Flow Synthesis of Biologically-Relevant Compound Libraries

Abstract

Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists' approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules.Molecules 2020, 25, 909 2 of 12 of urea-based biologically active compounds are present like vestipitant and trimefluor [14,15]. As a continuation of previous work [16], Rutjes and co-workers set up a new procedure for the synthesis in flow of a library made of urea-based molecules based on piperidin-4-ones (Scheme 1) [17]. Optimization studies have been performed using as test compounds ethylisocianate 2a and piperidin-4-one 1a employing a microreactor (100 µL effective volume). After using different solvents, temperatures, and reactants ratios, the authors identified as best reaction conditions those that employed tBuOH as solvent at 50 • C for 17 min. On the other hand, when isocyanate 2c bearing an aryl moiety was allowed to react with 1a, full conversion was obtained only by using 1,2 dichloroethane (1,2 DCE) at 80 • C for 17 min. Such conditions were applied then to isocyanates (2a-c) and piperin-4-ones (1a-c) for the synthesis of 15 urea-based products 3 containing different fluorine moieties as it has been shown that such functionalities could enhance bioactivity and metabolic profile [18]. The urea-based products were obtained with isolated yields values ranging from 55 to 99%. No further chromatography purification was necessary. This methodology, therefore, is suitable for the synthesis of a large number of molecules to be tested for biological activity.

Towards Antibiotic Synthesis in Continuous-Flow Processes

“…The new technologies and modern trends in the synthesis of drugs and natural products that have been developed by academia and industry are opening up opportunities on a scale previously considered unattainable in most laboratories and production lines. The use of high-throughput and breakthrough technology platforms, particularly flow chemistry and process analytics (PAT), is representative of the endless potential in the pharmaceutical field and the improvements over the current state that are possible ( Figure 1 ) [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”