Late-stage fluorination, what do you think ?

Hi Everyone,  I have really been appreciating the visits to my blog.  I had resurrected this dormant site blog a while ago and hoped I could get a fair number of visits.   I have been overwhelmed with the response.  Some of the posts were clear winners, like the Revlimid case, for sure.  I, recently, came across this review in Organic Process Research & Development and realized there probably would be two sides to this argument.

Late-stage fluorination.  The current review in OPRD can be found at Michael G. Campbell and Tobias Ritter*, “Late-Stage Fluorination: From Fundamentals to Application”, Org. Process Res. Dev. 2014, 18, 474−480

doi: 10.1021/op400349g  

I remember, many years ago, discussing this with a colleague about adding a fluorine group to a molecule.  We both agreed that it would be far better to add a fluorine early on the synthesis, so if there were side-products, you would take your hit in yield early on.  The chemistry may have improved since then.  Having said that, after a short secondment (some might call it a job, contract, etc.), I worked at a private company where they produce radiopharmaceuticals.

I didn’t directly work in the production, but suffice it to say, I gained a new appreciation for late-stage fluorination.  F-18 is definitely something you want to add as the last step in making a radioactive imaging agent.  The half-life for F-18 is 110 minutes.  You need to synthesize and be ready to inject very quickly (after QC release, of course).

So as you can see, I might have some reservations against dismissing late-stage fluorination.  Since I have written a few posts on what I have found in the literature to inform,  I am hoping I might be able to pick your brains collectively and we could have a discussion on your opinion of late-stage fluorination.  Are you for it ?

Are you against it ?  What would you want if you had fluorination as the last step in the synthesis ?   What would be the ideal conditions ?

To start you off, if I was considering fluorination late in the organic synthesis, I would not want to use palladium unless I really had to.  Why ?  Because level of palladium in the active pharmaceutical ingredient needs to be around 10 ppm, so I would also hope I wasn’t using a lot of palladium.  I would want as high a conversion to fluoro-product as possible.  You get the idea.  There are no wrong opinions.

I just want to know your thoughts on this.  The site was made for people to learn and by contributing, you are contributing to the better good.  Maybe you know of an instance that you can share where late-stage fluorination was critical for an industrial synthesis.  I want to learn ( and so do others).


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