布洛芬的合成方法，最好是环保的方法

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.

… and was thereafter referred to as the Green Synthesis Process." This revised process … The process of green synthesis exhibits certain advantages compared to other methods in …

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.

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.

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.

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.

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.

… With the successful optimization of each step in flow, we next focused on developing a continuous, four-step, durable production of ibuprofen (1) through building an integrated flow …

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.

It is often said that "time is money". This is certainly true in a multistep synthesis when a high-valued product or set of products is needed urgently. Fulfilling this need requires the sensible balancing of atom economy, step economy, and redox economy with the time taken to make the product. In this age of flu-based pandemics, the need for rapid provision of effective therapeutic agents makes the importance of "time economy" particularly clear. In this Perspective, the importance of time economy in total synthesis is described, as well as the general considerations underlining the timely production of desired molecules. As case studies, the syntheses of Tamiflu, Corey lactone, and ibuprofen are discussed, with emphasis on comparing classical and contemporary approaches to a rapid total synthesis. By using modern tactics such as one-pot reaction procedures and versatile synthetic methodologies such as organocatalyst mediated domino reactions coupled with strict-control technologies such as flow chemistry, Tamiflu and Corey lactone can now be synthesized within 60 and 152 min, respectively, using one vessel via a batch system. Tamiflu and ibuprofen can be prepared via flow system, and their total residence times are 11.5 and 3 min, respectively.

: 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.

… of process systems engineering (PSE) and process intensification (PI… process for new reaction schemes. The novel ‘green’ synthetic route of the ibuprofen compound developed by BHC …

… BHC ibuprofen process is much shorter in length, and significantly more atom-efficient than the Boots method. In terms of atom economy, the BHC process … the BHC process establishes …

… was made up by the selected solvent. The filtered solids of … The same mother liquor was reused as a suspending solvent … -loop recycle of the resolving agent and suspending solvent …

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.

… reactions in volume terms are the hydrogenation of CO, to make long chain hydrocarbons … The ibuprofen synthesis now relies on a key palladium catalysed carbonylation reaction fig. 4). …

… This review highlights recent advances in carbonylation strategies that enable the efficient transformation of inexpensive and readily available carbon monoxide and 13 C-labeled CO …

… hydrogenation, and carbonylation. For the carbonylation, they used PdCl 2 (PPh 3 ) 2 catalyst … More recently much attention has been paid to selective synthesis of the (S)-(+)-ibuprofen, …

… The manufacture of ibuprofen, one of the important antiinflammatory drugs … of new catalysts for carbonylation reactions. Various strategies developed for the heterogenization of catalysts …

… The carbonylation of IBPE to ibuprofen catalyzed by Pd(tppts) 3 at … by catalytic hydrogenation – can be excluded since no H 2 was detected in the gas phase and typical hydrogenation …

… We also recently reported carbonylation of IBPE for the regiospecific synthesis of ibuprofen … contributions of these hydrogenation function of the support and carbonylating function of Pd. …

… ibuprofen through the carbonylation of 1-(4-isobutylphenyl) ethanol (IBPE) (BHC process). The BHC synthesis of ibuprofen … acylation, hydroreduction and carbonylation is a typical atom-…

… ibuprofen and glycerol in solventless media without and with the optimum content in water to obtain ibuprofen … rpm, and showed that a 10% water content enhances both initial rate of …

Abstract The esterification of rac-ibuprofen and rac-ketoprofen with glycerol catalyzed with the commercial biocatalyst Novozym® 435 was investigated at 45 °C with various profen: glycerol molar ratios using 2-propanol as co-solvent in a batch type reaction. The conversion of rac-ibuprofen reached 46%, with an enantiomeric excess towards the S-enantiomer of 42%. When 1:4 ibuprofen:glycerol molar ratio was assayed, 75% of the R-ibuprofen reacted with glycerol towards the monoglyceride with 99% selectivity, which is highly relevant in the field of prodrugs synthesis. The conversion of rac-ketoprofen was lower, 17 % vs. 46 % of rac-ibuprofen, and the esterification afforded both the monoglyceride (70%) and diglyceride (30%) regardless of the ketoprofen:glycerol molar ratio. Investigations of the esterification at molecular level through concentration-modulated infrared spectroscopy, static ATR-FTIR and in situ Raman spectroscopy showed the continuous decay of the species belonging to rac-ibuprofen and glycerol providing further evidences of the reaction. Moreover, the interaction of CALB with ibuprofen modifies the contribution of the ordered structures of the lipase, which might be related with the improved catalytic performance in the esterification of that profen.

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.

… efficient continuous synthesis of ibuprofen that pushes the limits of existing continuous-flow … mitigated through a fundamental advantage of continuous flow over batch synthesis; only a …

… of reactions at high temperature and pressure (process intensification); possibility of automation; … catalyzed reactions, leading also to process intensification and a smaller footprint in a …

ABSTRACT Continuous flow chemistry is emerging as a transformative strategy for pharmaceutical synthesis, providing a sustainable and efficient alternative to conventional batch processes. Flow systems offer precise control over key reaction variables temperature, pressure, and residence time enhancing product consistency, accelerating reaction rates, and reducing waste in line with Green Chemistry principles. Recent applications include the synthesis of active pharmaceutical ingredients (APIs) such as flibanserin, celecoxib, valsartan, mesalazine, and other complex heterocycles, achieving higher yields, selectivity, and scalability. Multicomponent reactions in flow further enable the rapid construction of drug like molecules while minimizing step count and environmental impact. Although challenges remain in equipment cost and scale up, continuous flow technology represents a pivotal step toward safer, faster, and more sustainable pharmaceutical manufacturing. GRAPHICAL ABSTRACT

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.

… 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 first example of process intensification at DSM is the pilot-scale test of the enzymatic production of S-ibuprofen, a nonsteroidal, anti-inflammatory drug. The molecular scheme is …

The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process.