Org Prep Daily

May 23, 2009

Chloramphenicol base

Filed under: Uncategorized — milkshake @ 6:05 am

poster44376271

 

I have been doing some asymmetric hydrogenations recently. The pieces that I was making were carboxylic acids and since the highest optical purity that I could get from my system was about 90%ee and the product couldn’t be enriched by a simple recrystallization, I needed to make a salt  - preferably with some optically pure amine – to bring the material up to 98-99% ee.  I got quite lucky with chloramphenicol base: the salt enrichment in a single recrystallization proceeded with high recovery. 

I also tried few other chiral amines, norephedrine worked but it was not very efficient (with the salt being too soluble). And norephedrine is rather expensive and it is on the controlled precursor list – its delivery got halted for nearly a week by the bureaucracy and eventually we had to fax a statement to the supplier, declaring that we are not making a dope. 

This got me to realize that unlike with the chiral pool of acids, there is only a limited choice of inexpensive optically pure amines that one can buy both enantiomers of (a typical problem with many alkaloids and other natural-product derived amines). Chloramphenicol is a generic antibiotic made by old-fashioned racemic synthesis and resolution hence both enantiomers are available. And not every amine is likely to provide a nice crystalline salt; what probably makes chloramphenicol base effective is the combination of para-subst nitrophenyl group and the two hydroxy groups that contribute to ordered interactions in the crystal structure. 

Chloramphenicol base has been used as a resolving agent in industry: Roussel Uclaf, the company that commercionalized a large-scale production of chloramphenicol many years ago, is using the base as a resolving agent for racemic trans chrysantemic acid – a precursor for making synthetic pyrethroid insecticides such as Deltamethrin. The resolution takes place very early in the sequence. Given that pyrethroids are made on ton scale, the availability of the optically pure amine needs to be pretty good.

The actual resolution of racemic chloramphenicol base is noteworthy: Chloramphenicol base is among the rare (1-2%) compounds that crystallize as a conglomerate of optically pure crystals. This means that it can be resolved by selective crystallization based on seeding with one and then the other enantiomer. In reality the process is somewhat tricky – one has to work under carefully controlled conditions and use a massive quantity of the enantiomerically-pure seeding material to have a fast growth, and stop the crystallization very early to ensure that the other enantiomer keeps in the super-saturated solution. But this sort of process is doable in a chemical plant and “resolving stuff with nothing” helps to produce the optically pure material cheaply .

21 Comments »

  1. Norephedrine as a chiral amine resolving agent is weird but makes sense. Supposedly the different enatiomers have significantly different physiological effects, but for the most part they are a raecemic mixture when sourced behind the local 7-11. Chloramphenicol might be one possible precursor, but to eliminate the nitro and then reduce the hydroxy groups might be a little too much work.

    Another unique story for the milkshake memoirs…

    Comment by Rhenium — May 26, 2009 @ 11:50 am

  2. I don’t know what the situation is like in US but in Europe the ephedrine/pseudoephedrine/norephedrine alkaloids have been manufactured from optically active precursors so what you get at the pharmacy store there would be a single enantiomer. Until couple years ago there was a huge ephedrine plant operating in Roztoky near Prague (the main reason why the Czech Rep became the meth-making center of Eastern Europe) and they were getting their chiral ketone starting material from fermentation.

    I tried norephedrine because there is a published precedent on resolving a similar compound with it. There is actually one more precedent – with amphetamine – but I passed on that one

    Comment by milkshake — May 26, 2009 @ 12:09 pm

  3. What, no strychnine?

    Comment by Chemoptoplex — May 27, 2009 @ 8:28 am

  4. Hey Milkshake – glad to see a new post, and it brought up something a friend was asking me about a while back and I couldn’t think of anything off the top of my head. He was looking for a chiral pool (i.e. cheap) carboxylic acid with no alpha protons or active protons (OH, NH, etc.). Off hand, I couldn’t think of any – can you? Failing that, I wonder if you’ve had any experience with operationally simple chemistry to make such acids? (Just off the top of your head, of course we could do the searching, but sometimes human memory/creativity can be more effective than database searching in my opinion.)

    Comment by Russ — May 27, 2009 @ 9:03 am

    • How about Mosher’s acid? Ph(CF3)(OMe)C-COOH It’s used frequently in chiral resolutions. I used it a lot for my grad school work – a long time ago!! I remember that it is not prohibitively expensive and available from quite a few vendors. Hope that helps

      Comment by M. Blue — May 29, 2009 @ 11:05 am

  5. There is abietic acid – its inexpensive because it is extracted from wood rosin but the commercial product is not completely pure. I have been working a little on topical-antibacterials about 15 years ago and abietic acid was a building block for the project; the best-quality abietic acid available was from Aldrich (there are various other technical grades on the market) and I found an easy way to purify it – make a slurry in acetonitrile and reflux it for about half an hour, allow it to cool, collect the precipitate, discard the supernatants. You may need to repeat this acetonitrile treatment once more time if the filtered material is still not uniform on NMR and HPLC. You lose about one quarter of the material in each acetonitrile “re-crystallization”. This purification method worked well with the Aldrich stuff (but a big bottle of abietic acid we got from Pfaltz and Bauer contained some other polymeric gunk that did not separate in acetonitrile)

    Comment by milkshake — May 27, 2009 @ 3:19 pm

  6. That might be just the thing he’s looking for – thanks Milkshake! Also, thanks for the purification suggestion.

    Comment by Russ — May 28, 2009 @ 9:07 am

  7. Thanks for this post, very useful and interesting.

    Comment by krest17 — May 29, 2009 @ 3:58 am

  8. The compound on the picture is not really a chloramphenicol.
    It looks like an intermediate in the synthesis of the drug.

    Comment by horks — May 29, 2009 @ 8:10 am

    • That’s why Milkshake said ‘chloramphenicol BASE’ and not chloramphenicol

      Comment by anon — May 29, 2009 @ 10:13 am

    • in the process jargon they call the chloramphenicol amine precursor (without the dichloroacetyl group) in this way. I did not make it up, its in the books.

      Comment by milkshake — May 29, 2009 @ 5:57 pm

  9. ” unlike with the chiral pool of acids”.

    Hi Milkshake, can you share your experience of using chiral acids to resolve base. I am now trying to separate a racemic pyrrolidine and would like to hear any suggestions as I have never dealt with this kind of thing.

    Comment by Diketene — June 5, 2009 @ 6:53 pm

  10. I don’t have too much experience with finding a new resolution method – usually I would follow a lit procedure that said something like “make a salt with camphorsulphonic acid using this solvent mix and then re-crystallize it twice under such and such conditions.

    I think first you will need to find a good HPLC-based method to easily assay the optical purity of your material (because optical rotation-based determination of ee is awful and NMR-based assays are not much better). You can go two ways about it – either a chiral column or a derivatization with a commercial optically pure reagent such as alpha-naphtylmethyl isocyanate (and a non-chiral column). Also if your material is reasonably volatile, a chiral GC with a cyclodextrin-B column is probably the way to go.

    I would look at structurally-related compounds in Beilstein/Crossfire and Scifinder, to see how those were resolved. Most likely you will find camphorsulfonic acid, tartaric acid, and dibenzoyltartaric acid (or di-p-toluoyl tartaric acid) and malic and mandelic acid because those are cheap for both enantiomers. I would buy one enantiomer of each of these, combine it with one equivalent of your racemic amine in some solvent where you expect the salt to be only partially soluble and let crystallize. Then analyze the ee of the crystaline salt and the ee of the material left in supernatants, in hope that they are far apart – you want one of the enantiomers to accumulate somewhere. As you can see this can take quite a lot of time, to find the right acid, solvent mix, and volume and temperatures for the re-crystallization, hence finding a close precedent in the literature can save time.

    (Also, for faster acid screen – if you can get hold of few hundred mg quantity of your amine in optically-pure form, you can make a small quantity of salt with both enantiomers of the resolving acid, and simply measure the melting point. You look for the biggest difference in melting points (between R-R and R-S) because low-melting compounds are much more soluble than similar high-melting compounds. But I think a direct crystallization and the ee assay is more reliable way to go)

    This reminds me, I have seen a very nice compendium book, about 20-30 years old, which contained a collection of all nice published resolution experimentals, there were literaly hundreds and hundreds of collected resolution procedures – but I don’t remember the name nor the author. You can try to search Google books.

    Also you need to convince your boss that this project can easily take few weeks and there is no guarantee of a success.

    Comment by milkshake — June 6, 2009 @ 9:32 am

    • Wow, thanks for such a detailed reply!

      I do have some references in hand. But they are not about resolution. Instead, they are more about either using chiral auxilliary to achieve asymmetric [3+2] cycloaddition of azomethine yilides. I can probably give them a try first.

      Comment by Diketene — June 6, 2009 @ 11:30 pm

      • The book that you’re referring to is ‘Enantiomers, Racemates and Resolutions’ by Jean Jacques, Andre Collet and Samuel Wilen. There is an edition on Amazon (http://www.amazon.com/Enantoimers-Racemates-Resolutions-Jean-Jacques/dp/0894648764/ref=sr_1_1?ie=UTF8&s=books&qid=1245113609&sr=1-1) but they have ‘enantiomers’ spelled ‘enantoimers’! It’s a great reference and well worth tracking down if you’re about to embark on an resolution. There is a lot of practical advice, as well as a summary of resolution procedures reported in the literature.

        Comment by Telf — June 15, 2009 @ 8:58 pm

      • No its not Jacques-Collet (although that one is the definitive book on the theory and techniques of resolution). I saw a compendium book that was collected resolution procedures-only, with an index

        Comment by milkshake — June 15, 2009 @ 9:25 pm

    • Theere is one more excellent book on diastereomeric salt resolutions. It is: “CRC Handbook of Optical Resolutions Via Diastereomeric Salt Formation” by David Kozma; 17.7 MB. I have it and can upload it if somebody is interested.

      Comment by Sunil — July 31, 2009 @ 3:39 am

  11. I just resolved didesmethylsibutramine using tartaric acid following the procedure in US patent 6,974,838 B2. You can visit http://www.chirosolve.com for readymade solution to your problem.

    Comment by PPM — June 8, 2009 @ 1:09 pm

  12. You can speed up the process by using Chirosolv Kits (Aldrich). The kit is in 96 well format with various resolving agents/solvent combinations, so it allows you to rapidly screen various conditions. I’ve never used them myself, but it looks useful. They’re a little pricey and you may have to go through as many as 4 kits to find the conditions, but it could be a time-saver.

    Comment by Kimist — June 9, 2009 @ 10:12 am

  13. The book you referred to has a collection of all resolution procedures is “Optical resolution procedures for chemical compounds”, editted by professor Paul Newman of Manhattan College in 1978-1987. It has a total of 4 volumes. Vol 1 is for resolving Amines and related compounds,;Vol 2 is for Acids, Vol 3 for alcohols, thiols, aldehyde and ketone; Vol4 for sulfur and selenium containing compound. Nowawadays, with electronic database easily availble, this book is less mentioned by people.

    The latest / best book (in my opinion) you should refer to for a quick grasp of chiral resolution is ” CRC Handbook of Optical Resolutions via Diastereomeric salt formation”, Published in 2002. After reading this book, you could be the master of resolution in your company/group.

    Comment by Zhinong Gao — July 10, 2009 @ 5:35 pm

  14. Zhinong – thank you for this comment, this is very useful information

    Comment by milkshake — July 10, 2009 @ 7:07 pm


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