Sustainable Beckmann Rearrangement using Bead-Milling Technology: The Route to Paracetamol

To address the growing demand for more sustainable and greener chemistry, mechanochemical methodologies are emerging as key players. However, to date there has been little data highlighting the benefits of these rising mechanochemical technologies with regard to process scale-up activities or implementation in commercial production scale. Herein, we report the first application of bead-mill technology (Dyno®-mill) for the sustainable mechanochemical synthesis of Acetaminophen, known under the brand name Paracetamol. Using the Beckmann rearrangement, the optimized solvent-free methodology delivered a final product on a scale of several tens of grams. In comparison to current production solvent-based process, the proposed process achieves a higher yield while also allowing the removal of solvents in the chemical reaction, hereby reducing one of the extensive drivers to waste generation. The mechanochemical approach was compared to solvent-based process using a combination of green metrics and EcoScale score. The mechanochemical synthesis of paracetamol scores the highest for all the metrics over currently used solution-based processes.

Introduction

Although the first documented application of mechanochemistry, a method that use mechanical force, like grinding and milling, to drive chemical reactions, was document as early as 314 B.C. by Theophrastus of Eresos, the term “mechanochemistry” (MC) per se was only officially articulated in 1919, in the “Textbook of General Chemistry” by Wilhelm Ostwald. It took another six decades for the definition established by G. Heinicke, to materialize the outline of this new subdiscipline of chemistry. More recently, before the turn of the century, IUPAC defined a mechanochemical reaction as a “chemical reaction that is induced by the direct absorption of mechanical energy”. Solvent-free, or with extremely low amount of solvent for liquid assisted grinding (LAG) methods (0 ≤ η ≤1 μL/mg), mechanochemistry is a powerful methodology that increase the reaction energy-efficiency with respect to conventional methods. Solvents are one of the extensive drivers to waste generation,7 therefore, the possibility to conduct syntheses in neat conditions, intrinsically addresses the growing demand for greener and more sustainable chemistry.

Several examples demonstrate that mechanochemistry provides better green metrics compared to the corresponding solution-based processes and reduces CO2 emissions and costs, also confirmed by Life Cycle Assessment (LCA) studies9 applied to the mechanochemical continuous flow preparation of the World Health Organisation (WHO) essential medicine nitrofurantoin, a mass-produced antibiotic listed among the top 200 drugs sold in 2021. As a result, mechanochemistry is a very attractive approach to also improve the economic benefit of a process and its safety, eliminating the use of toxic or hazardous solvent, a desirable milestone for R&D industrial settings. As such, these features are critical attributes contributing to foster the development of sustainability policies aligned with the 17 sustainable development goals (SDGs) edited by the United Nations in 2015.

In 2020, major chemical societies (GDCh and ACS) highlighted seven of the seventeen interlinked SDGs where the chemical industry can play a central role especially through the growing implementation of green chemistry practices and engineering innovation.16 Within this framework, mechanochemical processes were already identifies by the International Union of Pure and Applied Chemistry (IUPAC) among the technologies to potentially make our Planet more sustainable,17 and comply with several of the 12 Green Chemistry principles. However, the implementation of mechanochemistry (both in batch and continuous) in manufacturing processes for covalent bond forming reactions has not reached yet the industrial era. The biggest challenge is especially in the manufacturing of Active Pharmaceutical Ingredients (APIs),19a-19d needing to solicit inquisitiveness in developing green-by-design chemical processes during early-stage development activities in laboratories, KiloLab or pilot plant of chemical companies. Such an approach does not include only green metrics or life-cycle assessment (LCA)9 but also by implementing emerging technologies such as mechanochemistry, currently underserved in chemical industries. Without this inescapable, canonical, transition the chemical industry will remain under continuous/increasing pressure to develop environmentally responsible processes.

Since the seminal contributions describing the preparation of the metallo-drug bismuth subsalicylate (Peptobismol), and the WHO essential medicine Phenytoin,10, 23 the preparation of API by mechanochemical processes is witnessing a growing interest (Figure 1).

In this respect, mechanochemical methods for the preparation of marketed APIs exploiting molecular rearrangements, a powerful and very efficient strategy to increase molecular complexity, are still underdeveloped. Since the seminal article on the mechanochemical preparation of phenytoin by Biltz method, involving a pinacolic rearrangement, only two examples were reported later on. Indeed, the mechanochemical synthesis of the anticonvulsant Ethotoin and the painkiller paracetamol, prepared by mechanochemical Lossen24a and Beckmann20c, 24b rearrangements respectively (at different scales, in batch or continously were also described. The pharmaceutical cocrystal rac-Ibuprofene:nicotinamide was also prepared in Kg-scale in a vibrating eccentric mill (EVM, Figure 2).

(click graphic to enlarge)

Access to paracetamol began at the end of the 19th century with the work of Hoechst A.G. for the synthesis of Antipyrine® and Amidopyrine®. The first synthetic drugs offering to the pharmaceutical industry substantial benefits with an annual production of 17 tons. However, these compounds also bring to light side effects of drugs which indirectly doped the progress in pharmacokinetics and metabolic studies. Thus, in 1948, process improvements allow to isolate the Paracetamol in its pure form thus allowing to show his activity and full potential against pain and fever. Paracetamol is the first line drug part of the analgesic and antipyretic for pain relief and fever reduction that is not part of the non-steroidal anti-inflammatory drugs (NSAIDs). It is currently used in the composition of more than 80 specific pharmaceutical formulations often in combination with NSAIDs or weak opioids.

Regarding economic metrics of Paracetamol production an increase has been observed for the past few years and the global paracetamol market is predicted to continue to grow with a compound annual growth rate (CAGR) of 5.22 % for the period from 2023 to 2028.28 In this context, the use of mechanochemical processes to make its manufacturing more sustainable, is appealing. Paracetamol can be produced by various multi-step methodology combining e. g. acetylation, nitration, reduction, Beckmann rearrangement, hydrogenation, Bamberger rearrangement. However, two main chemical routes are used at production scale: i) the classical route which consist of nitration, reduction by H2 in presence of Raney-Ni and acylation in presence of acetic anhydride (Scheme S1, ESI) or ii) Hoechst-Celanese process that incorporate a Friedel-craft acylation, an oxime formation, followed by a Beckmann rearrangement (Scheme S2, ESI). It is on this second strategy, which is elegant and powerful, that we based our mechanochemical project.

Along this line and in view of a growing exploitation of mechanochemical process for drug manufacturing, the investigation of process methodologies for large scale synthesis, and comparative studies relying on the use of different mechanochemical devices is of crucial importance. Several mechanochemical devices, providing different types of mechanochemical stresses, operating in continuous or in batch, enabled sustainable organic syntheses (Figure 2).

Notwithstanding, bead milling technology in a Dyno®-mill (DM), also known as agitator bead mill, usually applied for horizontal wet milling processes, was never explored for mechanochemical transformations, both in dry or in liquid assisted grinding (LAG) conditions (Figure 3 and supporting information). The mixture of solid can be fed, through the hopper, into the grinding chamber by a screw conveyor (semi- or continuous mode) or through the outlet lid by removing the sieve plate (batch mode). The patented Dyno-Accelerator (DA) throw the grinding media and chemicals which collide, providing high energy input, through share, impact, shock, and ensures mechanochemical reaction. In batch configuration, the grinding balls and chemicals are retained in the milling chamber by replacing the sieve by a screen plate. Bead-mills are extensively used in process fields e. g. manufacture of paints/lacquers, grinding of minerals, processing of chemicals, food, and drugs, disintegration yeast, cyanobacteria, and microalgae for the release of intracellular product.

Their efficiency depends on equipment parameters such as chamber and agitator geometry, as well as process parameters like concentration of the reaction medium, agitator speed, flow rate, mode of operation (recirculation or continuous mode), bead filling ratio, type, and diameter. In bead mills equipment, the product particles are stressed either by two-sided contact (compression) or by one-sided contact (impact). The large quantity of beads aims to maximize the occurring transferred energy per stress event and the number of stress events per unit of time. Thus, the overall performance is driven by the probability of the chemicals to be mechanically processed by the milling beads, respectively by the probability of the particles to be trapped in an active grinding zone by a grinding bead with sufficient energy to induce the reaction.

Herein, the bead milling technology in a Dyno®-mill was used for the mechanochemical Beckmann rearrangement (BKR) reaction, finalized to the preparation of the WHO essential medicine paracetamol.10 To benchmark the sustainability of this approach, comparative green metrics calculations were done for the bead milling process and compared with the current Beckmann rearrangement production process in solution use at commercial scale.31

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Romain Geib, Prof. Dr. Evelina Colacino, Prof. Dr. Ludovic Gremaud, Sustainable Beckmann Rearrangement using Bead-Milling Technology: The Route to Paracetamol, First published: 14 February 2024, https://doi.org/10.1002/cssc.202301921