Praziquantel Update October 20th 2010

20 Oct
Published by MatTodd

A lot has been happening here in the last few weeks, so I ought to summarise:
1) Further to Syncom's success with a resolution of PZQ, we have been working to replicate the results and expand on them. The whole process works really well. Together we have developed a nice way for anyone to resolve gram quantities of PZQ without the need for any chromatography. This should be useful to a number of pharmacology labs round the world, and a starting point for evaluating the use of resolution for the large-scale production of PZQ. This was one of our primary objectives. It's particularly exciting that this development happened with the help of industry - specialists who have copious amounts of the relevant expertise and who contributed freely to this open project.
Since we're posting a lot of raw data we're keeping on online electronic lab notebook for this part of the project. We're nearly done with the expetiments, and we've been working on the relevant paper openly on another wiki site, OpenWetWare, where we have our group protocols and stuff. We're gradually writing this paper, so please feel free to comment/suggest things. We're going to submit soon. If you have an account on OpenWetWare you can edit directly, but if you're going to do that please leave clear log notes and maybe drop me an email. We can't credit everyone who makes minor contributions to the paper, but substantial contributions can be credited with authorship.
2) Laurent Lefort at DSM has been screening catalysts for the asymmetric hydrogenation of the PZQ enamide. If we can find a catalyst this would be a really sensational solution to the whole challenge - we could convert racemic PZQ to an achiral intermediate and then convert all of that to enantiopure PZQ - no waste or recycling that is required for resolution. So far we do not have an active ligand - no conversion at all in any case. This is incredibly frustrating, but we need to keep trying. We can easily make the enamide at Sydney. Let us know of any groups we ought to send a gram of this material to - groups that specialise in ligands for asymmetric hydrogenations and who would embrace the open approach we're taking by donation of some time/expertise. DSM have become involved because they are specialists in this area and are able to include our substrate in screens they are doing in any case.
3) As part of this project, WHO/TDR have funded some extra research into PZQ via a contract research company, Development Chemicals. They've finished their investigations, which have centered on resolution, and we should be posting those results here shortly.
 

Comments

Mat
We have a few comments/clarifications on the posting above.

  1. Surely you mean PZQ-amine in this section? While we agree that this is a decent method to prepare grams of the required material (preferable by generating the amine from the commercially available benzoyl derivative- we can send you 50-100g if required) the problem is one of recycle; this can potentially be done by enamide formation followed by re-hydrogenation, but this is probably more expensive than discarding the material. The expensive resolving agent (more expensive than PZQ!- lab quantities available from TCI) would also need to be efficiently recycled to minimise the cost.
  2. The only way that this hydrogenation is going to be commercially viable on a low added value product is with a TON of 10,000+ due to the price of the metal and the ligands. As you say, it is a tricky problem though we have achieved some limited success on the benzoyl enamide achieving a 3:1 ratio of isomers at 50% conversion.
  3. It should be pointed out that the chemistry on the WHO funded project is being carried out by us; we have indeed investigated the resolution of an early stage commercial intermediate, which works very well. Additionally, we have found a simple method for the recycle of the undesired material should this be required/cost efficient. We are still waiting for a response from WHO regarding the posting of the results.

1)a) The resolution of praziquanamine with dianisoyl tartaric acid can be easily performed and upscaled to a multi-kilogram (> 1000 Kg) process.
b) The dianisoyl tartaric acid resolving agent can be recovered and be reused again in the resolution process. Examples of large batch scale (>1000 Kg) resolutions and recovery of this resolving agent are for example described in patent US2002/0151717.

ndt228's picture

I can confirm that I am aware of a very large-scale and long-term recycling operation for Dibenzoyl Tartaric Acid, utilised in a synthesis run by a major pharma company, and then sent (as liquors) to a contractor for reprocessing and return of "as new" resolving agent.  I am not however aware of the % recovery per cycle, though I do know from my own lab-scale experience with the Ditoyl equivalent that some care is needed to avoid partial hydrolysis of the aryl ester.  The alkaline extract must not be left too long before neutralisation and recovery of the DBTA.  Simple acid extraction and stripping did not yield a good quality product, and I never had time to develop a crystallisation.  I expect things are much the same for the Anisoyl derivative, but experience with its synthesis should come in handy.
regards, Nick

ndt228's picture

I have been following progress on the above with interest over the summer.  My compliments to Jean-Paul at Syncom, both for the screening work for an analytical method and subsequently for an effective resolving agent.  Also to Michael in Matt's lab for making his lab-book accessible to document his work in scaling up the synthesis of the reolving agent and the resolution.
I'd now like to offer my own services (and use of the facilities at Almac Sciences) to undertake some characterisation work upon the resolved and racemic PZQAmine, aimed at defining the phase diagram.  Past experience indicates that it is important to do this as a part of the overall development of a resolution, and I have obtained permission to utilise our well-equipped Solid State services lab to do this.
I will post separately a rationale for why such activity is of use.  For now, if you (Matt) are able to send ca 100 mg each of racemic and pure single enantiomer PZQAmine, I will make a start on the binary phase diagram via DSC.  If you can also confirm your preferred recryst solvent for the amine, I can also see if I can stretch this material to get some solubility measurements for a ternary phase diagram.  These two can sometimes differ significantly.  I also plan to get FT-IR and XRPD data on the two materials.
regards, Nick

MatTodd's picture

Awesome offer, Nick, thank you. This isn't something we can do in Sydney, but sounds like you're well-equipped to do. We'll prepare those samples asap and ship them to Almac. Also, this wasn't a scientific problem we had considered - very glad that you have pointed this out.

MatTodd's picture

... was done a few years ago here, for comparison.

MatTodd's picture

Nick - From our resolution approach we've a sample of enantioenriched PZQamine we'd like to mail you (along with a sample of rac). It's 97% ee. Is that good enough? If, as I suspect, it's not, then we will tinker with crystallizing the amine further, as well as crystallizing the salt it comes from a few times, to see if we can get the ee up.

ndt228's picture

Dear Matt,
97% ee is perfectly respectable at this point, and is almost as far away as you get from racemate.  The aim of the characterisation is to compare crystalline forms of the racemate and enantiopure material to establish what degree of difference exists, and whether that might be exploitable in some way(eg recryst possibilities for the amine rather than the diastereomeric salt).  The material you have should be quite good enough for that, so please send it along for evaluation.  At this point I will simply look make the comparison of "as recieved" material. There is also the theoretical possibility that polymorphs of the single enantiomer might exist (and be advantageous), but the search for them is an entirely different matter. Such studies become more feasible as the supply of material increases, and indeed can happen by serendipity as larger quantities are handled & stored in different ways in the course of scale-up work
regards, Nick