[Babcock_Hall]

We are trying to make the BOC-ornithine amide derivative of isonicotinic acid.  After extracting into bicarbonate, acidifying to pH 3, and extracting into ethyl acetate we had some material that had an NMR that was consistent with our desired product but that still had 4-nitrophenol (which is a side product).  Therefore, we used TLC to identify 20% MeOH/80% acetone as a solvent which moved our presumed product (Rf was about 0.2).  When we tried a silica column there were a few yellow fractions, then what we thought was product.  However, the mass of this material is only a few milligrams, whereas almost 200 mg was applied.  The top of the column is brownish.  I tried flushing with 40% MeOH, but this did not seem to move the brown material.  I was thinking of going up to 70% MeOH, then to 100% MeOH.  If the brown material is really our product, I will have to tolerate the silica, but obviously I need the product.  Should I try anything else?  Should I add a small amount of acetic acid to the solvent? Thanks in advance.

[Dan]

Yeah, acid doping may help - run a few TLCs on the crude. I've heard of chloroform/methanol/acetic acid/water for polar acids. Not sure what ratio to go with, this is fairly distant memory, but I think it was something like 60:25:10:5.

The other option is not to work with the free acid. Drop some diphenyldiazomethane (not explosive) into the crude and isolate it as the greased-up benzhydryl ester. Depends how important atom economy is to you.

[Babcock_Hall]

Thanks.  The original reference (Janecka et al., J. Med. Chem., 1994, 2238-41) said of the nicotinyl isomer, "For analytical purposes it was purified by column chromatography on silica gel (eluant CHCl₃:MeOH:AcOH, 94:5:1): R_f, = 0.36, CHCl₃:MeOH:AcOH, 94:5:1; R_f, = 0.71, n-BuOH:py:AcOH:H₂O, 30:10:3:12.  My student did not observe any mobility with this system, but I may ask him to try again with either this system or the one you suggested.

I will have to look into benzhydryl esters and their removal.  I am a little worried about any deprotection that employs hydrogenation, because some of our intended products are pyridinium, as opposed to pyridine derivatives.

[Babcock_Hall]

My next question extends beyond the scope of the opening post.  For compounds that are relatively polar, is there any reason to think that they will elute more easily from alumina than from silica?  We are having trouble getting all of our product compounds to move, which makes assessing recovery difficult, among other problems.  Thanks in advance.

[Doc Oc]

I find that some combination of ethyl acetate and methanol (~10% MeOH) is good for flushing just about anything, including free carboxylic acids.  It's a rare occasion where something is so stubborn that a pure MeOH flush is required, but I have done it.

[408]

"For analytical purposes it was purified by column chromatography on silica gel

this sounds like a wiggle sentence that could easily mean "we columned it but most of it stuck and we only got enough product for one nice NMR"

[OC pro]

I have done several pyridinecarboxylic acids (awful compounds). With silica gel it will be painful. I had good results in purification via cationic exchange purification (amberlite 120). Elution was performed with aqueous ammonia.

[Dan]

Yeah, I have also used cationic exchange resins for very polar amines and this is definitely the way to go for polar compounds with basic functionality. Beware in this case though that the Boc may not survive a strongly acidic resin.

Re: Alumina - I suggest you get some alumina coated TLC plates and check out the mobility vs silica. I do not know off-hand whether it is likely to be a better stationary phase, my experience with it is very limited.

[curiouscat]

It's a rare occasion where something is so stubborn that a pure MeOH flush is required, but I have done it.

Is there a downside to a pure MeOH flush?

[discodermolide]

It tends to dissolve a bit of silica-gel. This appears in your product!

[curiouscat]

It tends to dissolve a bit of silica-gel. This appears in your product!

Ah! Thanks. Didn't know.

[Babcock_Hall]

I will try to attach a figure of the intermediate compound of interest.  This is the isonicotinamide isomer, and we are also preparing the nicotinamide (carboxamide at the 3-position) isomer.  The next two steps will be alkylation of the pyridine nitrogen (to form a pyridinium compound) and deprotection (we were planning to use IEX after the deprotection step, but we will be satisfied with whatever works the best for this intermediate).  We tried the double extraction outlined in the J. Med. Chem. paper on several occasions, but our recovery has been poor.  Our most recent column used 80:20 acetone methanol and something eluted after 4-nitrophenol, which we are in the process of identifying (it may be the desired compound).  An additional compound eluted when we tried CHCl₃/MeOH/Acetic Acid/water, as suggested above.