Fully Automated Continuous Flow Synthesis of Highly Functionalized Imidazo[1,2-a] Heterocycles

Abstract

The first continuous flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids directly from 2-aminopyridines and bromopyruvic acid has been developed, representing a significant advance over the corresponding in-flask method. The process was applied to the multistep synthesis of imidazo [1,2-a]pyridine-2-carboxamides, including a Mur ligase inhibitor, using a two microreactor, multistep continuous flow process without isolation of intermediates.Over the past several years high-throughput chemical synthesis has become increasingly important because of its potential to positively impact the drug discovery process. [1][2][3] Two of the most common hurdles encountered in the development of high-throughput syntheses of libraries of complex molecules have been slow reaction times and reliance on harsh or inconvenient reaction conditions. Moreover, the optimization and purification of these reactions are often time consuming and inefficient. Automated microreactor-based (microfluidic chip) continuous flow systems have the potential to greatly accelerate the production of small molecule libraries. 4, 5 Advantages include efficient heat transfer, enhanced reagent mixing, small reaction volumes, and the potential to run multistep reactions in a single, uninterrupted microreactor sequence using continuous flow conditions. 6,7 We are developing flow chemistry methods for transformations that are either not possible or highly inefficient using in-flask chemistry. This will enable the rapid synthesis of highly functionalized, druglike small molecules in high purity and on a scale sufficient for evaluation in multiple biological The imidazo[1,2-a]heterocyclic scaffold is found in compounds with anticancer, antiviral and antimicrobial activities, and in modulators of the nervous system. 8, 9 Typically, the synthesis of imidazo[1,2-a]heterocycles requires long reaction times and high temperatures, limiting the accessibility of these biologically important structures. 10 Direct condensation of 2-bromopyruvic acid with 2-aminopyridines to generate imidazo[1,2-a]pyridine-2-carboxylic acids is inefficient due to competing decarboxylation of the product at high temperatures. Therefore, stepwise protocols are generally used for the formation of imidazopyridine carboxylic acid derivatives. For example, in a typical in-flask procedure, ethyl bromopyruvate is condensed with 2-aminopyridine (Scheme 1).The product ester is isolated and subjected to saponification to provide the product. 11 Naturally, each in-flask step involves work-up and purification of the intermediates. Herein we report the first continuous flow synthesis of imidazo[1,2-a]pyridine-2-carboxylic acids from 2-aminopyridines and bromopyruvic acid using a single microreactor to enable the rapid synthesis of these compounds. We further demonstrate the incorporation of this procedure into a continuous, two microreactor method for the highly efficient preparation of a diverse library of amide derivatives.Focusing initially on the flow synthesis of imidazo[1,2,a]h...

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…5). 32 The proper design of the conditions helped avoiding a separate quenching step in the multistep synthesis of 2-aminoadamantane-2-carboxylic acid. The carbonyl oxide intermediate of the ozonolysis was decomposed in situ, in an acetone/water solvent system, thus the use of stoichiometric amounts of solid-supported thiourea reagent was avoidable.…”

Continuous flow multi-step organic synthesis

“…12 Cosford recently described a continuous two-step synthesis of a focused 13-membered 15 library of imidazo[1,2-a]pyridine-2-carboxamides (Scheme 3). 13 No isolation of the carboxylic acid intermediate was required and a final off-line purification of the crude reaction mixture provided the targets. For their work the authors used the commercially available Syrris AFRICA flow system.…”

Continuous‐flow syntheses of heterocycles

“…Highly functionalized imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine carboxylic acids and carboxamides were synthesized in a fully automated continuousflow manner by Cosford and coworkers [46]. Using readily available starting materials such as 2-aminopyridines and bromopyruvic acids and catalytic amounts of p-toluenesulfonic acid in a single microreactor unit, nine different cyclic products were obtained in 52-72% yield.…”