End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts

Abstract

A 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. Fig. 1 Continuous end-to-end synthesis, purification, and crystallization of diphenhydramine hydrochloride (2).

Continuous Suzuki-Miyaura Reactions with Novel Ce-Sn-Pd Oxides and Integrated Crystallization as Continuous Downstream Protocol

“…5.000 g ammonium cerium(IV) nitrate, 1.861 g tin(II) oxalate, 0.033 g palladium(II) chloride, and 3.294 g glycine (fuel) were thoroughly mixed by grinding the components using mortar and pestle. The solid mixture was suspended in 2 mL of water in a borosilicate dish with 600 mL capacity.…”

“…Several examples for continuous multistep API syntheses or even end-to-end manufacturing plants have been reported [3][4][5][6][7][8][9] and reflect the great effort which has been done to establish suitable continuous protocols for the primary and secondary manufacturing of APIs. Although the advantages of continuous processes are well-known [10,11] (e.g., increased throughput, reduced waste, simplified scale-up or improved safety, especially when hazardous reagents are used [12]), the application of continuous processes is not yet standard practice in pharmaceutical manufacturing, despite the effort of the Federal Drug Administration (FDA) [13,14].…”

Beyond Organometallic Flow Chemistry: The Principles Behind the Use of Continuous-Flow Reactors for Synthesis

“…Precipitation of highly polar compounds can be also avoided by heating the reactor above the melting temperature of the solid material. 91,160 Consequently, the material is processed in its molten state and will not clog the microchannels. Another strategy is to use mechanical energy to keep the solids in suspension.…”

A Systems Approach towards an Intelligent and Self‐Controlling Platform for Integrated Continuous Reaction Sequences

“…[2][3][4][5][6] This requirement inspires a second design layer when planning multi-step flow procedures, which encompasses the engineering requirements for the system. This layer includes the new flexible, low cost in-line processing tools, [7][8][9][10][11] which enable some of the concepts of multi-step manufacturing processes to be applied within the research laboratory. [2,3,7] Increasingly elaborate reactor assemblies rapidly become difficult to manage, and so an additional design layer must be invoked, incorporating the necessary data management.…”

“…This layer includes the new flexible, low cost in-line processing tools, [7][8][9][10][11] which enable some of the concepts of multi-step manufacturing processes to be applied within the research laboratory. [2,3,7] Increasingly elaborate reactor assemblies rapidly become difficult to manage, and so an additional design layer must be invoked, incorporating the necessary data management. [4c] The key role of the information layer is to take overall control of the system, coordinating each module or instrument to run a prescribed sequence of events.…”