Many important drugs, such as Lipitor and Ciprofloxacin, have either a polysubstituted pyrrole or quinolone core structure. We are developing versatile continuous flow processes based on well-established batch methods for the syntheses of polysubstituted pyrroles, and in so doing have reduced the number of unit operational steps and simplified the chemistry and solvents required.  The fully telescoped process has resulted in a high yield conversion of benzyl-aryl-ketone starting materials into valuable polysubstituted pyrrole products, in a much shorter total synthesis time with a significantly higher purity level and thus lower solvent consumption/waste generation than by the established batch processes.

     We will report on our results converting this multistep synthesis into a continuous, optimized, single-solvent flow process. The basic scheme starts with POCl₃ reacting with DMF to very rapidly generate the Vilsmeier reagent which is then telescoped with a flow step that introduces benzyl-aryl-ketone which produces the corresponding chloroenal in near quantitative yield. This is followed by telescoping with a high temperature step that introduces sarcosine, which upon reaction ring closes to the pyrrole product. The known batch route has been shown to have broad scope, tolerating a large range of substituents and functionality.  Additionally, this synthetic scheme makes possible the synthesis of polysubstituted pyrroles that are unsubstituted at the pyrrole nitrogen by using glycine in the final step with equally high yield and purity pyrrole formation. Thus, an optimized flow process is amenable to a generation of large libraries of polysubstituted pyrroles with strategic variation of substituents at all five pyrrole ring positions.

    We have been able to significantly reduce reaction times and have found conditions where all steps can be performed in the same solvent instead of the three noncompatible solvents necessary for the batch process – a key advance for a continuous flow process.