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.
PZQamine a secondary amine. We need a resolution that is inexpensive, and will work on a large scale.
One of the original patents in this area (US 3,993,760, 1976) details a way to do this resolution, shown below. This patent actually concerns a benzoyl analog of PZQ, but the effect is the same since PZQamine is the amine resolved.
Quinic acid is employed. The initially-formed crystals are the salt formed from the undesired enantiomer of PZQamine, so the mother liquor is concentrated to yield new crystals of the desired enantiomer. The exact procedure as reported is (page 5, column 7, "Example 1" lines 32-50):
"[(-)-PZQamine] may be obtained as follows: 24.3 g. of [(rac)-PZQamine] (m.p. 118-119 oC; obtainable by treating [(rac)-benzoyl analog of PZQ] with methanolic hydrochloric acid and subsequent heating to 180 oC at 15 mm Hg) are dissolved in 100 mL methanol and added to a warm solution of 30 g. quinic acid in 500 mL methanol. The mixture is refluxed for 15 minutes and then cooled to 20 oC. The crystals obtained are separated by filtration, the mother-liquor is evaporated to 100 mL and the crystals precipitating now are separated. The quinic acid salt of [(-)-PZQamine] is obtained; m.p. = 196 oC. The salt is dissolved in water, the solution is made alkaline and extracted with chloroform. After drying and evaporating the organic solvent the laevorotatory free base is obtained; m.p. = 120 oC, [a]D 20 = -306 o C (sic)"
The most obvious thing about this procedure is that the mass recovery of the desired enantiomer is not given. It is also doubtful that enantiopure material is produced without a final recrystallisation, but this is not specified. Nor is the solvent/concentration employed in the measurement of optical activity. Having to obtain the desired material from the mother liquor is also sub-optimal. This is a problem with using quinic acid as a resolving agent, since the unnatural enantiomer is not available in quantity.
Update August 27th 2010: Syncom BV rapidly identified a simple resolution method for PZQamine below. This method employs either quinic acid (which was also mentioned in the original Merck patent on PZQ) or dianisoyltartaric acid. (-)-PZQ is the active enantiomer desired in this project. Resolution with naturally-occurring D-(-)-quinic acid gives (+)-PZQamine. If we make the assumption that (-)-PZQamine leads to (-)-PZQ, and if we assume that we want to isolate PZQ from the solid component of the resolution rather than the mother liquor, then we would need L-(+)-quinic acid for this PZQ resolution which is not available. However (-)-dianisoyl-L-tartaric acid also gives (+)-PZQamine, implying (+)-dianisoyl-D-tartaric acid will give the desired (-)-PZQamine and hence (-)-PZQ. Both enantiomers of dianisoyltartaric acid are available commercially (for the same price), e.g. from TCI. The procedure and spectra are shown below, and will now be repeated in our lab here in Sydney. We'd encourage others to verify/check this also.
Syncom have done a fantastic job here. If there are remaining questions, they are these:
1) Which other chiral acids are good candidates for this resolution?
2) Which other solvents should we examined?
3) Which conditions should we optimize 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 other 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.
Relevant publications and groups (please just edit the page and add below using DOI to link):
Screen for resolution conditions using composition of mother liquor (Eli Lilly)
Please feel free to post any other suggestions below. Even better – plan to have a go in your own lab and post data here.