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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 3, 2010

Know How to Make Praziquantel? Tell The World.

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Posted by Derek

One of the people I met this past weekend was Matt Todd, chemistry professor at the University of Sydney. We talked about a project his lab is working on, and I wanted to help call attention to it.

They're working on praziquantel, also known as PZQ or Biltricide, which is used to cure schistosomiasis in the tropics. It's on the WHO's list of essential medicines for this reason. But PZQ is used now as a racemate, and this is one of those cases where everyone would be better off with a single enantiomer - not least, because the active enantiomer is significantly easier for patients to stand than the racemic mixture. Problem is, there's no cheap enantioselective synthesis or resolution.

So what Todd's group has done is crowdsourced the problem. Here's the page to start with, where they lay out the current synthetic difficulties - right now, those include enantioselective Pictet-Spengler catalysts and help with the resolution of a key intermediate. They were in need of chiral HPLC conditions, but that problem has recently been solved. I'd like to ask the chemists in the crowd here to take a look, because it wouldn't surprise me if one of us had some ideas that could help. Don't leave your suggestions here, though; do it over at their pages so it's all in one place.

This sort of thing is an excellent fit with open-source models for doing science: it's all pro bono, and the more eyes that take a look at the situation, the better the chance that a solution will emerge. I don't think it's getting the publicity it deserves. And no, in case anyone's wondering, I don't think that this is how we're all going to end up discovering drugs. Figuring out how to do this for large commercial projects tends to bring on frantic hand-waving. But in cases like this - specific problems where there's no chance for profit to push things along - I think it can work well. It makes a lot more sense than that stuff I was linking to last week!

Comments (22) + TrackBacks (0) | Category: Business and Markets | Chemical News | General Scientific News | Infectious Diseases


COMMENTS

1. chucky on August 3, 2010 9:43 AM writes...

I reckon a distereoselective salt formation of the amine prior to the presumed acylation (cyclohexanoyl portion) would do the trick. I know its not elegant but it probably would get the job done given the simplicity of the presumed starting materials and low relative cost. Might even find a way to recycle or otherwise use what's left. Ask a medchemist and those are the kind of non-elegant solutions you get.

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2. sleepless in ssf on August 3, 2010 10:18 AM writes...

"It makes a lot more sense than the stuff I was"...?

Don't leave us hanging man -- finish your sentences :)

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3. milkshake on August 3, 2010 11:01 AM writes...

the best way to make this one on scale would be to develop a catalytic asym hydrogenation of C=C using a chiral Ru, Rh or Cu catalyst. The substrate would be the dehydropiperazinone, a compound which should result from intramolecular Vilsmeyer - like cyclization (I think it is called Pomaranc-Fritz cyclization) of the 1N-phenethyl-4n-benzoylpiperazine-2,5-dione which is itself easily available from iminodiacetic acid.

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4. Quintus on August 3, 2010 12:27 PM writes...

I contributed one or two things to this project. They may be of no use, but I never received any feedback from the "web site"

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5. Anonymous on August 3, 2010 1:50 PM writes...

Gentlemen, maybe I'm too "Old school", but here we're talking about a chiral switch with no one who's planning to file an INDA or his equivalent.
Maybe the WHO will take care of the clinical trials, I don't know, but the impression is that Prof Todd is totally new to this line of work (or maybe someone is thinking that *we know* that the active entantiomer is *this one* and that we can use it without problems in the patients because they're third world people?).
Second: let's have a second look at this bright and altruistic example of "open source pharmaceutical science": prof Todd, with a strong background in solid phase synthesis, gets 400.000 dollars from the australian governement and 75.000 from WHO to work on this project for 3 years: a scalable and economical r0oute for the desired enantiomer of PZQ. Again, this is not his job (neither the one of his group, that I read is in serious trouble trying to reduce to amine an aliphatic nitro group): no idea about how to practically approach a real world crystallization or resolution or chiral synthesis. So prof Todd ask the global scientific community for: FREE HELP. Hilarious. This open source thing is giving hilarious results. My best wishes.

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6. ronathan richardson on August 3, 2010 3:49 PM writes...

Merging multiple posts here, maybe open-source drug discovery is a self-evident solution to 2 problems: drugs for neglected diseases, and chemists bored with their current work and in need of intellectual stimulation. If a large number of these projects were somehow collaboratively available for work, and chemists were allowed to escape their normal work to mess with them (only from the virtual perspective) for 30 minutes a day, something good might come out of it all.

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7. DLIB on August 3, 2010 3:56 PM writes...

@#5

Well it's kind of true what you say, the problem is the people and industry with all the capabilities are not that interested in putting new dollars into diseases of the poor. The Gates foundation likes to fund this kind of stuff.

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8. CMCguy on August 3, 2010 10:05 PM writes...

While I applaud the work of the Gates Foundation (and many other non-profits) tackling either rare or diseases predominate in under developed areas its not entirely true that industry is not interested. Although limited I believe most pharmas have directly or indirectly contributed to such ventures (likely less common today than once was). However in the end as a part of industry and not a non-profit, particularly in this shareholder first era, companies can not invest in many projects without possibly of profit or they will not survive.

May be stereotyping as what #5 states does seem to reflect some of the naivety of academics in dealing with real world issues. If correct numbers above rather than funding an academic group $475K I think would have be wiser to engage one or more of many Custom Synthesis Labs out there that have that skill set of scale-up of chiral molecules to work this out. Probably could be done cheaper to establish a feasible route and time line would certainly be less than 3 years.

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9. barry on August 4, 2010 12:25 AM writes...

looks like an asymmetric hydrogenation of 1-carboxy-3,4-dihydroisoquinoline. those dehydro-alpha-aminoacids are great cases for asymmetric hydrogenation. There's nothing interesting about the subsequent refunctionalization

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10. cliffintokyo on August 4, 2010 1:07 AM writes...

Hydrogenating acid-heads!
Post your synthesis suggestions to the crowd-sourcing Todd website like Derek told you to!
BTW: agree with *CMCguy* that a CusSynLab would probably be able to crack this reasonably quickly.

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11. A Nonny Mouse on August 4, 2010 3:57 AM writes...

Feel like I could have written #5's comments.....

I've been looking at that site for a year now and am in despair at some of the requests for chemical help (as pointed out). As for the chiral switch, this has been recently brought up by a "guest" poster on the site.

MT is now getting help on the resolution of a late stage intermediate from a Dutch contract house, but this is clearly a bit of work on the side.

WHO has now contracted a preliminary look at this work out to a custom synthesis house so we will see if this now goes at a faster rate.

As for Milkshake's suggestion, any chiral catalyst would require a turn over number of between 3-10,000 to make it economically viable. When intermediates are available from China and India at very low cost it is stupid not to use these in some way.

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12. Mat Todd on August 4, 2010 5:57 AM writes...

To address a few of the comments above:
1) This project is currently being led by us, since we received some funding to do it, but it is not “our” project. We started to post kernel data in earnest in January. Anyone can discuss, contribute and add if they wish, and we would all coauthor papers. There is no requirement to help – if you don’t want to contribute, you don’t have to! It would be very helpful if specific points could be raised on the relevant pages on the site hosting the project (Synaptic Leap) or hosting the raw data (http://www.ourexperiment.org/racemic_pzq).
2) The cost factor is crucial. There are several obvious ways of solving this problem if cost was no issue. #9 – your solution is clearly a good approach, but will be steppy. PZQ can be made in two steps (http://www.thesynapticleap.org/node/317).
3) Milkshake: Thanks. We thought so too, but our experience to date with asymmetric hydrogenations of intermediates (actually one derived from PZQ itself: http://www.thesynapticleap.org/node/202) has suggested that these routes will not work with some fairly standard catalysts (e.g. Rh-Duphos and Ru-BINAP). We haven’t posted much on this yet, since the work was done a while ago but these data will go up, apologies. We may have missed something obvious.
4) Reductions of aliphatic nitro to amine are not trivial when the nitro is part of a beta-nitro amine, see e.g. http://dx.doi.org/10.1055/s-2006-950229. There are few good general procedures, though we just yesterday had a paper accepted in Eur. J. Org. Chem. with a detailed prep for a related system using the more predictable Raney Ni. We’ve been told offline by a very reliable source that another procedure commonly used for aliphatic nitro also works for beta-nitro amines, see http://dx.doi.org/10.1016/S0040-4039(00)99014-2.
5) #1: the Dutch company Syncom quickly worked out a good process for resolving the enantiomers based on a secondary amine intermediate in the synthesis. The data for the HPLC method for the analysis of the enantiomers are here: http://www.thesynapticleap.org/node/315, and I hope the rest of the resolution data will be posted soon.
6) At the moment we’re interested in a catalytic, asymmetric Pictet-Spengler reaction. If anyone has any suggestions for catalysts to try here, or conditions, or examples of large-scale processes employing this reaction, that would be useful. Our latest results are discussed here: http://www.thesynapticleap.org/node/322. Use of this starting material, which is the current industrial precursor to PZQ, is a realistic solution to the problem if we can find the right catalyst.

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13. processchemist on August 4, 2010 12:02 PM writes...

Just had a look at the wiki page about PZQ; wonderful product: one single shot, problem solved.
So who really needs this chiral switch? From a WHO point of view it seems that the problem is the low supply to african countries (10% of the needed product). Maybe the best way to solve the real problem is a negotiate with a group of indian pharmas (I think about Dr. Reddy, Jubilant, Piramal, Ranbaxy) to establish the right volume of supplies at a sustainable price.

By a look at the pharmacological profile of PZQ, I see more utility in some efforts in the medchem field: heavy first pass metabolism, low plasma stability, etc etc (by the current standards today this product would not be able to reach the animal model). Or maybe is so effective just because is so "dirty"?

About the resolution/scalable route issue, I couldn't agree more with CMCguy and the others.
And about open source medchem on this project, the risk is a change from amateurish process chemistry to dilettante drug development.

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14. MTK on August 4, 2010 1:36 PM writes...

SMB.

They've got an analytical method to determine ee of the amine. Should be easy to determine appropriate scale-up conditions for SMB and to calculate cost and throughput.

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15. DrSnowboard on August 5, 2010 2:56 AM writes...

Mat Todd - the DOI links don't work for me in #12.

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16. DrSnowboard on August 5, 2010 2:58 AM writes...

But they do if you lose the trailing period, apologies

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17. DrSnowboard on August 5, 2010 4:19 AM writes...

And you'll all have seen this but for the jaded cynics..
http://www.ted.com/talks/clay_shirky_how_cognitive_surplus_will_change_the_world.html

'the gap is between doing nothing and doing something'

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18. Mat Todd on August 5, 2010 5:10 AM writes...

#17 Indeed. Great practical example in today's Nature: http://www.nature.com/nature/journal/v466/n7307/abs/nature09304.html

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19. LarryMiller on August 5, 2010 6:22 AM writes...

Regarding comment 14:

The current HPLC method is: The S(+)- and R(-)-enantiomers of praziquanamine could be separated well with good baseline resolution using the Chiralcel OJ-H, as well as the Chiralpak IA, and the Chiralpak AS-H column with heptane/EtOH/Et2NH (60/40/0.2) as eluent (0.5 ml/min flow rate).

Without retention times and column dimensions, alpha can't be calcualted but based on the need for a low flowrate I'd be suprised if the separation is good enough for a cost effective simulated moving bed (SMB) separation. An additional difficulty is the 3 component mobile phase, making solvent recycling more complicated. Not to say that SMB is not a viable option but a more purification friendly separation (ie methanol/diethyalmine or other polar organic mobile phase) would have a better chance of being cost effective.

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20. Mat Todd on August 5, 2010 6:59 AM writes...

MTK and LarryMiller
Yes, the SMB is possible, and has been published by people at Intervet, see:
http://www.thesynapticleap.org/node/315#comment-578
...though I should emphasise it has not been costed.

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21. milkshake on August 5, 2010 8:03 AM writes...

Asym Pictet-Spengler: the chiral catalysts that do ene reaction of glyoxylate esters are also good at asym condensation of glyoxylate esters with el-rich aromatics. So I suggest you try those. The first ones to try would be Cu(OTf)2 and TiCl4 and SnCl4 in dichloromethane, to see if you can get any cyclization.

Cu(OTf)2 can be made into chiral complex by simply mixing it with phenyl- or tert-butyl bisoxazoline ligands (which are commercial from Aldrich), TiCl4 and SnCl4 is used with BINOL. See Evans papers on asym glyoxylate reactions, there was quite large one in 2000 JACS I think, and the japanese group that did lot of work on TiCl4-BINOL and the system was more general than just for glyoxylates. Maybe you can also try the Jacobsen "mighty fist" chiral Cr(III) indane Lewis acid catalyst, I think their "hetero-Diels-Alder" is stepwise and I remember faintly that they used it for other aldehyde condensations also.

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22. Murzban Karai on October 4, 2010 8:53 AM writes...

Dear sir,
we are a professional custom synthesis company based in mumbai.We shall be ready to help out.

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