[kriggy]

Hi guys

Is there anyone experienced with resolution of racemates by crystalization? Im strugling with it a bit and since my project stands on the fact that I will be able to resolute the racemate into the enantiomers i really need to succes

My problem is that my acid is not soluble in water and very soluble in organic solvents so I failed to induce the crystalization. (I did recrystalize the racemic compound to purify it from methanool but it was 2g in 4 ml of MeOH and the yield of crystalization was about 1g while the HPLC purity before crystalization was about 90%)
 
I read this book CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation and it was realy helpful to get the basic idea.
Anyway, in the book, I saw some examples of using phenethylamine in water but the amine is not realy soluble in water so I only get brown goo or just the solution after cooling if I use organic solvents. There is not realy anyone at my department that has experience with this so Im asking here.

I dont have any specific questions (yet) but Im looking for more general tips or experiences.
Thank you

[AWK]

did you check this discussion?
http://www.chemicalforums.com/index.php?topic=89079.0

[kriggy]

Thanks for the link, I did miss it somehow. There are few interesting points in the discussion

[TheUnassuming]

I've played with it before, though was never able to get significant enough enrichment to pursue further because the stereocenter was just too far away for this to work in my case.  That said, when it came time to get x-ray crystals to prove stereochemistry I already knew the conditions I would use!

The best advice I can give (and got from others) is in the beginning to use a brute force route.  First I would grab every single solvent you can get your hands on, and try the crystallization with all of them (single solvent per experiment with your salt combo with varying conditions).  Unless you are lucky, you will probably end up having to use a mixed solvent system; so then with your data from the single solvent experiments, set up as many logical combinations of conditions as you can think of to try.  If you still aren't getting anywhere, grab another amine known for resolutions, and try it all again. 

The best results for my substrate were with a para-nitro- alpha methyl benzyl amine and a MeOH/Et2O system but there are much cheaper salt options to start with.   

[kriggy]

And on what scale did you try the solvents/reagents for crystalization? Im working on 100 mg scale but it seems too much but Im not sure if I can go lower due to solubility (the compound has good solubility in pretty much everythign except water)

[TheUnassuming]

In the beginning I was just using a few mg's and was using little 200uL vials for my production line.  At that point I was just looking to see if anything dropped out, and if it did I moved up in scale to where I could fully analyze what I was making.  If you are careful you should be able to get almost complete recovery of your material from runs that don't work, so going on a larger scale should be fine as well. 

How are you determining ee?

The chiral amine salt of your acid has good solubility in non-polar solvents? Can you clip a greasy protecting group to bring it into the more polar range? 

[kriggy]

Hm I didnt expect just few mg´s

We have SFC with chiral collumn and then its just integration of peaks.

It didnt crash out from EtoAc, MeOH, EtOH. It precipitated from toluene but it was just racemic but Im going back to this using just 0,5 eq of amine.

[Doc Oc]

It didnt crash out from EtoAc, MeOH, EtOH. It precipitated from toluene but it was just racemic but Im going back to this using just 0,5 eq of amine.

Am I reading this correctly that you're trying to separate enantiomers without an additive? Because that will never work. You need to add a chiral resolving agent to create a diastereomer that will preferentially crystallize. Tartaric acid is a common one, but there are many others.

[pgk]

Doc Oc, you are  absolutely right.
Enantiomers have the same solubility properties, in contrast to diastereosimers that have different solubility properties. Thus:
Resolution of enantiomeric amines can be effectuated by salt formation with an enantiopure acid (e.g. enentiopure tartaric acid, while enantiomeric acids by salt formation with an enatiopure base (e.g. enantiopure 2-phenylpropylamine-1).
Attention to the selection of the enatiopure acid and base (it depends on the structure of your compound), in order to achieve an easy crystallization and beautiful crystalls.
 

[pgk]

Mayday-Orthographic errors, above: diastereoisomers and not diastereosimers. Also, enantiopure and not enatiopure.
Very sorry.