Enantioselective Synthesis of Praziquantel

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

 

 
 

Alternative synthesis of PZQ using Phenylglycine

I was looking at all the difficulty that is occuring with finding a cheap source of chiral catalyst for the Pictet-Splenger and mused about using Phenylglycine, as this avoids the issue due to it being part of the chiral pool.
Anyway here is my attempt at getting the key ring system together for the system. Don't think anything I used is particularly expensive. Sorry about the conditions being vague, was just a quick thought that I came up with.
Alternative synthetic route to PZQ

Aza-Henry Route to PZQ

Aza-Henry route to PZQ
 

We have designed a new synthesis of PZQ based on a catalytic, asymmetric aza-Henry reaction (Scheme 1). The key step is the generation of the new stereogenic centre in 4. From here, the reduction to 5 should be facile with e.g. samarium iodide.1 From 5, the two steps to PZQ are known from the original report.2
 

Aza-Henry Route to Praziquantel
Aza-Henry route to PZQ
The catalytic, asymmetric Henry reaction has recently been the focus of some interest in the literature (Figure 1). Some of the most promising methods are organocatalytic.3 The reaction in our case needs to be performed on the sometimes problematic substrate 3. We will be attempting this reaction with a couple of known catalysts, followed by some simple variants, and will report the results when we have them. If any groups who have published on this subject would be willing to donate small quantities of existing catalysts to this effort, this would be enormously appreciated.
 
Aza-Henry Catalysts
Aza-Henry Catalysts

 
A final issue is that the dihydroisoquinoline 3 is not commercially available. There are many simple routes to this compound, such as a potassium permanganate-mediated oxidation from tetrahydroisoquinoline. However, the synthesis of 3 also needs to be efficient and inexpensive if the whole route is not to be compromised.
 
Recrystallisation of PZQ may be achieved with diethyl ether in hexane.8

 
What the Community can do

 
With regards our first proposed route:
a) Advice from groups experience in this chemistry would be very useful.
b) Donations of catalysts for screening of the aza-Henry reaction would also be very useful.
c) Students in such groups can attempt one or more of the reactions in our proposed route and try to maximize the route's efficiency. This applies to all steps, but is particularly relevant for the asymmetric step.
 
With regards scale-up, advice from process/industrial chemists on any given step with regards to scale-up issues would be very valuable. This applies to both synthesis and purification.
 
Technical Issues:
 
For discussions of routes, a regular blog-style of discussion is probably fine. For posting chemical structures, I would recommend using e.g. Chemdraw and posting gifs. To do this you 'creat content' and submit gifs to the image gallery. There is an option when doing this of attaching Chemdraw .cdx files, which may be useful for us. When inserting images please use thumbnails - image sizes can be a little erratic.
For reporting of experimental data, it would be most useful if quality scientific conventions were maintained, and that if a result is claimed, it is properly reported. The open source community relies on honesty and repeatability rather than peer-review. Certainly the route we arrive it will need to work well in the real world!
1. K. Yamada, S. J. Harwood, H. Gröger and M. Shibasaki, Angew. Chem. Int. Ed. 1999, 38, 3504-3506.
2. J. Seubert, R. Pohlke and F. Loebich, Experientia 1977, 33, 1036-1037.
3. J. Seayad and B. List, Org. Biomol. Chem. 2005, 3, 719-724.
4. A. P. Venkov and S. M. Statkova-Abeghe, Tetrahedron 1996, 52, 1451-1460.
5. J. H. Kim, Y. S. Lee, H. Park and C. S. Kim, Tetrahedron 1998, 54, 7395-7400.

 
 

 

Reduction of Aliphatic Nitro Groups

Subject 

Request for Help

We have been working for a little while on the aza-Henry route to PZQ. We're going to submit a paper to an open access journal on some of this work, but I thought we should post on something we're looking at now, since we've come up against an unexpectedly difficult step and need some help.
We've been trying to reduce an aliphatic nitro group (picture is below). The compound is a model case for PZQ that we've been looking at. This reduction looks to be a very simple reaction, and we did not expect problems.
Aliphatic nitro reductionAliphatic nitro reduction
Shibasaki has reported on the reduction of aza-Henry beta-nitroamines like this.1 The literature contains few reliable procedures for aliphatic nitro reduction2 – aromatic nitro groups are no problem. We've tried regular hydrogenation, Raney Nickel, SmI2 and LiAlH4. Jim Anderson at Nottingham recently published a very nice paper resurrecting Al-Hg amalgam as a reagent for this transformation, and we are having luck with it.3 This post is a very overdue appeal to the community at large:
a) Does anyone know of any other good reaction conditions for this reaction?
b) Does anyone have any advice on good ways to isolate the resulting diamines?
Cheers,
Mat
 
1. K. Yamada, S. J. Harwood, H. Groger and M. Shibasaki, Angew. Chem. Int. Ed. 1999, 38, 3504-3506.
2. S. L. Ioffe, V. A. Tartakovskii and S. S. Novikov, Russ. Chem. Rev. 1966, 35, 19-32.
3. J. C. Anderson and H. A. Chapman, Synthesis 2006, 3309-3315.

Suggested conditions

Dear Matt,
This may come too late, but you could look into using conditions published by AGMBarrett for aliphatic nitro group reductions, by transfer hydrogenation.  Its in Tet Lett but there's an open-access link here:
http://www.erowid.org/archive/rhodium/chemistry/nitro2amine.cth.pd-af.html
regards
Nick

Updates to Aza-Henry Catalysts

Just a quick update compiled by one of my students, Wing Yan, on some aza-Henry catalysts not included in the first post.
Cheers,
Mat

Aza Henry Catalyst Update 1

Pictet-Spengler Route to (R)-PZQ

The Pictet-Spengler reaction is used in the current industrial synthesis of rac-PZQ, and these reactions have been looked at on the Synaptic Leap here.
 
The PS has been used in the synthesis of PZQ, and we used it as the final step in our solid phase synthesis of PZQ, but both these syntheses were racemic.
 
Catalytic, asymmetric
General aim is this:

We have now started an Electronic Lab Notebook for the raw data for this specific aspect of the project here. Comments can be left here or there.
Essentially we need to start with literature catalysts for the catalytic, asymmetric Pictet-Spengler reaction. We therefore need to assemble a list of these catalysts here (literature help needed from anyone please!):
1996 Nakagawa
1998 Nakagawa
2004 Jacobsen
2007 Jacobsen
2009 Franzen
2010 Wu et al.
2010 Jacobsen
Need more candidate catalysts!
 
We are looking for people to help screen known catalysts for the relevant reaction. If your lab has any such catalysts we can send you starting material to screen. Substantial contributors to the project will be invited to be authors on the resulting papers.
Log of labs contacted for help with screening: (Important note: declining a request to participate will never be criticised - people may have very valid reasons for not wanting to participate, or may just be too busy. This log is here purely for record, to stimulate readers to suggest alternative/additional collaborating labs, and to avoid duplication of effort. If you know of a lab working on the asymmetric Pictet-Spengler reaction please feel free to contact them and leave a note of the request here.)
 
 
Diastereoselective
Wayne Best of Epichem has suggested an alternative approach based on a PS reaction of a chiral phenylethanolamine. This is an interesting idea, since 1 to 2 (below) might work well with asymmetric induction, and the products resemble PZQ. The use of a chiral starting material, in the generation of some analogue of PZQ that contains an extra stereocentre, could be an interesting project, but it's not clear these analogs would be active.  Anyone have a suggestion for a suitable commercially-available chiral starting material? Anyone want to try this?
Pictet-Spengler route to PZQ?

A chiral auxiliary-mediated PS was reported by Ma et al. (J. Chem. Res. 2004, 2004, 186-187 - paper doesn't seem to have a DOI?) where the key asymmetric step is shown below.
Literature PS Approach to PZQ

Other examples: Comins 1991
The use of an auxiliary is of course atom-inefficient, however, and likely to be expensive.

Catalyst screening for the Brønsted-catalysed Pictet-Spengler reaction to PZQ

We started catalyst screenings for the asymmetric Pictet-Spengler reaction. So far, we have tested several achiral Brønsted-acidic catalysts to determine acid strength which is required to cyclize the open-chain praziquantel intermediate 1 to the tetrahydroisoquinoline heterocycle 2.
 
Scheme1
 
Catalysts:
 
(+/-)-BINOL-N-triflyl phosphoramide     NN-bis[3,5-bis(trifluoromethyl)phenyl]thiourea
 (+/-)-BINOL-N-triflyl phosphoramide 3  and N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea 4
 
As previous experiments showed only strong Brønstedt-acids (e.g. conc. sulphuric acid, methane sulfonic acid) are able to convert the inactivated arene compound 1 to the Pictet-Spengler product 2. Therefore we are looking for strong chiral proton donors to catalyse this specific reaction.
 
We are using the racamate/achiral equivalents 3 and 4 of chiral catalysts in order to prove the activity of these Brønsted-acids for the acid-catalysed PS reaction. However, the conversion of the dimethoxyacetal 1 hasn't been successful yet as a result of the too low acidity of the catalysts.
 
To increase the acidity of the catalyst we have started the synthesis of 1,1-Binaphthyl-2,2-disulfonate 5 and 1,1-Binaphthyl-2,2-disulfonimide 6.
 
BINOL-sulfonate

The recent results and the raw data of these experiments can be viewed at our Electronic Lab Notebook here.
 

Sandbox for Synthetic Ideas

This is a post of random synthesis ideas for praziquantel that have been sitting in my inbox for too long. Both sources are industrial. If anyone has any comments, please post. If anyone has any further ideas, please post directly here – you can see how long it can take things to emerge if you use email...
 
Back in June I gave a talk at Stanford to a group called SPARK hosted by Kevin Grimes. This was a very interesting collection of people - highly interdisciplinary. Students and staff give talks, and the idea of the meetings is to brainstorm ideas on the projects underway, many of which were relevant to tropical diseases. These were like normal science group meetings, but with a much broader audience who were not shy of asking tough questions on detail and overall project direction. I really liked the way that a) students were actively involved along with faculty in meetings, and b) much of the stuff under discussion was in progress and incomplete, allowing real input from the audience.
 
My talk about the stuff The Synaptic Leap's project with praziquantel was interesting because of the diverse nature of the questions I got. This is one of the benefits of talking to a mixed audience of smart people. One of the most vocal skeptics of the approach was Steve Schow from Telik. His questions were excellent because they were grounded in economics. Essentially the arguments centered around where the money would come from for open compound development (or even drug discovery). I won't rehash the discussion here, because that's for a separate post that's building, but after the meeting Steve (who is an organic chemist by training) sent in a bunch of suggestions for other syntheses of enantioenriched PZQ. After checking with him, I am posting them here - his schemes posted directly. I'm posting them for completeness, in case the ideas chime with anyone or anyone wants to chip in. I want to thank Steve for contributing them.
 
This first idea is essentially the approach that's already been described. DSM are currently conducting catalyst screens for this reaction on the enamide shown and Development Chemicals had a hit with a related benzoyl substrate.
 

Steve's appeal to literature was the following:
 



Most of these examples have coordinating groups such as carbonyls that are well-placed to deliver the metal (and H) from a defined side. This has already been discussed here. There are a couple of examples above that do not require this. Perhaps the relevant ligands would be of interest - if anyone has the literature references for these? Steve's second suggestion involves an asymmetric hydrogenation at an earlier stage.

With the following precedents:

We have found working with dihydroisoquinolines to be rather annoying, given how prone they are to oxidation, but certainly the chances of a successful asymmetric hydrogenation here look to be better. Anyone have any comments on this approach, or literature sources for a comparison? Steve's final suggestions were as follows:

We'd thought of the first two, but have not done much/any work on them. It's a challenge because the enamide is not terribly reactive - it takes a lot to protonate the molecule. In the middle case, the tautomer shown is less stable than that where the double bond is conjugated with the ring. In the final case, the asymmetric reduction approach is no use since introduction of acid is required for the cyclization and this produces the acyliminium ion which scrambles stereochemistry. The introduction of the chiral acid is essentially the problem we're having with the Pictet-Spengler approach, in that the Ar ring needs methoxy groups to be active in this reaction. Thus far we have drawn blanks.
 
More recently, the guys at Creative Chemistry, who were looking into a route to enantioenriched PZQ, and developed a resolution approach, also contributed a few ideas they had been playing around with, but had not pursued. Again, I want to thank them for sending these along, which is in the spirit of this open project. Apologies for taking too long to post these. The following is essentially as received from DC. Idea 1: Reaction of tetrahydroisoquinoline with peroxide/tungstate/cyanide gives the unsaturated nitrile (TL, 1987, 6469). Yields when this was attempted were lower than described and the product was obtained by distillation. It may be possible to reduce this material enantioselectively, but the centre adjacent to the nitrile will be very acidic. This could also offer an easy entry to the diamine for resolution.

Idea 2: The asymmetric synthesis of praziquantel via a Bischler-Napieralski reaction was attempted as described by Czarnocki. Unfortunately, on reading the experimental, it became apparent that the 96% yield of the B-N reaction was based on recovered starting material and that the yield of product was only 15%. In our hands, the reaction gave several products and very little remaining starting material. Using the simpler chloromethyl amide the reaction went very cleanly. Unfortunately, the material is possibly too unstable for any further reaction unless kept under acidic conditions. 

Idea 3: The preparation and hydrogenation of the tartaric acid derivative has been documented (Can J Chem, 1992, 70, 1555 (MHT - annoying journal website - the paper is meant to be here); Acta Chim Acad Sci Hung, 1976, 89, 161 (seemingly not online)). It may be possible to perform this reaction with the unsubstituted analogue shown. If so the amine could be reacted with glycine followed by cleavage and reductive amination (or cleavage/reduction to create a chirally stable centre). A similar reaction using R-(+)-glyceraldehyde has been documented and, after hydrogenation, gives product of the desired stereochemistry (Can J Chem, 1986, 2205).

Idea 4: Speculatively, a suitable B-N product could be converted to the amide and the resulting product hydrogenated using, for example, a Binap type catalyst. This type of reaction has been documented.

Starting from the Racemate

AttachmentSize
Seubert Resolution.pdf270.29 KB

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
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. [update - this approach has now been given its own page here]. 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
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.

Asymmetric Hydrogenation of PZQ-enamide

A possible solution to the large-scale preparation of enantiopure PZQ is the approach shown below, originally suggested by Craig Williams.
 

 
First step:
We have a decent approach to this involving heating in a sulfur melt. This needs improvement, but we can generate gram quantities of the intermediate PZQ-enamide easily.
 
Second step:
This is the key. A number of different catalysts for this reaction have been tried [data coming soon, sorry] but no conversion has been observed. Reduction with rhodium on carbon quantitatively generates rac PZQ, so the enamide is reactive. The geometry of the enamide here is awkward in that the exocyclic carbonyl is not able to direct a metal-based asymmetric catalyst to the double bond, as in the classical model. It's a challenging reduction.
 
This second part of the synthetic route needs people who have expertise in screening hydrogenation catalysts, or people who have in their posession unusual catalysts for asymmetric hydrogenation that might be appropriate for this kind of reaction. The Todd group can mail people samples of the PZQ-enamide for this screening (plus samples of PZQ for the assay). Most any column will separate PZQ enantiomers. If you are interested in helping with this part of the project, please reply below.
 
Relevant groups/papers to consider (please fee free to suggest others here by editing the page):
Bernhard Breit
 
August 2010: We received our first offer of help with the asymmetric hydrogenation. Laurent Lefort from DSM in the Netherlands, has offered to include our substrate in future catalyst screening that they are undertaking. This is a great offer. Laurent has a great deal of relevant experience in this area. Aug 31st: The Todd lab has mailed a sample of the enamide plus a reference sample of PZQ to DSM. October 20: Second set of DSM results posted here. January 25 2011: Third, larger screen from DSM posted in the same place as the others.

Characterization of PZQ-enamide

The PZQ-enamide is shown below. This is an intermediate in the stereoablative route to enantiopure PZQ.

HPLC trace for PZQ-enamide (using ChiralcelOD-H, solvents: Hex:IPA:TEA 60:40:0.1, Flow Rate: 0.7 mL/min) gives retention time: 15.772 mins. Original HPLC trace attached below.
 
(Note comparison HPLC trace for PZQ itself is here.)
 
Other data: RF =0.35(1:1 Hexane: EtOAc); m.p. 131-134 ºC; 1H NMR (300 MHz, CDCl3): δ 1.15-1.85 (10H, m, cy), 2.35-2.65 (1H, m, cy ), 2.84 (t, 2H, J 5.2, H7), 3.82 (t, 2H, J 5.5, H6), 4.35 (1H, s, H4), 6.70 (1H, s, H2), 7.10-7.51 (4H, m, Ar); (Proton NMR spectrum attached below) 13C NMR (75 MHz, CDCl3): δ 26.1, 29.4, 38.8, 41.4, 45.9, 48.7, 106.0, 106.0, 123.1, 123.6, 126.9, 127.7, 128.2, 128.4, 128.6, 128.8, 129.0, 134.5, 164.3, 174.5; IR (CHCl3): 2952-2870 cm-1, 1652 cm-1, 1463 cm-1; MS (ESI) m/z: 311.1 [(MH)+, 100%], 333.3 [(MNa)+, 55%] HRMS (ESI) Calcd. for C19H22N2NaO2 (MNa+): 333.15735. Found: 333.15765.

Failed Attempts at Asymmetric Hydrogenation of PZQ-enamide

AttachmentSize
DSM 48 vial screen.pdf1.26 MB

This page will contain all examples of failed reactions in the attempted asymmetric hydrogenation of the PZQ enamide.

 

We are very grateful to Sigma-Aldrich for an initial donation of the catalysts employed below. Please note that we do not hold a library of other hydrogenation catalysts. Any suggestions for alternative catalysts are welcome, but in the interests of speed, the best suggestions here are catalysts + who could run the reactions (other than the Todd group) and to whom we could send PZQ enamide. This will accelerate the research.

 

In the Todd lab, we used a bespoke hydrogenator vessel of 15 mL capacity able to take pressures of 2000 psi and where the addition of reagents can be performed under Ar/H2. To verify that this set-up was able to reproduce literature results, we carried out the following asymmetric hydrogenation:

 

 

See a review of phospholane ligands for asymmetric catalysis for more, as well as the original paper [need ref] that the above reaction is taken from. While the results don't exactly match, the experimental set-up is clearly adequate for carrying out asymmetric hydrogenation reactions.

 

Under the same conditions as above, using the PZQ enamide, no reaction was observed, even after heating at 50 oC for 24 hours or increasing the pressure to 600 psi. Starting material is quantitatively recovered in each case.

 

Other conditions tried (no conversion in any case. Unless otherwise stated, the reactions were carried out in 5 mL solvent on 100 mg PZQ enamide) using the same conditions as for the test reaction above.

2 mol% (R)-RuCl[(p-cymene)(BINAP)]Cl.

(Formed in situ from 5 mol% Ru2(C6H6)2Cl4 and 10 mol% ligand)

PipPHOS (2 mol%) and Rh(COD)2BF4 (4 mol%)

[Details coming]

 

Let's assume that catalysts like those above do actually function by delivery of the metal centre (and bound H) to the olefin by intramolecular coordination of e.g. a neighbouring carbonyl:

(taken from this PNAS paper)

 

...then the geometry of the PZQ enamide prevents such delivery. This is the basic problem here.

 

Update September 20th - First results from DSM (results will periodically be posted as screens are carried out):

Two conclusions from this:

1) The method of preparation of the enamide (using a sulfur melt) does not in this case lead to contamination with sulfur that deactivates catalyst.

2) MonoPhos does not give conversion under these conditions.

 

Update October 20th 2010 - Second update from DSM

Conditions were: cat = 0.01mmol, substrate PZQ = 0.2mmol, 5mL solvent, 25 bar H2, 16h

Catalyst structures are:

Update Jan 25th 2011 (data from DSM received December 21st 2010)

 

New attempts with Rh. Preparation of the 48 catalysts: The catalyst is preformed by stirring Rh(COD)2BF4 with 1.1 eq ligand for 1 h in DCM at rt. [Rh] = 0.042 M. See table below for the list of the 48 ligands used.

 

Preparation of the 48 reaction mixtures: The catalyst Rh/L (0.0042 mmol Rh in 0.5 mL DCM) in DCM solution is transferred to hydrogenation vials with the liquid handling robot. The substrate in MeOH (0.035 mmol in 2.2 mL MeOH) is added. S/C = 8.

 

Hydrogenation conditions: 25 bar H2, 60°C, 18 h, stirring = 300 rpm

 

Results

No product was obtained for almost all catalysts - except for traces (a few %) of product for vials 29, 40, 42 corresponding to ligands CTH-PhanePhos (E4), JosiPhos-2-1 (H5), JosiPhos-212-1 (B6). These results are rather consistent. PhanePhos was already identified as a good substrate for a related substrate. The 2 JosiPhos present similar structural features: aryl-aliphatic phosphines with in both cases t-Bu groups.

 

 

See attached file “DSM 48 vial screen” for raw data for this screen, including the structures of the ligands employed.

 

Update July 3 2012 (using results obtained from DSM 22/09/2011)

Some promising results - the best to date. In the first run, below, there is full conversion for the first two entries, with some enantiomeric excess. The solvent change to TFE was probably important.

Conditions: cat = 0.01mmol, substrate PZQ = 0.2mmol, 5mL solvent, 25 bar H2, 16h. SL-M004-1 is the MandyPhos ligand of Solvias - structure may be seen in their catalog.

The second run used TFE. There is a lot of variation depending on ligand, but again some promising results here, with JosiPhos and PipPhos both doing well but wth low conversion.

Note added July 3 2012 - all results to date have been collated in a Google Spreadsheet for easier viewing.

Resolution of Praziquanamine

Subject 

Request for Help

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)
Merck Patent
 
Please feel free to post any other suggestions below. Even better – plan to have a go in your own lab and post data here.