1,721,069 research outputs found
The Assembly and Use of Continuous Flow Systems for Chemical Synthesis
No full textThe adoption of and opportunities in continuous flow synthesis ('flow chemistry') have increased significantly over the past several years. Continuous flow systems provide improved reaction safety and accelerated reaction kinetics, and have synthesised several active pharmaceutical ingredients in automated reconfigurable systems. Although continuous flow platforms are commercially available, systems constructed 'in-lab' provide researchers with a flexible, versatile, and cost-effective alternative. Herein, we describe the assembly and use of a modular continuous flow apparatus from readily available and affordable parts in as little as 30 min. Once assembled, the synthesis of a sulfonamide by reacting 4-chlorobenzenesulfonyl chloride with dibenzylamine in a single reactor coil with an in-line quench is presented. This example reaction offers the opportunity to learn several important skills including reactor construction, charging of a back-pressure regulator, assembly of stainless-steel syringes, assembly of a continuous flow system with multiple junctions, and yield determination. From our extensive experience of single-step and multistep continuous flow synthesis, we also describe solutions to commonly encountered technical problems such as precipitation of solids ('clogging') and reactor failure. Following this protocol, a nonspecialist can assemble a continuous flow system from reactor coils, syringes, pumps, in-line liquid–liquid separators, drying columns, back-pressure regulators, static mixers, and packed-bed reactors. Keywords: Flow chemistry; Synthetic chemistry methodologyUnited States. Defense Advanced Research Projects Agenc
A Unified Continuous Flow Assembly-Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines
No full textA rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N‐alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst‐free conditions. This assembly‐line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four‐step, telescoped synthesis of measles therapeutic, AS‐136A, in a total residence time of 31.7 min (1.76 g h⁻¹). Keywords: active pharmaceutical ingredients; agrochemicals; assembly line synthesis; multi-step continuous flow synthesis; pyrazole
Enhanced Reaction Efficiency in Continuous Flow
No full textContinuous flow reactors are enabling tools that can significantly benefit chemical reactions, especially those that are path length dependent (e.g., photochemical), mixing or transport dependent (e.g., gas‐liquid), exothermic, or utilize hazardous or unstable intermediates. In this review, it is demonstrated how the nearly instantaneous mixing, exceptionally fast mass transfer, safe access to high temperatures and pressures, and high surface area to volume ratio can be leveraged to improve product yield, reaction rates and/or selectivity. By showcasing five synthetic methodologies examined by our group, it is hoped that the reader will gain an appreciation of the accessible and transformative nature of flow chemistry for improving existing transformations, enabling rapid optimization, and for developing new methodologies that depend on precise parameter controls. Keywords: flow chemistry; process intensification; microreactors; photochemistry; synthesis desig
Rapid Continuous Synthesis of 5′-Deoxyribonucleosides in Flow via Brønsted Acid Catalyzed Glycosylation
No full textA general, green, and efficient Brønsted acid-catalyzed glycosylation serves as a key step in the one-flow, multistep syntheses of several important 5′-deoxyribonucleoside pharmaceuticals.Novartis- MIT Center for Continuous Manufacturin
Rhodium-catalyzed dehydrogenative borylation of cyclic alkenes
No full textA rhodium-catalyzed dehydrogenative borylation of cyclic alkenes is described. This reaction provides direct access to cyclic 1-alkenylboronic acid pinacol esters, useful intermediates in organic synthesis. Suzuki–Miyaura cross-coupling applications are also presented.National Institute of General Medical Sciences (U.S.) (GM-63755
Continuous Flow Photochemistry for the Rapid and Selective Synthesis of 2'-Deoxy and 2',3'-Dideoxynucleosides
No full textA new photochemical flow reactor has been developed for the photo-induced electron-transfer deoxygenation reaction to produce 2′-deoxy and 2′,3′-dideoxynucleosides. The continuous flow format significantly improved both the efficiency and selectivity of the reaction, with the streamlined multi-step sequence directly furnishing the highly desired unprotected deoxynucleosides.Novartis-MIT Center for Continuous Manufacturin
Diisobutylaluminum Hydride Reductions Revitalized: A Fast, Robust, and Selective Continuous Flow System for Aldehyde Synthesis
No full textA continuous flow system for the multiparameter (flow rate, temperature, residence time, stoichiometry) optimization of the DIBALH reduction of esters to aldehydes is described. Incorporating an in-line quench (MeOH), these transformations are generally complete in fewer than 60 s. Mixing of the DIBALH and ester solutions was observed to be an exceptionally critical parameter for optimum results. This system thus provides general guidelines based on the structure of the ester for selective reduction of an ester without overreduction.Novartis-MIT Center for Continuous Manufacturin
On the Synergism Between H[subscript 2]O and a Tetrahydropyran Template in the Regioselective Cyclization of an Epoxy Alcohol
No full textA regioselective epoxy alcohol cyclization promoted by the combination of neutral water and a tetrahydropyran template was investigated through a series of mechanistic experiments carried out on an epoxy alcohol containing a tetrahydropyran ring (1a) and its carbocyclic congener (1b). In contrast to 1a, cyclizations of 1b were unselective and displayed significantly faster reaction rates suggesting that the tetrahydropyran oxygen in 1a is requisite for regioselective cyclization. Reactions for both substrates were shown to occur in solution and under kinetic control without significant influence from hydrophobic effects. Kinetic measurements carried out in water/dimethyl sulfoxide mixtures suggest that 1b reacts exclusively through an unselective pathway requiring one water molecule more than what is required to solvate the epoxy alcohol. Similar experiments for 1a suggest a competition between an unselective and a selective pathway requiring one and two water molecules in excess of those required to solvate 1a, respectively. The selective pathway observed for 1a but not in 1b is rationalized by electronic and conformational differences between the two compounds.Petroleum Research Fund (47212-AC1
Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water
No full textDespite the myriad of selective enzymatic reactions that occur in water, chemists have rarely capitalized on the unique properties of this medium to govern selectivity in reactions. Here we report detailed mechanistic investigations of a water-promoted reaction that displays high selectivity for what is generally a disfavored product. A combination of structural and kinetic data indicates not only that synergy between substrate and water suppresses undesired pathways but also that water promotes the desired pathway by stabilizing charge in the transition state, facilitating proton transfer, doubly activating the substrate for reaction, and perhaps most remarkably, reorganizing the substrate into a reactive conformation that leads to the observed product. This approach serves as an outline for a general strategy of exploiting solvent-solute interactions to achieve unusual reactivity in chemical reactions. These findings may also have implications in the biosynthesis of the ladder polyether natural products, such as the brevetoxins and ciguatoxins.Petroleum Research Fund (47212-AC1)National Institute of General Medical Sciences (U.S.) (GM72566
End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts
Full text linkA continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1 : 1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional solvent at high temperature gives the target compound directly as a molten salt (ionic liquid above 168 °C) in high yield. This represents the first example of continuous active pharmaceutical ingredient (API) production in this manner. Six of the twelve principles of green chemistry as defined by the American Chemical Society are achieved, most prominently waste minimization and atom economy.United States. Defense Advanced Research Projects Agency (DARPA N66001-11-C-4147
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