Abstract
The development of miniaturized flow platforms would enable efficient and selective synthesis of drug and lead molecules by rapidly exploring synthetic methodologies and screening for optimal conditions, progress in which could be transformative for the field. In spite of tremendous advances made in continuous flow technology, these reported flow platforms are not devised to conduct many different reactions simultaneously. Herein, we report a metal-based flow parallel synthesizer that enables multiplex synthesis of libraries of compounds and efficient screening of parameters. This miniaturized synthesizer, equipped with a unique built-in flow distributor and n number of microreactors, can execute multiple types of reactions in parallel under diverse conditions, including photochemistry. Diazonium-based reactions are explored as a test case by distributing the reagent to 16 (n = 16) capillaries to which various building blocks are supplied for the chemistry library synthesis at the optimal conditions obtained by multiplex screening of 96 different reaction variables in reaction time, concentration, and product type. The proficiency of the flow parallel synthesizer is showcased by multiplex formation of various C–C, C–N, C–X, and C–S bonds, leading to optimization of 24 different aryl diazonium chemistries.
Highlights
The development of miniaturized flow platforms would enable efficient and selective synthesis of drug and lead molecules by rapidly exploring synthetic methodologies and screening for optimal conditions, progress in which could be transformative for the field
The advent of the technology has led to the development of “universal” automated flow synthesis platform for efficient optimization of organic synthesis[11,12], computer-aided synthesis planning (CASP) and robotically executed targetoriented or diversity-oriented flow synthesis of specific molecules for exploration of new drug development[13,14,15,16,17,18,19,20,21,22]
The baffle discs with complex structures in the distributor were fabricated by 3D metal printing, and the components and modules were made by computer numerical control (CNC) machining
Summary
The development of miniaturized flow platforms would enable efficient and selective synthesis of drug and lead molecules by rapidly exploring synthetic methodologies and screening for optimal conditions, progress in which could be transformative for the field. We report a metal-based flow parallel synthesizer that enables multiplex synthesis of libraries of compounds and efficient screening of parameters This miniaturized synthesizer, equipped with a unique built-in flow distributor and n number of microreactors, can execute multiple types of reactions in parallel under diverse conditions, including photochemistry. The synthesizer can concurrently execute multiple reactions in parallel under diverse reaction conditions, including photochemistry This desk-top type of synthesis platform is utilized to explore diazonium-based reactions as a test case for multiplex screening of 96 different reaction variables in reaction time and concentration in building the chemistry library. No reconfiguration of modules and components is involved in demonstrating the capabilities of this flow parallel synthesizer that can expedite the workflow in the discovery stage for a lead molecule
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