Avoiding a reactive starting material: The Synthesis of PA-824 (old)

I need to update my collection of journal articles to talk about.   I will try and go next week.  While you are waiting for a new blog post, I figured I would post another article from PHARMNBIOFUEL.COM.  This was posted 2011-01-22

I am running a little behind my postings.  Although I am now employed on a temporary assignment and figure I can commit that same amount of time on my website as before, however, I am having to re-organize my daily activities.  The postings on this website may grind to a slow dribble.  I will still forge ahead to provide you with what I find interesting in current chemical literature.  I am dipping into some of the choices I picked from last year, but promise to update my collection soon as to what is happening currently in the chemosphere, particularly in process research.

I think that more than some of us, the “us” being process chemists, have had to redesign a synthetic route to produce an API because of a safety issue.  In fact, I think it is one of the strongest reasons to re-evaluate your approach.  Safety is paramount.  Now, I was trying to find a rationale, a page number in a book, on how I know what looks like a starting material that you would not want to deal with.  It might have been something I learned at Pfizer or during my career, that if a molecule looks particularly energetic, like an alkyne, aziridine, nitro compounds, you might want to get the compound tested by DSC, ARC, RC1, etc.

The following paper that I found in Journal of Organic Chemistry is one of these cases.  “A Concise and Convergent Synthesis of PA-824”, by P.J. Reider et al, J. Org. Chem, 2010, 75, 7479-82.  If you were given a synthetic route that had the following starting material, I am pretty sure you would want to re-evaluate.  Remember that picric acid and trinitrotoluene have three nitro groups on them and are explosive.  The number of nitro groups and the additional nitrogens in this starting material would give me the jitters, just a feeling.


It looks pretty scary for a starting material.  Before I go on, I will show you what the final target molecule looks like.   This is a antituberculosis candidate, not a final established drug product.  I will just make a quick comment and say that this is not a marketed product yet, so there is no name mentioned in the paper, other than BA-824.  I wanted to clarify this because I have been asked in the past about other syntheses.  This will save me from related questions later.


The paper goes into what the original production route was for PA-824 (1).  I am not going to go into talking about this chemistry because I figure it is quite straightforward.  The reasons given for an alternative synthetic route were the starting material (as I alluded to, which was explosive),  four chromatographic separations (yeah, way too many columns there, buddy ) and an inefficient protection-deprotection procedure (not too elegant, but you do what you have to for clinical material).


Unlike the first synthesis, the second synthetic route uses (R)-3-chloro-1,2-propanediol (7) as part of its strategy, a starting material that is easily available on ton-scale and in enantiomerically pure form (>99.9 % ee).  This material (7) is protected with a p-methoxybenzoyl group, which is readily removed.  The free hydoxyl group in 8 is protected with trifluoromethoxybenzyl alcohol through formation of the trichloroacetimidate to prevent epoxide formation.  The dinitroimidazole is replaced with a chloronitroimidazole, a safer starting material.


A lot of the synthetic steps seem pretty mild with exception to the alkylation of 11 with 12 to provide 13 at 120 °C .  The anionic cyclization at the end provides the desired compound with the desired purity after column chromatography and recrystallization.

It has been sometime since I posted a pharmaceutical paper.  So there ye be.  Stay tuned for more chemistry.





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