent re-isolation of the free amine?
5) Does anyone know of papers where amines resembling praziquanamine (with a stereocentre a couple of carbons away from the NH) have been resolved?
6) What can we do with the undesired (S)-enantiomer of praziquanamine? Throw it away? Our default plan is to dehydrogenate and re-hydrogenate (via 2, above) to re-form (rac)-praziquanamine, but this is not elegant.
Possibly relevant publications and groups:
Screen for resolution conditions using composition of mother liquor (Eli Lilly)
Please feel free to post suggestions below, and we can take a look at them. Even better – have a go in your own lab and post data!