The Quinoline Tag to enable Phase Switching Isolations in Chemical Synthesis Process Development

 

The KiloMentor blog is dedicated to transmitting useful ‘tricks of the trade’ to the synthetic organic chemists who do the actual laboratory experimentation that creates chemical processes that are intended to be performed at scale.

The KiloMentor blog therefore particularly highlights the importance of the workup of chemical reactions with their separations, isolations, and purification operations since it is these that consume the most time in the plant setting. It is also these methods which are most difficult to uncover by electronic database searching.

In 1999, Hélène Perrier and Marc Labelle published a paper titled Liquid-Phase Synthesis with Solid-Phase Workup: Application to Multistep and Combinatorial Syntheses, J. Org. Chem. 1999, 64, 2110-2113 which was designed to make the workup of every step of a reaction sequence a simple filtration until the tagged target molecule was completely assembled whereupon the facilitating functional ‘tag’ could be cleaved off to leave the target molecule itself in practically pure form.

Another way of looking at what they were enabling is an alcohol-protecting group that so long as it remains in process intermediates makes them simple to isolate and purify from their reactions. In the terminology of Dennis P. Curran, it makes phase switching of these intermediates possible. In the terminology of Jun-ichi Yoshida, it introduces tags on these intermediates.

These chemists discovered that if an alcohol functionality in a starting material was made into the ester of 3-quinoline carboxylic acid then other functionalities in that starting material could be used to elaborate some larger assemblage and all the intermediates in that sequence could be easily isolated and purified by first precipitating them from the reaction solvents as insoluble sulphuric acid salts and then reconstituting the free quinoline by neutralizing the salts and extracting the intermediate back into the solvent for the next reaction in the desired synthetic route.

The salts with sulphuric acid were found to be the choice that most dependably crystallized from a wide range of solvents. The original paper should be consulted for the experimental details.

Finally, in their examples, the 3-quinoline carboxylic acid could be recovered at the end of their test sequences and was sufficiently pure to be reused!

Although these authors don’t go that far, KiloMentor concludes that protection groups generally, besides protecting functional groups, should be selected to promote the isolation and purification of the intermediates into which they are introduced.