Dehydrogenation of PZQ and final EtOH recrystallization results

26 Oct
Published by RyanPakula

Trying to dehydrogenate PZQ using elemental sulfur.

Total yields including second batch of recrystallization are 86.4%, 74.34% (no second batch), 78.7%, and 80.1%, respective to 0x, 0.5x, 1x, and 2.5x hexanes volume to ethanol volume.
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We're trying to find a good way to dehydrogenate praziquantel at the benzylic position (vide supra).  If we can cheaply obtain this product then we'll be able to, first, study and find a good way to enantioselectively hydrogenate it, and then, if we find a cheap method, we'll be set and we can produce (R)-PZQ cheap!  So that's the path we're looking at right now.  We're trying a sulfur melt first (mix the two solids, heat to melt the sulfur) because sulfur's cheap.  The reaction works pretty simply, and the components separate nicely on a TLC plate, but I messed up the column a bit (5% EtOAc in hexanes ramp to 100% EtOAc) so I only have a 9.3% yield of the desired product (16.2 mg pdt from 174.5 mg s.m.).  I'm rerunning the reaction to get a better feel for what the yield is until these simple conditions and also to get more product to characterize it fully.  Still haven't fully figured out the spectra uploading thing yet, but they'll come so you can see what I'm looking at.  Turns out starting around 30% EtOAc in hexanes is better.  I plan to use this eluent to start the next column.  Any ideas for column eluents (in case someone's done this or a similar column and had good success) or, more importantly, any ideas relating to this dehydrogenation reaction?  Also, I did try this reaction with 5 eq. sulfur and 0.1 M (for PZQ) in DMF.  Nothing happened at all (as observed by TLC).
 
In terms of the recrystallizations from 50ºC EtOH: with the second batch, I took the motherliquors from the first batch, concentrated them down, dissolved in minimal 50ºC EtOH, added 1 mL 50ºC hexanes to each, then chilled at 5ºC over the weekend.  All had crystals except the 0.5x.  In filtering, the crystals were rinsed with 5ºC EtOH.  Yields for the second batch were 12.9%, nada, 7.83%, and 11.9%, respective to 0x, 0.5x, 1x, and 2.5x.  The melting points for these second batches were 138.0-138.1ºC, n/a, 137.2 - 137.9ºC, and 137.0 - 137.5ºC, respectively.  This brings the total recovery yields to: 0x - 86.4%, 0.5x - 74.34%, 1x - 78.7%, and 2.5x - 80.1%.  I plan to look a little more at this and try 5x and 10x, and to repeat 0x and 1x.