布洛芬的合成方法

Conventional wisdom and many published histories of “Green Chemistry” describe its start as being a result of governmental and/or regulatory actions at the US Environmental Protection Agency (“EPA”) during the early 1990’s. But there were many Real World industrial examples of environmentally friendly commercial processes in the oil and commodity chemicals industries for decades prior to the 1990s. Some early examples of commercial “Green Chemistry” are briefly described in this article. The Boots/Hoechst Celanese (“BHC”) Ibuprofen process was one of the earliest multiple-award-winning examples of industrial “Green Chemistry” in the fine chemical/pharmaceutical industry. The author, who conceived the BHC Ibuprofen synthetic strategy in 1984, reveals and documents that the BHC Ibuprofen process was not primarily a result of governmental or regulatory mandates, or environmentalist or political motivations. The BHC ibuprofen process, and probably many other early industrial “green” inventions, evolved from, and their development and commercialization motivated and guided by, a long prior industrial culture of both scientific and technical evolution. The invention and commercialization of these early industrial commercialized processes, and the BHC Ibuprofen process were also guided by both competitive and economic market needs, personal human motivations, and a low waste culture of “Quality” and “Continuous Improvement” that the commodity chemical industry internally promoted in the 1980’s. The author comments on some perceptions of the status of Green Chemistry now, and directions it should consider going in the future. The author recommends that young Green Chemists and/or Green Engineers reconsider “Quality” approaches in order to genuinely lead Society toward a Greener future.

This paper makes a parallel between the original route versus the green route of Ibuprofen (non-steroidal anti-inflammatory drugs most commonly recommended) synthesis. The original route contained six steps with stoichiometric reagents (some reagents are very toxic: hydrochloric acid, ammonia), a lot of intermediate products, relatively low atom efficiency equal to 40.04% and substantial inorganic salt formation (aluminium trichloride hydrate). The green route of Ibuprofen synthesis developed only three steps, a lower amount of waste and by-products (only acetic acid that can be used for another applications) and an atom efficiency of 77.44%. The green route for Ibuprofen synthesis is an exquisite example of a simple and elegant chemical/pharmaceutical manufacturing process and the nearly complete atom utilization of this streamlined process truly makes it a wasteminimizing, environmentally friendly technology.

The ACS Green Chemistry Institute Pharmaceutical Roundtable was formed in 2005 to encourage the incorporation of green chemistry techniques into the synthetic pathways of pharmaceuticals. Through this initiative, synthetic pathways of several pharmaceuticals have been altered to adapt more environmentally friendly procedures. The amount of electricity required to complete chemical reactions have become an environmental concern due to depleting fossil fuels. A technique was recently developed in which satellite dishes were repurposed as solar reflectors capable of providing a heat source through solar irradiation. The ability to use the solar reflector as the sole heat source for synthetic reactions has been analyzed for the commercially important pharmaceutical, ibuprofen. Ibuprofen synthesis also incorporates chemicals that are not particularly friendly to the environment. The exchange of these chemicals with more environmentally friendly substitutes has been analyzed. The goal of this study is to incorporate a solar energy heat source to develop an alternative energy, more environmentally friendly pathway to ibuprofen.Graphical abstractThe synthetic route designed to synthesize ibuprofen using an alternative energy heat source and more environmentally friendly reagents.

Ibuprofen is a common anti-inflammatory drug (NSAID) that was first invented and patented by Boots UK back in the 1960s. Even though ibuprofen is made in huge amounts worldwide nowadays, researchers are still trying to improve how it's synthesized to make the process more efficient, sustainable, and less harmful to the environment. This paper looks at how ibuprofen synthesis methods have evolved over history, from Boots' original approach to more recent stuff like the BHC process, using electrochemistry, and continuous flow systems. It examines the mechanism, green chemistry measures, and the pros and cons of each technique. While it gave the first usable manufacturing method, Boots' synthesis wasn't so great with its atom economy. The BHC synthesis boosted yield and atom economy a lot by streamlining the process. Newer ways aim to make it even more selective and sustainable by using novel chemistries and tighter process control. Basically, ibuprofen synthesis has steadily progressed over time thanks to step-by-step innovation and a better understanding of the mechanisms. The paper suggests ways forward to produce this important drug in safer, more efficient, eco-friendly ways using modern green chemistry practices. Any pharmaceutical synthesis impacts people and the environment, so we gotta keep improving processes.

… ACS Green Chemistry Institute Pharmaceutical Roundtable took place in 2005 with the primary objective of promoting the integration of green chemistry methodologies into the synthetic …

Abstract In China, the most commonly used method for the synthesis of ibuprofen is aryl-1,2–translocation rearrangement, which comprises several main processes: the Friedel-hydrolysis reaction, ketal reaction and so on. There are some problems in the process of industrial production. The temperature control of the Friedel-hydrolysis reaction is a problem because excessive temperatures will lead to the occurrence of side reactions, and low temperatures will lead to the crystallization of raw reaction materials. The reaction time of the ketal reaction is up to 24 h, which limits the productive capacity of ibuprofen. Otherwise, the emissions of the ibuprofen synthesis processes are more than 5000 m3/h of waste gas with VOC contents of over 1000 mg/m3 and highly concentrated organic wastewater, with a COD up to 20,000 mg/L. Therefore, process intensification and waste minimization of the ibuprofen synthesis process is described in this paper. A new reactor is designed for the Friedel-hydrolysis reaction. The reaction temperature can be precisely controlled at 13–15 °C, which effectively inhibits the occurrence of side reactions. The industrial applications showed that the ketal reaction time is reduced from 24 h to less than 8 h. The VOC content is reduced to less than 100 mg/m3, and the COD value is reduced to 150 mg/L in the improved processes, which meet national emissions standards.

Herein, we review the recent progress in the synthesis of representative nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen. Although these drugs were discovered over 50 years ago, novel practical and asymmetric approaches are still being developed for their synthesis. In addition, this endeavor has enabled access to more potent and selective derivatives from the key frameworks of ibuprofen and naproxen. The development of a synthetic route to ibuprofen and naproxen over the last 10 years is summarized, including developing methodologies, finding novel synthetic routes, and applying continuous-flow chemistry.

In this study, the environmental impacts of three ibuprofen production routes, namely, the BHC, the Bogdan, and the newly developed enzymatic synthetic routes (modified Bogdan process), are assessed and compared by the application of life cycle assessment (LCA). Based on the data obtained through literature and laboratory-based experiments, a pilot-scale production with a capacity of 500 g/day of ibuprofen was simulated to generate inventory data for the LCA study, using Aspen Plus V11. The well-established BHC process was chosen as the benchmark to quantify the operational and environmental benefits of the innovative enzymatic Bogdan flow synthetic process. The comparison highlights the benefit of adopting the modified Bogdan synthesis route via an enzymatic catalyst. Results show that a general reduction of environmental impact is achievable across the whole set of impact categories of the analysis, and the magnitude of such reduction depends on the efficiency of recycling in the production system. Considering a 50% efficiency of recycling, the modified Bogdan system achieves lower environmental impacts in some impact categories like Acidification, Ecotoxicity of freshwater, Human toxicity, Particulate matter, and Resource depletion (mineral, fossils, renewables) while having higher impacts on the rest of the impact categories. Yet, the new process proposed here scores better environmental performances in all of the impact categories when the enzyme recycling is close to 100%, which is promising for future technology development.

Ibuprofen, a widely used nonsteroidal anti‐inflammatory drug (NSAID), is valued for its analgesic, antipyretic, and anti‐inflammatory properties. While batch synthesis remains dominant in industry due to its maturity, it presents drawbacks such as long reaction times, high energy consumption, and complex byproduct profiles. In response to growing demands for greener pharmaceutical manufacturing, continuous flow technology has emerged as a promising alternative. It offers enhanced efficiency, scalability, and environmental compatibility. This review highlights recent advancements in ibuprofen synthesis via batch and continuous flow approaches, with a focus on the development of catalytic systems, reactor optimization, and process intensification. The fundamental principles of flow chemistry and the current technical challenges are discussed. The study aims to provide insights into transitioning toward sustainable, high‐efficiency production of ibuprofen and to offer insights into broader applications of flow technology in pharmaceutical synthesiser.

Green chemistry has revolutionized pharmaceutical synthesis by promoting sustainability and reducing environmental impact. This review aims to present the recent advancements in …

… This flow synthesis has drawbacks associated with … synthesis that provides 1 in an integrated four-step process, providing a highly practical and economical approach toward ibuprofen …

Scalable processes have been developed to convert β-pinene into 4-isopropenylcyclohexanone which is then used as a feedstock for the divergent synthesis of sustainable versions of the common painkillers, paracetamol and ibuprofen. Both synthetic routes use Pd(0) catalysed reactions to aromatise the cyclohexenyl rings of key intermediates to produce the benzenoid ring systems of both drugs. The potential of using bioderived 4-hydroxyacetophenone as a drop-in feedstock replacement to produce sustainable aromatic products is also discussed within a terpene biorefinery context.

Biocatalytic ibuprofen synthesis enhanced via in silico -guided rational enzyme design.

This work was focused on the enzymatic esterification of glycerol and ibuprofen at high concentrations in two triphasic systems composed of toluene+ibuprofene (apolar) and glycerol or glycerol–water (polar) liquid phases, and a solid phase with the industrial immobilized lipase B from Candida antarctica named Novozym®435 (N435) acting as the biocatalyst. Based on a preliminary study, the concentration of the enzyme was set at 30 g·L−1 and the stirring speed at 720 r.p.m to reduce external mass transfer limitations. To obtain more information on the reaction system, it was conducted at a wide range of temperatures (50 to 80 °C) and initial concentrations of ibuprofen (20–100 g·L−1, that is, 97 to 483 mM). Under these experimental conditions, the external mass transfer, according to the Mears criterion (Me = 1.47–3.33·10−4 << 0.15), was fast, presenting no limitation to the system productivity, regardless of the presence of water and from 50 to 80 °C. Considering that the enzyme is immobilized in a porous ion-exchange resin, limitations due to internal mass transfer can exist, depending on the values of the effectiveness factor (η). It varied from 0.14 to 0.23 at 50 to 80 °C and 0.32–1 mm particle diameter range in the absence of water, and in the same ranges, from 0.40 to 0.66 in the presence of 7.4% w/w water in the glycerol phase. Thus, it is evident that some limitation occurs due to mass transfer inside the pores, while the presence of water in the polar phase increases the productivity 3–4 fold. During the kinetic study, several kinetic models were proposed for both triphasic reacting systems, with and without first-order biocatalyst deactivation, and their fit to all relevant experimental data led to the observation that the best kinetic model was a reversible hyperbolic model with first-order deactivation in the anhydrous reaction system and a similar model, but without deactivation, for the system with added water at zero time. This fact is in sharp contrast to the use of N435 in a water-glycerol monophasic system, where progressive dissolution of ibuprofen in the reacting media, together with a notable enzyme deactivation, is observed.

… , 4 which includes ibuprofen (1). Inspired by McQuade’s landmark continuous synthesis, 5 we sought to develop a scalable continuous synthesis of this generic pharmaceutical. …

… as the key step of the synthesis. Compound 2a was obtained in … same synthetic strategy was employed to obtain Ibuprofen … for the synthesis of arylpropanoic acids including Ibuprofen. …

This study investigates the enzymatic esterification of glycerol and ibuprofen in a solventless medium catalyzed by immobilized lipase B from Candida antarctica (Novozym®435). Fixing the concentration of this enzymatic solid preparation at 30 g·L−1, and operating at a constant stirring speed of 720 rpm, the temperature was changed between 50 and 80 ◦C, while the initial concentration of ibuprofen was studied from 20 to 100 g·L−1. Under these conditions, the resistance of external mass transport can be neglected, as confirmed by the Mears criterion (Me < 0.15). However, the mass transfer limitation inside the pores of the support has been evidenced. The values of the effectiveness factor (η) vary between 0.08 and 0.16 for the particle size range considered according to the Weisz–Prater criteria. Preliminary runs permit us to conclude that the enzyme was deactivated at medium to high temperatures and initial concentration values of ibuprofen. Several phenomenological kinetic models were proposed and fitted to all data available, using physical and statistical criteria to select the most adequate model. The best kinetic model was a reversible sigmoidal model with pseudo-first order with respect to dissolved ibuprofen and order 2 with respect to monoester ibuprofen, assuming the total first-order one-step deactivation of the enzyme, with partial first order for ibuprofen and enzyme activity.

… -isobutylphenyl) propionic acid (ibuprofen). We have applied PdCl 2 –PPh 3 –HCl catalyst system with several additives for the synthesis of ibuprofen under moderate conditions. Effects …

… catalysis for the synthesis of high-value pharmaceutical and agrochemical products. The synthesis … (9) Hydromagnesiation of olefins can be used for the synthesis of Grignard reagents …

This study presents a comprehensive application of integrated machine learning tools for modeling and optimizing the ibuprofen synthesis process. Initially, a database of 39,460 input combinations is created using chemical reaction theory and validated with experimental data. The CatBoost meta-model, optimized by the snow ablation optimizer, outperforms conventional algorithms in predicting reaction time, conversion rate, and production cost. Importance analyses through SHAP values identify critical input variables, notably, the concentration of the catalyst precursor (L2PdCl2), hydrogen ions (H+), and water (H2O), validating known catalytic principles and providing quantitative parameter guidance through data-driven analysis. Multiobjective optimization using NSGA-II generates a Pareto front of solutions, from which four industrial strategies are derived: balanced performance, maximum output, maximum yield, and minimum cost, each suitable for different production scenarios. The results identify optimal catalyst concentration ranges (0.002–0.01 mol/m3) that achieve high conversion rates while maintaining low costs. Uncertainty analysis conducted through Monte Carlo simulation reveals that reaction time exhibits particularly high sensitivity to parameter fluctuations, with a distinctive nonlinear response peaking at moderate perturbation levels (σ = 0.3). This study provides valuable insights for the rational design of ibuprofen synthesis conditions and demonstrates the effectiveness of integrating physics-based modeling with machine learning for chemical process optimization.

… of (S)-ibuprofen production is carried out using ASPEN PLUS ® process simulation software. A pilot scale production with the capacity of 500g/day of (S)-ibuprofen acid is considered in …

… The purpose of this work was to explore NIR spectroscopy as a PAT tool to monitor the formation of ibuprofen and nicotinamide cocrystals during extrusion based solvent free …

… process efficiency of mechanochemical versus conventional solution-based routes for producing rac-ibuprofen… HM) were integrated with process modeling, green chemistry metrics, and …

… Novozym 435 has also been used for (R,S)-ibuprofen resolution in solvent-free medium, which required temperature levels above 70 C.9-12 In those conditions, applying vacuum in …

… a continuous flow synthesis process for ibuprofen intermediates and proposed a solvent-free continuous reaction for Friedel-Crafts acylation. The rearrangement reaction was integrated …

… The synthesis of fine particles with controlled particle size … CO2, which has to be miscible with the organic solvent. In the PCA process, particles are dissolved in suitable solvent and …

Electrocarboxylation of organic halides is one of the most widely used approaches for valorising CO2. In this manuscript, we report a new greener synthetic route for synthesising 2-(4-isobutylphenyl)propanoic acid, Ibuprofen, one of the most popular non-steroidal anti-inflammatory drugs (NSAIDs). The joint use of electrochemical techniques and ionic liquids (ILs) allows CO2 to be used as a C1-organic building block for synthesising Ibuprofen in high yields, with conversion ratios close to 100%, and under mild conditions. Furthermore, the determination of the reduction peak potential values of 1-chloro-(4-isobutylphenyl)ethane in several electrolytes (DMF, and ionic liquids) and with different cathodes (carbon and silver) makes it possible to evaluate the most “energetically” favourable conditions for performing the electrocarboxylation reaction. Hence, the use of ILs not only makes the electrolytic media greener, but they also act as catalysts enabling the electrochemical reduction of 1-chloro-(4-isobutylphenyl)ethane to be decreased by up to 1.0 V.

Ibuprofen was prepared from an inactive and inexpensive p-xylene by 3-step flow functionalizations through chemoselective metalations of benzyl positions in sequence using an in-situ generated LICKOR-type superbase. The flow approach in the microreactor facilitated to comprehensively explore over 100 conditions in the first-step reaction by varying concentrations, temperatures, solvents, and equivalents of reagents, enabling to find the optimal condition with 95% yield by significantly suppressing the formation of byproducts, followed by the second C-H metalation step in 95% yield. Moreover, gram-scale synthesis of ibuprofen in the final step was achieved by biphasic flow reaction of solution-phase intermediate with CO₂, isolating 2.3 g for 10 min of operation time.

… experiments started from different organic solvents. The amount of used CO 2 to reach 50% yield … , temperature and CO 2 mass flow. Different values of ss can be calculated by Eq. (7). …

Organic chemistry is continually evolving to improve the syntheses of value added and bioactive compounds. Through this progression, a concomitant advancement in laboratory technology has occurred. Many researchers now choose to mediate transformations in continuous-flow systems given the many benefits over round bottom flasks. Furthermore, reaction scale up is often less problematic as this is addressed at the inception of the science. Although single-step transformations in continuous-flow systems are common, multi-step transformations are more valuable. In these systems, molecular complexity is accrued through sequential transformations to a mobile scaffold, much like an in vitro version of Nature's polyketide synthases. Utilizing this methodology, multi-step continuous-flow systems have improved the syntheses of active pharmaceutical ingredients (APIs), natural products, and commodity chemicals. This Review details these advancements while highlighting the rapid progress, benefits, and diversification of this expanding field.

Abstract The continuous‐flow production of active pharmaceutical ingredients is a spreading applicative research field. Process simulation tools are effective means for in silico process design, but care is needed. A paradigmatic example is the synthesis of ibuprofen. First, the most appropriate thermodynamic models must be selected. The rich databases now available to collect thermodynamic properties are often insufficient because unconventional molecules are usually part of the recipe or found as intermediates or products. Furthermore, in some reaction steps ionic properties may be needed rather than those of the neutral molecules. All these points need a careful optimization of the methods for the estimation of the properties, with possible huge discrepancies of the results.

… Recent advances in the field of continuous flow chemistry allow the multistep preparation of … aiming to exploit flow chemistry systems for the synthesis of biologically active molecules. …

… In Pfizer we now carry out nitrations routinely in continuous flow with the acid resistant … At Pfizer a continuous flow process for the synthesis of pyrrolidines via [3 + 2] dipolar cycloaddition …

Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and microreactor technology. Over the past few years, continuous flow enantioselective catalysis has grown into a mature field and has found diverse applications in asymmetric synthesis of pharmaceutically active substances. The present review therefore surveys flow chemistry-based approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis and metal-free organocatalysis to introduce asymmetry in continuously operated systems. Single-step processes, interrupted multistep flow syntheses, combined batch/flow processes and uninterrupted one-flow syntheses are discussed herein.

An active pharmaceutical ingredient (API) is any substance in a pharmaceutical product that is biologically active. That means the specific molecular entity is capable of achieving a defined biological effect on the target. These ingredients need to meet very strict limits; chemical and optical purity are considered to be the most important ones. A continuous-flow synthetic methodology which utilizes a continuously flowing stream of reactive fluids can be easily combined with photochemistry, which works with the chemical effects of light. These methods can be useful tools to meet these strict limits. Both of these methods are unique and powerful tools for the preparation of natural products or active pharmaceutical ingredients and their precursors with high structural complexity under mild conditions. This review shows some main directions in the field of active pharmaceutical ingredients’ preparation using continuous-flow chemistry and photochemistry with numerous examples of industry and laboratory-scale applications.

We developed a continuous, integrated production system for all reaction processes targeting ibuprofen. We succeeded in obtaining pure ibuprofen at 38% for all steps, and a production efficiency of 47...

… Figures 8 and 9 show the dynamic behavior of the upstream synthesis of ibuprofen with continuous disturbances, on key process variables. These disturbances were introduced 5 min …

Summary Multi-step organic syntheses of various drugs, active pharmaceutical ingredients, and other pharmaceutically and agriculturally important compounds have already been reported using flow synthesis. Compared to batch, hazardous and reactive reagents can be handled safely in flow. This review discusses the pros and cons of flow chemistry in today’s scenario and recent developments in flow devices. The review majorly emphasizes on the recent developments in the flow synthesis of pharmaceutically important products in last five years including flibanserin, imatinib, buclizine, cinnarizine, cyclizine, meclizine, ribociclib, celecoxib, SC-560 and mavacoxib, efavirenz, fluconazole, melitracen HCl, rasagiline, tamsulosin, valsartan, and hydroxychloroquine. Critical steps and new development in the flow synthesis of selected compounds are also discussed.

This paper describes an alternative and simple procedure for the synthesis of Ibuprofen using Silica-Supported Preyssler Nanoparticles (H14[NaP5W30O110]/SiO2) (SPNPs), as an eco-friendly, inexpensive, and efficient catalyst. High yields, simplicity of operation, and easy work-up procedure are some advantages of this protocol. Silica-Supported Preyssler Nanoparticles (H14[NaP5W30O110]/SiO2) (SPNPs) offer the advantages of a higher hydrolytic and thermal stability. The salient features of Preyssler’s anion are availability, nontoxicity and reusability. We believe this methodology can find usefulness in organic synthesis.

… ibuprofen ester occurred but most of the (S)-methyl ibuprofen … ester of (R)-ibuprofen was observed to completely racemize in … The synthesis of the same ester via its acyl chloride was …

… is the manufacture of the drug ibuprofen.H The latter is an … Two routes for the production of ibuprofen are compared in … of ibuprofen) involves a further five steps, relatively low atom …

Abstract Atom economy is the second of the 12 green chemistry principles. This principle is particularly useful for the synthesis of fine organic chemicals and active pharmaceutical ingredients. The power of this principle comes from its quantifiable nature. Moreover, this metric can be applied at the stage of the synthesis planning prior to real experiments. However, atom economy as a sole criterion of the process greenness is deficient and should be applied for such assessments together with other principles. Being very important for the design of synthesis routes, atom economy may turn into a minor contributor to the overall greenness of a synthesis when experimental results become available. This chapter illustrates the role of atom economy in the synthesis of three important medicines (ibuprofen, praziquantel, and sildenafil citrate) via different synthetic routes, including commercial ones.

The drive towards greater economic and environmental efficiency in chemicals manufacture has led to a growing need for processes that produce minimal waste and avoid, as much as possible, the use of toxic and/or hazardous reagents and solvents. This has led to a reassessment of many existing technologies. Alternative processes to particular products are compared on the basis of their atom utilization and E factor (kg byproduct per kg product). The use of high-atom utilization, low-salt catalytic processes as clean alternatives to conventional technologies for the manufacture of fine chemicals is discussed. In particular catalytic oxidations and catalytic carbonylations are highlighted using citral, caprolactam, paracetamol, ibuprofen and methylmethacrylate as commercially relevant examples. The question of catalyst recovery and recycling is also addressed, e.g. with the use of redox molecular sieves as solid catalysts for liquid phase oxidations and the use of a water-soluble palladium(0)trisulfonated triphenylphosphine complex, as a catalyst for carbonylation in aqueous media. © 1997 SCI.

… New norms for pollution management can be developed with … an atom economy , and the proportion of atom economy can … In an effort to manufacture and sell ibuprofen in conjunction …

: Green chemistry demands efficient, sustainable chemical processes, yet atom economy (AE) calculations often rely on tedious, error-prone manual methods, limiting their educational and practical use. We introduce rxnSMILES4Ato-mEco , a Python module which computes atom economy from reaction SMILES using RDKit , paired with https://mybin-der.org Jupyter Notebooks for easy accessibility. This tool assesses elementary, simple reactions and composite, stepwise reactions, exemplified by acetone synthesis, spanning cumene decomposition (38.2% AE), isopropanol dehydrogenation (96.6% AE), and propene oxidation (100.0% AE), and ibuprofen synthesis, contrasting Boots company wasteful six-step route (40.1% AE) with BHC company efficient three-step process (77.5% AE), visualized for intuitive learning and optimization. For educators, rxnSMILES4AtomEco supports classrooms teaching of green chemistry and cheminformatics (e.g., SMILES generation and parsing) hands-on with no software setup required, whereas, for process designers, it streamlines sustainable pathway optimization. The AE calculation used in this tool, however, excludes chemical yield: future enhancements could integrate yield data, enhancing real-world applicability.