Source
r/Chempros•
synchemist

Looking for tips: freebasing very polar molecules

I have some very polar molecules I isolate from preparative HPLC (for an idea on their polarity, in 99% methanol, 1% triethylamine they have an Rf of 0.2 on normal phase silica). They come off the prep as TFA salts (they salted at a secondary amine). I’m trying to get through 50 compounds so lyo and freebasing in organic media is too slow, I’m looking to neutralize and extract but I loose a lot of material (35 out of 50 mgs) in the aq phase. I’m going to try salting out next but was looking for some tips on how to improve the recovery?

Posted Oct 3, 2019, 11:20 AM UTC

1117
FitzarrMed Chem•

Do you have to use acidified solvents for the HPLC? Seems like the simplest solution would be to just use standard acetonitrile/methanol and water gradients and run it for longer/to a higher organic percentage, then just vac down your fractions to get the neutral material.

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synchemistOP•

This is a really good point, I could look into this for sure. I guess it can be hard to get reproducible resolution without a buffer and the super user may not be happy with me messing with their methods but... needs must.

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FitzarrMed Chem•

Don't know how it works where you are, but swapping out solvents has been standard procedure on any prep-HPLC I've ever used. Maybe ask your super-user to make a new method called "synchemist" and then you can just fiddle with that as you need?

Alternatively, if you need to end up with the TFA salt, there are other things you can try rather than an aqueous workup. One thing I've had success with is adding excess aqueous base (usually NaOH), stirring it for a bit, then vaccing everything down to get a mix of the inorganic salts and organic material. If you then stir that in ethanol overnight, you can filter off the salts and then vac down your ethanol to give you your freebased compound.

2
Nelonski•

So.. One way is to swap the salt and precipitate out. As mentioned, tetrafluorborate salts also work well. I'm surprised dcm/hexane, toluene/meoh or just using hot ethanol to re crystallize doesn't work. Technically, you can just keep extracting the water with appropriate organic solvent and it'll improve the yield, make sure the pH of the water is indeed basic so you can assume it's deprotonated. Alternatively, perhaps just add triethylamine or pyridine in an organic solvent with your compound, then remove the basic net3 Salt. Gl

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synchemistOP•

Good suggestions, I actually have to isolate the freebase as I’m using DFT nmr prediction to assigned relative stereochemistry. HPLC is needed to resolve the diastereomers so direct crystallization is out. How would you remove the salt of an organic base without an aqueous wash? I guess normal phase chromatography?

1
Nelonski•

You might be able to precipitate it out for example triethylamine hydrobromide is pretty insoluble in thf and toluene. If your compound stays in the solvent it's ideal

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Nelonski•

Chromatography will be shitty unless you can find the right gradient I think the amine salt can come off with 5 percent maybe less of DCM meoh but you have to make sure Ur compound doesn't move in that gradient

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XylosaurMedChem•

Maybe after the first extraction, add brine to the aqueous layer and re-extract. All the organics should be "pushed" into the organic layer.

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Or just add brine at the get-go!

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Nelonski•

This is a good idea to.

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synchemistOP•

Yup salt out is a good shout! Is brine best? I’m trying to think which counterion will coordinate the least

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wildfyrPolymer•

Just to reiterate, tetraphenyl borate. Its a noncoordinating anion, its sodium salt is soluble in water and organics, organic cation salts seldom have much aqueous solubility. Not expensive either.

Has worked like a dang charm on everything I've ever crashed out with it. Beautifully pure white powders with no further workup needed.

One caveat, it has poor acid stability, will degrade into phenyl boronic acid and benzene if you leave it in acidic media.

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synchemistOP•

Will tetraphenyl borate do counterion metathesis with a TFA salt of an amine? This could be great for getting crystal structures. I actually need the freebase at the moment for DTF nmr comparison reasons. I was just concerned I would get protonolysis (or so Wikipedia warned me)?

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wildfyrPolymer•

Yes, it should exchange. The precipitation of the salt out of aqueous solution usually drives the reaction to 100% completion via Lechatlier.

For the acidic bit, I don't know how acidic your molecule is, but it will fall apart in things like glacial acetic acid. As a solid or dilute solution it should have considerably more stability. You might just have to try this one. I'll note that Sigma sells 99% ammonium tetraphenylborate.

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wildfyrPolymer•

Make tetraphenylborate salts they have garbage water solubility

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SuperBeastJOrganic PhD•

You can try using an eluent that doesn't contain TFA on your prep HPLC. Alternatively, if your compound is organic soluble as a free base you could stir in THF/toluene etc, freebase with something like Hunig's base, Et3N, pyridine and then flush it down a pipette column of activated basic alumina. Should be able to get your compound to move and the salt to stick.

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MountainTurn•

Triturate with dry alcohol to remove the less soluble salt i.e. EtOH is good for NaCl removal.

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