[JustaNovice]

Hey everyone.

I'm synthesizing a fairly lipophilic compound which I will then radio-label with fluorine-18 and use in a primate model.

But, I must first synthesize the "cold" standard. The route I've developed requires me to go through the tosyl-intermediate step prior to my "cold" fluorination. The tosylation is simple enough, however, I seem to be losing my tosyl group on my Silica column, making the fluorination quite difficult.

Does anyone have any suggestions for purifying my tosylated compound that doesn't involve silica? I've only been conducting synthetic chemistry for a couple of months, so forgive me for my amateurism. Any suggestions would be greatly appreciated. You can see the scheme attached.

Thanks.

{Mod note:  attached jpg version}

[Honclbrif]

Are you displacing the OTs with an F, or are there other steps between the tosylation and the fluorination?

If you're only using the OTs to activate that site, you may be able to directly convert the OH to an F with something like DAST or Ishikawa reagent depending on what else is in there. See if you can get the hot versions of those reagents.

You can try deactivating your silica by pretreatment with triethylamine, or use something less active like alumina, or Florisil. Prep HPLC is also usually an option if you have access to the equipment. If I was working with a hot compound I would feel like that might be a good way to go because it usually provides the best separation the fastest. However, you may also end up with an unusable radioactive HPLC when you're done, so consult the local powers that be before trying it. You can also get bulk C18 cartridges for reverse phase separation that work just like tiny chromatography columns. Finally, if your tosylate is a solid you can try recrystallizing it: no column necessary.

You could also try converting the alcohol to a halide and displacing that instead of the tosylate.

If there's steps between the tosylation and fluorination, sometimes it worth it to say "ahhh screw it" and try to run the next step without cleaning it up. I usually try this on the small scale first though if its on something that's hard to get. (maybe convert the tosylate to an iodide without intermediate cleanup, then purifying the iodide?)

[fledarmus]

Only the fluorine is radioactive, so you shouldn't have to worry about a radioactive column from the tosylate.

Alumina is a possibility - you can get it in acid-washed, base-washed, or neutral forms. Your tosylate might be stable in one of them.

For most of the radioactive compounds I've needed to synthesize, if my starting alcohol is pure and my tosylate reaction went to completion, a simple workup was sufficient to get pure enough material for the substitution reaction. Depending on the purpose for your fluorinated compound you may not need it ultrapure, you will just need to know that only the product you intend is fluorinated. You measure the specific activity of the compound by radiation produced, and non-radioactive components basically disappear in the assay. If the tosylation is high yield and the fluorination of the crude tosylated material is high yield, that may be sufficient.

[Dan]

if my starting alcohol is pure and my tosylate reaction went to completion, a simple workup was sufficient to get pure enough material for the substitution reaction.

This. Tosylations are usually so clean that an aqueous-organic extraction should be sufficient. Just to check, do you have direct evidence for de-tosylation on silica gel? If the answer is yes you can pretty much ignore what follows, but I find it quite unlikely since they are usually stable (unless you get some NGP from from the ether I suppose?).

Out of interest, what fluoride source are you using for the displacement?

I worked on some fluoride displacements of alkylsulfonates a while back, from what I remember tosylates are generally not good enough leaving groups to achieve good results, and that triflates and imidazolesulfonates are generally preferred. My dabbling in the area was brief though. I'm just wondering that if the major symptom you have is that the fluoride displacement doesn't work, perhaps this is the problem and not de-sulfonylation?