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      Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

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          Abstract

          The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring, optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time scale of operation. This classification will cover the broader range in the multistep synthesis literature.

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          Most cited references91

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          On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system.

          Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.
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            Continuous flow multi-step organic synthesis

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              Taming hazardous chemistry by continuous flow technology.

              Over the last two decades, flow technologies have become increasingly popular in the field of organic chemistry, offering solutions for engineering and/or chemical problems. Flow reactors enhance the mass and heat transfer, resulting in rapid reaction mixing, and enable a precise control over the reaction parameters, increasing the overall process selectivity, efficiency and safety. These features allow chemists to tackle unexploited challenges in their work, with the ultimate objective making chemistry more accessible for laboratory and industrial applications, avoiding the need to store and handle toxic, reactive and explosive reagents. This review covers some of the latest and most relevant developments in the field of continuous flow chemistry with the focus on hazardous reactions.
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                Author and article information

                Contributors
                Role: Guest Editor
                Journal
                Beilstein J Org Chem
                Beilstein J Org Chem
                Beilstein Journal of Organic Chemistry
                Beilstein-Institut (Trakehner Str. 7-9, 60487 Frankfurt am Main, Germany )
                1860-5397
                2017
                19 May 2017
                : 13
                : 960-987
                Affiliations
                [1 ]Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory (NCL) Campus, Pune 411008, India
                [2 ]Chem. Eng. & Proc. Dev. Div., CSIR-National Chemical Laboratory, Dr. Homi Bhaba Road, Pashan, Pune 411008, India
                Author notes
                [§]

                Tel: +91 20 25902153

                Article
                10.3762/bjoc.13.97
                5480366
                f1c779ff-8a52-46fe-aad8-eee54119192c
                Copyright © 2017, Shukla and Kulkarni; licensee Beilstein-Institut.

                This is an Open Access article under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: ( http://www.beilstein-journals.org/bjoc)

                History
                : 5 January 2017
                : 31 March 2017
                Categories
                Review
                Chemistry
                Organic Chemistry

                Organic & Biomolecular chemistry
                automation,control strategy,flow chemistry,in-line monitoring,multistep synthesis optimization

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