Green chemistry

The use of ionic liquids (ILs) as organocatalysts is reviewed for transesterification reactions, specifically for the conversion of nontoxic compounds such as dialkyl carbonates to both linear mono-transesterification products or alkylene carbonates. An introductory survey compares pros and cons of classic catalysts based on both acidic and basic systems, to ionic liquids. Then, innovative green syntheses of task-specific ILs and their representative applications are introduced to detail the efficiency and highly selective outcome of ILs-catalyzed transesterification reactions. A mechanistic hypothesis is discussed by the concept of cooperative catalysis based on the dual (electrophilic/nucleophilic) activation of reactants. Review Introduction Transesterification catalysts The transesterification is one of the classical organic reactions that has found numerous applications in laboratory practice as well as in the synthesis of a variety of intermediates in the pharmaceutical, cosmetic, fragrance, fuel and polymers industries [1]. Transesterification reactions are catalyzed under acidic, basic or even neutral conditions [2]. An excellent review by Otera et al. has detailed many applications of the most popular catalytic systems [3]. These include both acids such as sulfuric, sulfonic, phosphoric, and hydrochloric, and bases such as metal alkoxides, acetates, oxides, and carbonates. It is worth mentioning, that transesterification reactions are frequently carried out over solid (heterogeneous) catalysts to facilitate work-up, recycling, and purification of products, especially for large-scale preparations. These heterogeneous systems include supported metal oxides and binary oxide mixtures. For example, MoO3/ SiO2 and sol–gel MoO3/TiO2 is used for the preparation of diphenyl oxalate monomer (DPO, Scheme 1) in polycarbonate chemistry [4,5], and TiO2/SiO2 and similar binary combinaBeilstein J. Org. Chem. 2016, 12, 1911–1924. 1912 Scheme 1: The transesterification of diethyl oxalate (DEO) with phenol catalyzed by MoO3/SiO2. Scheme 2: Transesterification of a triglyceride (TG) with DMC for biodiesel production using KOH as the base catalyst. tions are applied in the transesterification of β-ketoesters [6], and in the synthesis of unsymmetrical carbonates R1OC(O)OR2 [7]. Superacidic solids have also been described as transesterification catalysts and a remarkable example is the recently patented synthesis of sucrose-6-ester – a food sweetener – carried out over a mixture of sulfated oxides of various metals [8]. In addition, acidic ion exchange resins are worth mentioning in this context. Van de Steene et al. have proved the performance of such systems in an elegant investigation on the model transesterification of ethyl acetate with methanol [9]. The production of biodiesel blends is another sector in which the catalytic transesterification is extensively used. In particular, heterogeneous catalysts including calcium, manganese and zinc oxides as such or as mixtures are widely used to convert natural triglycerides into FAMEs or FAEEs (fatty acid methyl or ethyl esters) with methanol or ethanol, respectively [10]. The most commonly used system is CaO, which is obtained by calcination of readily available and cheap resources including waste products such as shells and even livestock bones [11-14]. However, traditional catalysts such as alkali hydroxides or alkaline methoxides are still encountered even for novel syntheses of biofuels. An example is the transesterification of oils by dimethyl carbonate (DMC) in the presence of KOH (Scheme 2) [15,16]. The reaction allows obtaining FAMEs and fatty acid glycerol carbonate monoesters (FAGCs), without the concurrent formation of glycerol, a frequently formed highly undesirable byproduct. Enzyme catalysts: A major driving force for the choice of enzymes is their high efficiency, which allows reactions to be performed under very mild conditions and with a variety of raw materials. However, the high cost and relatively short lifetime of enzymes partly offset their advantages and an implementation of biocatalytic processes makes sense almost exclusively for the preparation of high added-value chemicals. This holds true also for enzyme-catalyzed transesterification reactions. To cite a few examples, the literature claims the use of lipase as a biocatalyst for i) the reaction of glycerol with DMC for the synthesis of glycerol carbonate (GlyC) under solvent-free conditions. A 60% yield was achieved along with an effective recycle of the catalyst [17], ii) the formation of six-membered cyclic carbonates by the transesterification of dialkyl carbonates with trimethylolpropane. The products were achieved in high yields (85%) and used as monomers for polyurethanes and polycarbonates [18], and iii) the conversion of oils for which lipase was identified as the most suitable enzyme for an innovative and green production of biodiesel [19]. Other catalytic systems: In addition to the above-described catalysts, amines and organometallic derivatives also find applications in the field of homogeneous catalytic systems for transesterification reactions. Remarkable examples are those of triethylamine (TEA) and Fe–Zn double-metal cyanide complexes [20,21]. Among other applications, these compounds successfully catalyzed the reaction of DMC and other organic carbonBeilstein J. Org. Chem. 2016, 12, 1911–1924. 1913 Scheme 3: Top: Green methylation of phosphines and amines by dimethyl carbonate (Q = N, P). Bottom: anion metathesis of methyl carbonate onium salts. ates with polyols (e.g., glycerol) to produce the expected transesterification products with total conversion and selectivity. Ionic liquid-based organocatalysts Conventional acid or base liquid catalysts for transesterification processes often entail several synthetic and environmental concerns including equipment corrosion, separation and purification drawbacks, and production of waste. As already mentioned in the previous paragraph, practical solutions to such problems are offered by using solid acids, although these systems may suffer from mass-transfer limitations causing low activity, and consequently, extended reaction times and deactivation from coking [22,23]. Valuable alternatives are biocatalysts, which are very active but costly. Economic issues usually restrict the use of enzymes to highly specialized productions rather than to large commercial applications [24]. In this scenario, the implementation of transesterification procedures based on innovative and possibly green catalysts remains still a highly desirable target. A strategy can be conceived by the use of task-specific ionic liquids (ILs). These compounds have shown to catalyze a number of different reactions. Only to cite a few: nitrations, Michael reactions, Friedel–Crafts alkylations and acylations are successfully promoted by ILs [25,26]. The key to such a flourishing research lies in the unique physical properties (negligible vapor pressure, wide liquid range, and non-flammability) of ILs, but mostly on the virtually infinite number of different chemical structures for liquid organic salts. These properties are often referred to as “tunable catalysts”, “task-specific ionic liquids”, and “designer solvents”, which involve the concept of optimizing the use of ILs by tailoring their chemical features for a specific transformation or for classes of similar processes [27,28]. Notably, the screening of the reaction variables includes not only the required reaction steps, but also the associated operations including separation and purification of products, recycling of solvents and catalysts, and waste treatments as well. All these additional steps contribute to the impact of the chemical process as the whole from an environmental and sustainability standpoint. For example, the isolation and purification of the desired product and reuse of the IL-based catalyst may require additional solvents for extraction and/or complex and energy-intensive separation and purification technologies. Therefore, when designing a catalytic IL-based process, one should factor-in all the reagents and solvents as well as all the downstream operations, in order to evaluate the advantages of the proposed process correctly. In this context, green metrics can provide a screening guide. IL-based catalysts for transesterification reactions Synthesis of IL-catalysts: IL-based catalysts for transesterification reactions mostly comprise imidazolium, phosphonium, ammonium, sulfonium and pyridinium salts. The conventional syntheses of such compounds usually start from the protonation or quaternization of neutral precursors (imidazoles, amines, phosphines, pyridine or sulfides) with Brønsted acids or haloalkanes/dialkylsulfates, respectively. In the next step, a variety of ionic liquids are obtainable by anion exchange, either through direct treatments with Lewis acids or by anion metathesis [29]. There are several reviews detailing these synthetic procedures [30,31]. More sustainable methods that avoid the use of noxious and undesirable halogens have also been recently designed [32,33]. An example is the preparation of methyl carbonate onium salts ([Q1nnn][MeOCO2]; Q = N, P; n = 4, 6, 8, Ph), obtained by the methylation of trialkylphosphines or -amines with nontoxic DMC (Scheme 3, top) [34,35]. Such methyl carbonate onium salts are versatile platforms as they allow access to a number of ionic liquids via anion-metathesis reactions, which produce only CH3OH and CO2 as byproducts (Scheme 3, bottom). Seedon et al. reported another green protocol for the preparation of ILs. The authors described the synthesis of aqueous hydroxide solutions of organic cations, subsequently neutralized by simple acid–base reactions, giving access to ionic liquids that are difficult to prepare by any other route. This protocol avoids the use of halides, and generates water as the only byproduct [33]. Synthesis of supported ion


BACKGROUND
Chemistry is an integral part of our pharmaceutical business. Green chemistry is understood to have minimal impacts on the environment and on human health, and also to be cost effective.
Over the past decade, the pharmaceutical industry has been moving toward the application of green chemistry principles, mainly by introducing new production and analytical technologies, using greener solvents, and emphasizing catalysis and enzymatic chemistry.
Green chemistry focuses on making industrial chemistry safer and cleaner, and on giving more consideration on how energy could be used more efficiently while generating economic benefits. This concept is driven by efficiency combined with environmental responsibility, to offer enhanced chemical-process economics.
To quote the words of Paul Anastas, who introduced the term "green chemistry" in 1991: "It's more effective, it's more efficient, it's more elegant, and it's simply better chemistry!" To discover the 12 Principles of Green Chemistry, visit the ACS Green Chemistry Institute® website: http: //www.acs.org/content/acs/en/greenchemistry/what-is-green-chemistry/principles/12principles-of-green-chemistry.html

POLICY
With a long history in active ingredient manufacturing, Sanofi is committed to improving its drug manufacturing processes so that it minimizes the impact on the environment.
Each development team involved in the design and improvement of our chemical and biotechnical processes for producing our active ingredients is intently focused on this goal. In support of our corporate commitment, we have taken a number of tangible steps to reduce our environmental footprintfrom the design of our R&D synthetic pathways, to the production of active pharmaceutical ingredients (APIs) in our plants.

Optimizing raw material use and processes
Throughout the chemical and biochemical product development stages that are part of manufacturing drugs, Sanofi teams make decisions about the processes they use based on criteria designed to protect the health and safety of employees while preserving the environment.
Sanofi uses a KPPI (Key Process Performance Indicators) analysis tool for all its projects to guide chemists in the selection of synthesis routes, evaluate the critical parameters in terms of cost and HSE performances and allow a more targeted process improvement.

Tracking the greenness of our processes
Medicines are often produced using large amounts of input materials to obtain very small amounts of active ingredients, which corresponds to low mass efficiency. Developing and producing drugs this way is not only costly, but harmful for the environment.
Benchmarking shows that the pharmaceutical industry typically uses about 100 kg of raw material to produce 1 kg of active pharmaceutical ingredient. This 1% mass efficiency compares to about 20% for fine chemicals and 50% for bulk chemicals.
We also face the trend of shifting towards biotechnologies, i.e. processes based on fermentation with micro-organisms for the synthesis of active molecules. This evolution means that fewer chemical steps are necessary, but fermentation processes have other environmental impacts (mainly biological chemical oxygen demand, or COD, load to wastewater treatment).
Experts from within the industry, as well as health authorities such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), recommend that drug companies focus greater attention on this issue. To this end, it is essential to adopt a common metric to measure progress toward more sustainable manufacturing.
To meet these requirements, the American Chemical Society-Green Chemistry Institute-Pharmaceutical Roundtable (ACS-GCI-PR) implemented, among other indicators, the Process Mass Intensity (PMI) indicator. PMI measures the mass (weight) of the produced API compared to the mass (weight) of substrates, reagents, solvents, and process water used to manufacture the API. As a member of ACS-GCI-PR, Sanofi uses PMI as a key metric for process greenness.
The initial PMI assessments of our products reveal that our figures are clearly within the pharmaceutical industry range.
However, the PMI alone does not enable a detailed view of process improvement.
In order to remedy to this limitation, a working group from Process Development has met several times since 2013 to investigate appropriate qualitative and quantitative indicators including process efficiency as well as economic and environmental criteria at different development stages, such as:  Design of industrial synthesis pathways at laboratory scale  Process development and optimization  Continuous process improvement at industrial level The aim of this investigation is to give better guidance to the operating teams, based on relevant KPIs, and focus on the key sustainable activities.
The key process performance indicator (KPPI) tool and our solvent selection guide were some of the deliverables of this working group.
The amount of solvent and the amount of water used in the process are also considered to be important environmental metrics.
In 2018 most of our commercial products were evaluating using KPPI tool and action plans for process improvement identified. For instance, for Apomorphine, process improvement should lead to a cost of goods decrease of 50% and a capacity increase of 270% In each case, the process improvement program was oriented by the outcome of the study.
In parallel, within the framework of our continuous process improvement program we were able to achieve a remarkable reduction of either solvent or water consumption for some of our industrially manufactured products (APIs or intermediates). The solvent index (SI) calculates the ratio of the total solvent consumed in the process to the mass of the isolated product.
The water index (WI) calculates the ratio of the total process water consumption to the mass of the isolated product.
In 2017, the process improvement in Ankleshwar (India) won the golden award at Sanofi Industrial Affairs Innovation Awards for their project "Environment Protection by reducing waste water of Lasamide".
In 2018, a new working group has been initiated with the objective to develop a complete assessment based on raw data already available in our KPPI tool, and to provide an easy-to-understand visual representation that quantifies improvements throughout the development process. This global evaluation of the performance of our processes will not be only based on economic or overall yield aspects but also on all HSE considerations. 14 key parameters have been identified and the team is currently focusing on a reflection on scoring parameters (metrics). Among these parameters, we can mention, productivity, solvent recycling, HSE scores of solvents and reagents used, nature of COV, PMI, water and solvent index, energy, etc…

Making choices when it comes to solvent use
From the earliest stages of product development, teams are encouraged to use reagents and solvents that pose the least possible hazard. To help teams make decisions on a daily basis, Sanofi has developed an internal guide on the appropriate use of solvents for the design of drugmanufacturing processes.
The vast majority of energy, chemical reagent, and solvent reduction occurs during scale-up and the manufacturing of medicines, rather than during the drug-research phase. Even after an active ingredient is in the production phase, industrial development teams continue to optimize chemical and biochemical processes whenever possible. Choices made during the industrial development phase are often difficult to change later on, which is why it is important to make sustainable decisions early in the development process, taking into account future manufacturing and scale-up.
To choose substances and materials with the least environmental impact, the company has established processes designed to:  Select the least toxic solvent  Reduce the quantities of solvents used in industrial processes  Recycle solvents whenever possible The guide that was developed, "Sanofi's solvent selection guide: a step toward more sustainable processes 1 ," was published in November 2013 and is available at http://pubs.acs.org/doi/abs/10.1021/op4002565. More recently, in 2016, a new guide 2 has been published by Chem21 with the contribution of several players from the pharmaceutical industry, including Sanofi. This new guide largely inspired from the previous Sanofi's guide in now largely shared within Sanofi's chemists teams and become more and more the new reference guide: this guide is available on line at http://learning.chem21.eu/methodsof-facilitating-change/tools-and-guides/solvent-selection-guides/guide-tables/

Optimizing solvent consumption
Solvents used in the production processes are either purchased ("consumed" quantities) or regenerated at Sanofi sites.
To decrease the use of non-renewable raw materials, the company focuses on three areas:

Change for greener reagents
Depending on the type of chemical conversion to be carried out, the choice of reagents is often limited to products that are toxic to humans and environment, or that are not very safe to use and that can also generate large amount of waste. For example, this is the case of oxidation reactions, reductions, fluorinations, formation of amides.
The best choices of reagents are studied during the development of the processes and the stoichiometries are optimized. To help chemists, reagents selection guide such as Chem21's is widely used: http://learning.chem21.eu/

Promote catalytic transformations
Even if reagents generate less waste compared to solvents, it is our duty as recommended by the 12 principles of the green chemistry to implement as much as possible catalytic chemical or enzymatic transformations. For example, Palladium catalyzed Suzuki type C-C bond formation reactions are very regularly used. In order to not impact the COGs, the recycling of catalysts is studied. More recently, based on work published in the literature, the application of different reagents for catalytic amidation on our products has been successfully tested. Development work will follow in the coming months.

Membership of learned societies
Sanofi is a member of several learned societies in the chemistry field, including the Société française de chimie (SFC) and the American Chemical Society (ACS), among others. Since 2011 Sanofi has taken an active part in a workshop organized by the Union des industries chimiques (UIC) on "Chemistry and Sustainable Raw Materials," which focuses on the importance of designing green processes.

Our partnership with the ACS-GCI Pharmaceutical Roundtable (ACS-GCI PR)
In 2011 Sanofi joined the ACS-Green Chemistry Institute (GCI)-Pharmaceutical Roundtable, which aims to catalyze the implementation of green chemistry and engineering throughout the pharmaceutical industry globally.
Sanofi has launched various collaborative initiatives in line with these general objectives, including:  Assessment of PMI improvements for the production of key active pharmaceutical ingredients  Contribution to the training program developed by the GCI-Pharmaceutical Roundtable in Europe  Contribution to the current review of the solvent guide with members of the GCI-

The Innovative Medicines Initiative (IMI)-CHEM21 project in Europe
The discovery of green and sustainable synthesis methodologies is a long-term endeavor. Today, collaborations between academia and pharmaceutical companies provide an opportunity to develop green, safe, and more effective processes to deliver medicines for the 21 st century.
The Innovative Medicines Initiative (IMI) is a pan-European public-private partnership supported by the European Federation of Pharmaceutical Industries and Associations (EFPIA). It was created in 2007 to bolster the development of better and safer medicines for patients in the European pharmaceutical industry. To find out more about IMI, visit www.imi.europa.eu.
Sanofi makes the largest contribution of all EFPIA member companies and has contributed more than €5 million over the course of the program. In 2011, Sanofi, together with other European pharmaceutical companies (GSK, Janssen, Bayer, and Orion), suggested that IMI launch a call for proposals in the field of sustainable chemistry.
Sanofi participated as co-coordinator of the IMI-CHEM21 project, which aims to generate a range of technologies to manufacture medicines that are demonstrably more sustainable than existing methods. Six work packages were developed covering chemistry, biochemistry, synthetic biology and education. Each work package has a Sanofi lead scientist and two packages, WP2 and WP4, are co-led by employees from Sanofi Chemistry & Biotechnology Development. The program ended in June 2017. To find out more about IMI-CHEM21, see: http://www.chem21.eu.
The aim of WP2 of IMI-CHEM21 was to develop more sustainable chemical process for important chemical transformations.
One objective of this consortium was to use these sustainable methodologies in order to contribute to the development of more efficient and greener process for Essential Medicine molecules manufacture. A decrease in the manufacturing cost was expected making Essential Medicine more accessible to African Continent. Flucytosine was identified as good target molecule (In sub-Saharan Africa around 625000 mortalities per annum (20% of HIV/AIDS related deaths) result from Cryptococcal meningitis (CM) fungal infection. WHO recommends Flucytosine in combination with Amphotericin B for first line treatment of C. Meningitis).
Sanofi studied a new fluorination methodology based on the use of elemental Fluorine gas as electrophilic reagent and continuous process using flow conditions as technology (milli-reactor). As a great achievement, a new, readily scalable method for the direct synthesis of Flucytosine from cytosine using fluorine gas has been developed. A full process to manufacture Flucytosine API has then been designed and pre-industrial studies have been achieved successfully (kg scale) in order to demonstrate the potential of this new methodology.
In 2018, Sanofi proposed to valorize these results through Corporate Social Responsibility program. A tech transfer to Inicio/Pelchem, a South African startup that has confirmed interest in the project, would be proposed.
These important results have been partly communicated to scientific community through one publication and two talks (Alain RABION & al, Org.Proc.Res. Dev, 2017, 21, 273 The aim of WP5 of IMI-CHEM21 was to influence the next generation of chemists by exemplifying low environmental impact chemistry, through the preparation and delivery of high quality training and educational materials. In working package No. 5 (WP5), Sanofi contributed to "medicinal and process chemist education," with the goal of augmenting employee awareness, as well as setting up a "green chemistry index." To promote and embed the achievements of the CHEM21 project, an online training platform has been developed by the University of York as part of WP5 (http://learning.chem21.eu). This platform is available to all, and the material it provides may be copied and used for any training activity, provided CHEM21 is cited. Sanofi again played an important role in this platform in terms of structure, training on process safety, and solvents. An on-line tool has been developed to assess the greenness of a solvent, using the methodology set out in the CHEM21 solvent guide.