Continuous flow synthesis of Thien[2,3-c]isoquinolin-5(4H)-one scaffold: A valuable source of PARP-1 inhibitors


    Using the Vapourtec R-Series the Vapourtec R-Series flow chemistry system researchers from the Universita di Perugia, the Universita degli Studi di Napoli Federico II and TES Pharma have shown the continuous flow multi-gram synthesis of Thien[2,3-c]isoquinolin-5(4H)-one (TIQ) an important PARP-1 inhibitor. The group show how the combination of flow chemistry, statistical DOE and automation enabled them to develop a robust experimental protocol for large scale production while increasing yields, reducing cost, hazards and manpower.

    PARP-1 inhibitors have a wide range of potential therapeutic applications including diabetes, cancer, neurodegenerative, inflammation and cardiovascualar disorders. TIQ-A has been shown to exhibit catalytic activity of PARP-1 however no larger scale preparation of this important building block has been demonstrated.

    The current synthesis strategy is based on a Suzuki coupling, followed by the formation of an acyl azide and cyclisation via thermal Curtius rearrangement. This method gives a low 33% yield and involves the use of hazardous reagents and lengthy synthesis, work-up and purification protocols. The group aimed to reduce these factors.

    Each reaction step was studied independently in sequence to optimise the reaction conditions applying design of experiment (DoE) and central composite design (CCD) in an automated process. Once the optimised conditions were established the group worked to combine these into a continuous flow synthesis.

    The continuous multi-gram synthesis of TIQ-A was demonstrated with an increased yield of 50% (vs. 33% batch) with a single chromatographic purification step. The group show that the concerted process is facile, safe and easy to scale.

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    Have a look at the Organic Process Research & Development paper

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