Enantioselective Synthesis of Praziquantel

Published by ndt228 on 30 January 2006 - 11:06pm

Aims:

  1. To develop an efficient enantioselective synthesis of the bioactive enantiomer of Praziquantel
  2. To optimize such a synthesis so it is suitable for large-scale manufacture.

Background

Praziquantel (PZQ, 1) is the drug of choice for the treatment of schistosomiasis.1 It is synthesized as a racemate, where one enantiomer is active, and the other has no effect on the parasite.2 Half the currently-administered pill is hence unnecessary. The World Health Organisation and the international schisto community recommend that a way be found to produce PZQ tablets containing only the active enantiomer.3 This would have the following pharmacological advantages:
i) Optically pure PZQ is twice as active as the racemate;4 but with a reduced ‘drug burden.'
ii) An increased dose would be possible. It has been argued convincingly that the current dose is subcurative, favouring the progressive selection of partially resistant survivors.5
iii) The size of tablets could be reduced, thereby helping children take the drug.

The (S)-(+)-enantiomer is inactive and harmless [NB It is said to contribute significantly to the bitter taste of the racemate; see "Resolutions of PZQ"], and the (R)-(-)-enantiomer is active.6 The control of the single stereogenic centre is at the centre of the project.
In general it is easier to synthesise racemic molecules than it is to synthesise one enantiomer of a racemate. The current very low price of racemic PZQ reflects this. PZQ is being distributed in mass chemotherapy programmes in six African countries as part of the Schistosomiasis Control Initiative (SCI), funded by the Gates Foundation.7 (Other African countries are attempting to follow suit with their own national control programmes.) The drug has been purchased by SCI from the South Korean company Shin Poong for US¢7 per 600 mg tablet. The target efficiency for a competitive synthesis of optically pure PZQ is hence US¢23 per gram.
Many syntheses of PZQ have been reported. The original synthesis was in 1977.8 The more recent report based on peptide acetal chemistry may reflect the current generics route.9 Our group has also published new radical- and solid phase-based methods.10, 11

The original patent literature detailed a method for the separation of PZQ enantiomers, based on co-crystallisation and recycling of the unwanted enantiomer.12 It is likely that such a method is expensive (it has never been adopted). [See also a 2009 paper in "Resolutions of PZQ"].  It is likely an efficient enantioselective synthesis would be less expensive.
The first enantioselective synthesis of PZQ was reported in 2004 using a chiral auxiliary-mediated Pictet Spengler reaction.13 The method is not suitable for scale-up, not least because chiral auxiliary-mediated processes are inherently less efficient than catalytic ones.

Summary of the Project

The aim of the project is to design and execute a catalytic, asymmetric synthesis of the active enantiomer of PZQ. The synthesis must be highly efficient and low cost. It is not enough that the synthesis works because the route needs to be scaled up for multi-ton production.  The object of this open source chemistry project is therefore to share synthetic strategies and results towards this target.
There are two ways in which organic chemists can help. One is to design synthetic routes or share experience on those being discussed. The other is to attempt one or two steps and share results, so that an optimized route may be arrived at.
As an example, our group at Sydney has devised a new synthesis of PZQ and are currently exemplifying it in the lab. We would value advice on this route, and, once we report it, practical improvements on any given step (in other words beat the yield or enantiomeric excess!) On the other hand, people are encouraged to devise alternative routes and post these as new entries on Synaptic Leap.
References
 
1. A. Fenwick, L. Savioli, D. Engels, R. Bergquist and M. H. Todd, Trends in Parasitology, 2003, 19, 509-515.
2. P. Andrews, H. Thomas, R. Pohlke and J. Seubert, Med. Res. Rev. 1983, 3, 147-200.
3. Second meeting of the second EU Concerted Action on Praziquantel, Yaound&eactute;, Cameroon, March 2004.
4. M. H. Wu et al., Am. J. Trop. Med. Hyg. 1991, 45, 345-349.
5. M. J. Doenhoff, Parasitol. Today, 1998, 14, 434-435.
6. C. A. Redman et al. Parasitol. Today 1996, 12, 14-20.
7. http://www.schisto.org/
8. J. Seubert, R. Pohlke and F. Loebich, Experientia 1977, 33, 1036-1037.
9. J. H. Kim, Y. S. Lee, H. Park and C. S. Kim, Tetrahedron 1998, 54, 7395-7400.
10. M. H. Todd, C. O. Ndubaku and P. A. Bartlett, J. Org. Chem. 2002, 67, 3985-3988.
11. S. El-Fayoummy, W. Mansour, and M. H. Todd, Tetrahedron Lett. 2006, 47, 1287-1290.
12. J. Seubert, German Patent Application 2,418,111.
13. C. Ma, Q.-F. Zhang, Y.-B. Tan and L. Wang, J. Chem. Res. 2004, 186-187.


Chemical Structure of Praziquantel

Praziquantel
Praziquantel

 

 
 

Comments

jcbradley's picture

In case it has not been covered, ChemRefer has found a thesis relating to this synthesis and posted it on UsefulChem.

MatTodd's picture

Thanks for the link, I hadn't seen this. The thesis describes some new synthetic methodology for related compounds (i.e. the methodology is the focus). This is applied to PZQ. However it's a very long synthesis of PZQ and uses expensive reagents. Interesting chemistry, just not relevant here...

 

Check this paper "May 2006" regarding the synthesis of request

Tetrahedron: Asymmetry 17 (2006) 1415–1419

Enantioselective synthesis of (R)-()-praziquantel (PZQ)

MatTodd's picture

Yes, this paper is the first report of a catalytic, asymmetric synthesis of the correct enantiomer of PZQ. There are some interesting things in the paper, particularly with regards the previously-reported (non-catalytic) route to PZQ as a single enantiomer.

The route described uses an asymmetric Noyori-type hydrogenation which gives a moderate e.e. that is improved by a crystallisation. I think it's a nice piece of work, carefully done, that will need considerable modification if it is to be viable for this project. Remember that the synthesis eventually required needs to generate (R)-PZQ for approximately 23 cents per gram! Any ideas?

Cheers,

Mat