Flow-oriented synthetic design in the continuous preparation of the aryl piperazine drug flibanserin

Abstract

The first integrated continuous-flow synthesis of the drug substance flibanserin was developed, using an uninterrupted four-step sequence, via an unprecedented route.

C-N Bond Formation by Consecutive Continuous-Flow Reductions towards A Medicinally Relevant Piperazine Derivative

“…Reductive aminations also proved their utility in flow chemistry [ 39 ], especially when catalytic hydrogenation is used, which is well-suited to continuous transformations, since it is typically free from side-products, and the removal of excess hydrogen is fairly simple [ 40 , 41 ]. The application of reductive amination in continuous-flow hydrogenation equipment for API production has been reported in the literature [ 22 , 42 ]. However, to the best of our knowledge, these transformations have not been used directly after each other in a consecutive continuous-flow reaction sequence before.…”

“…Besides the well-known strategies to solve these limitations [ 20 ], the flow-oriented design of the synthetic route might be needed [ 21 ]. Several successful approaches have been recently described within the field of central nervous system (CNS) drugs, including the integrated continuous-flow syntheses of flibanserin [ 22 ], ketamine [ 23 ], paroxetine [ 24 ], tramadol [ 25 ], or baclofen [ 26 ].…”

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

“…In addition, many other diverse reduction processes have been effected by the H-Cube ® system. It has been utilised for the reduction of amides [239], nitro compounds [240][241][242], nitriles [243][244][245], azides [246,247], diazo compounds [248], and for carrying out reductive aminations [249][250][251] on a laboratory scale, while the H-Cube ® midi, has been designed specifically to be used in larger scale processes [252][253][254]. Recently, the H-Cube ® apparatus has also found use in the evaluation for biomass-derived chemicals recovery, such as Ru-catalysed hydrogenation of methyl levulinate (262) from lignocellulosic biomass to γ-valerolactone (263) [255], and scrap waste recovery, such as the scrap ceramic-cores of automotive catalytic converters (CATs) employed in the chemoselective hydrogenation of cinnamaldehyde to hydrocinnamyl alcohol [256,257].…”

“…The column was prepared by attaching microencapsulated gold onto amine functionalities within a modified polysiloxane capillary performed at elevated temperatures. The optimisation of the oxidation process was carried out on 1-phenylethanol (250) and the established conditions were then applied to 9 additional substrates. Good yields were obtained in all cases except for the oxidation of benzyl alcohol which required a column coated with a bimetallic Pd/Au matrix.…”

Optimisation by Design of Experiment of Benzimidazol-2-One Synthesis under Flow Conditions

“…Traditional synthetic approaches include the cyclocarbonylation of o -phenylenediamine ( 2 ), transformation of benzimidazolium salts, synthesis from arylureas, Curtius reaction of anthranilic acids or phthalic anhydrides, decarbonylative ring contraction of benzodiazepinones or quinoxalinediones, decarbonylative cycloaddition of isocyanates to isatins, and assembly of 2-iodoarylcarbodiimides with acrylates, one-pot reaction of hydroxylamines, aldehydes, and trimethylsilyl cyanide [1,8,18,19]. It is worth noting that a four-step continuous flow synthesis of flibanserin that involved a 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU)-promoted thermal cyclisation of an N -Boc-substituted o -phenylendiamine derivative as the key step to prepare the benzimidazolone ring has been recently reported [20]. Although a number of synthetic alternatives is currently available, the cyclocarbonylation of o -phenylenediamine ( 2 ) with phosgene, triphosgene, carbon dioxide, carbon monoxide, dimethyl carbonate, urea, and 1,1′-carbonyldiimidazole (CDI) still remains the most widely used approach because of its broad substrate scope and low cost.…”