Wednesday, February 6, 2013

Process Wednesday: direct benzylation on scale

Credit: Campbell et al., Org. Process Res. Dev.
If it wasn't blindingly apparent by now, C-H activation is a pretty interesting subfield of chemistry. I was wondering when we might see an example of C-H activation in the pharmaceutical process literature and now Campbell and coworkers [1] from Lilly have brought us a nice example. They were attaching a halobenzyl moiety by using an alpha-chloro ketone in their original route, but a subsequent ketone reduction used a TFA/triethylsilane reduction. As someone who finds hazardous waste disposal an interesting topic, I was amused to read their rationale for avoiding that reduction:
Second, the ketone deoxygenation step, which utilized trifluoroacetic acid (TFA) and triethylsilane, was a liability from a waste disposal perspective. Incineration of fluoride-containing waste is known to corrode waste incinerators and reduces the useful life of incinerator refractory brick. Silicon dioxide which results from triethylsilane incineration leads to particulate agglomeration on the heat transfer media of regenerative thermal oxidizers.
If I interpret that correctly, I believe they're saying, "If we decided to scale this reaction up, we wouldn't be able to find anybody to take our waste." A problem, that.

Rather than forming the key imidazopyridazine with the ketone intact and reducing it off, the authors decided to attempt a direct benzylation. After they found that the C3 carboxylate would not couple with 10, they were able to use 4N sulfuric acid to decarboxylate the ethyl ester to arrive at 13, which they subjected to direct benzylation conditions. After a number of attempts at optimization, the authors note that the original conditions were pretty much the best ones, providing them with a 50% isolated yield on 235 gram scale.

I wonder if this is the largest "modern" C-H activation yet performed? I am excited to see more and different examples, as much as I hope that we're still going to be making boronic acids on ton scale for Suzuki reactions for ages to come. All in all, a pretty neat example by the Lilly team -- congratulations to them.

[1] Campbell, A.N.; Cole, K.P.; Martinelli, J.R.; May, S.A.; Mitchell, D.; Pollock, P.M.; Sullivan, K.A. Org. Process Res. Dev. ASAP. doi: 10.1021/op300344m

2 comments:

  1. Interesting paper and worth a read. Don't think the C-H activation was their first thought, but a very nice observation that 1) the ester seemed amenable to decarboxylation and 2) the decarboxylated substrate would be amenable to C-H activation. Good example of making lemonade out of lemons.

    The V-catalyzed NMO addition reaction is also interesting, especially the use of wiped-film evaporation to prepare the dehydrated NMO solution.


    What happens to waste on scale would make an excellent Process Wednesday topic. I always remember the shock I felt when I learned that the multiple drums of distillates, crystallization filtrates, and wet cake washes I'd generated for various processes went straight to the incinerator. My previously perceived carbon footprint was shattered that day.

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  2. I wonder to what happens to all the waste from all those new perfluoroalkylation and (almost-perfluoro)alkylation reactions, then, let alone all that TFA from peptide deprotections and HPLC runs? It's not like there's a facile way to remove it, unless you reduce the bejesus out of it, either electrochemically or with alkali metals (and that doesn't seem economical or compatible with the rest of the waste stream (such as the CH2Cl2 that probably comes along with the TFA).

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