Evolution of flow-oriented design strategies in the continuous preparation of pharmaceuticals

Abstract

The dynamic progress in the multi-step continuous-flow synthesis of active pharmaceutical ingredients is part of the current industrial revolution. The recently implemented examples are the forerunners of safer and more...

Continuous Flow Synthesis of Anticancer Drugs

“…Next, four sequential transformations in a continuous-flow system were envisaged to generate (E/Z)-tamoxifen (Scheme 3). This sequence utilized seven perfluoroalkoxy (PFA) reactor coils carefully integrated to perform the four key steps of the synthesis: (a) lithiation of aryl bromide 9 in a cryogenic reactor at −50 • C, (b) addition of the resulting aryl lithium species (10) to ketone 8 at 30 • C, (c) activation of the lithium alkoxide intermediate (11) using trifluoroacetic anhydride (TFAA) at room temperature, and (d) base-mediated elimination at 100 • C. The procedure generates tamoxifen (12) with an excellent productivity of 9.35 g/h, which is equivalent to one daily dose every 5 s. It is worth noting that batch processing would not provide the flexibility to easily vary temperatures as exploited in this continuous route. In addition, the continuous system provides fine control over reaction conditions minimizing side-product formation and at the same time maximizing productivity and product quality.…”

“…Because of the many advantages (Figure 2) that can be leveraged by developing continuous flow processes over batch routes, many pharmaceutical companies have been investing heavily into this technology to produce fine chemicals, as well as drugs and their To improve the manufacturing process, the chemical industry has started to embrace more advantageous emerging technologies, particularly continuous flow chemistry which allows for various improvements on the manufacturing process as documented previously [7][8][9][10][11][12][13]. In the last 20 years, a growing number of publications have demonstrated the positive impact of continuous manufacturing in industrial applications and now, continuous flow processing is recognized as a game-changer that pharmaceutical companies have largely welcomed [14][15][16][17][18].…”

Improved Synthesis of Bioactive Molecules Through Flow Chemistry

“…The scalability is easily and quickly studied simply leaving the continuous flow operation in optimized activity for an extended period, with the facility of remote control linked to a cell phone. Currently, chemists and chemical engineers have proved it to be possible to think and design reaction protocols and processes on demand, taking into account many technological limitations before they appear, and highlighting the concept of flow-oriented design (FOD), recommending the development of the complete process in flow and aimed at flow systems since the beginning [2].…”

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

“…Still, the implementation of pre-existing batch procedures can be challenging. 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 ].…”