QDIS Blog

Changing Solvent Can Eliminate or Reduce Impurities

by Ed Vawter @ 9:27 am. Filed under Chemistry Articles

Most chemists know that a solvent change can have a dramatic effect the course of a reaction but what is not commonly appreciated is that a change of solvent can dramatically reduce impurities formed in a reaction and make the subsequent purification much easier or allow it to be eliminated entirely. I recently came across an example of this sort of can be seen in the following article:

The Synthesis of a Novel Inhibitor of B-Raf Kinase (Org. Process Res. Dev. 2006, 10, 70–77)

The reaction of 7-hydroxyisoquinoline with (CF3SO2)2O in EtOAc–pyridine gave the triflate in moderate yield (48%) after an aqueous work-up and a thin-film vacuum distillation. Quite a bit of material is lost in the course of the distillation due to the use of ethylene glycol which was used as a lubricant and to solubilize pyridinium salts.

Changing the reaction solvent from EtOAc to t-BuOMe led to more efficient removal of the salts during the aqueous work-up, the use of less ethylene glycol which gave a higher yield (75-85%) as well as allowing the distillation to proceed at a lower temperature. All this from a simple change from EtOAc to t-BuOMe.

I’ll be honest, this wasn’t the reason this article first caught my eye. I read it because I noticed they used a Negishi coupling in their synthesis. I received my PhD from Purdue University under the supervision of Dr. Negishi and spent quite a bit of time working on this sort of coupling back in the late 80’s. I’m always pleased to see the words “Negishi coupling” and “uneventful” in the same sentence. It was interesting, although disturbing, to see some of the same problems we experienced back 20 years ago. This includes control of temperature for the Li halogen exchange and that the Pd catalyst nature is vital. It would have been interesting to look at other ligands. My experience is that trifurylphosphine instead of triphenylphosphine sometimes gives much better results. It would also be interesting to investigate using the Pd catalyst for the amination as well (Buchwald coupling) instead of dealing with the hydrogen evolution resulting from deprotonation of the amine with NaH and then coupling with the aryl chloride.