Taming reactive (poly)alcohol derivatives in continuous flow systems

Evolution within Industrial Chemistry in recent days has led to the prohibition of hazardous reactions to avoid serious accidents in particular for high scale processes. The current emergence of continuous flow technology has completely redefined how we approach this kind of procedures and enabled the revival of the so-called “forbidden chemistry” by allowing safer processes to be developed. Within the context of this work we tackled the upgrading of various (poly)alcohol derivatives with reactive, corrosive, and toxic reactants or intermediates by implementing safe process tools and protocols that enable the efficient and quick production of various high value-added end-products. Two main topics are discussed herein i.e. the upgrading of biobased platform molecules and the handling of (chlorinated) organophosphorus species. The various research programs addressing these two themes allowed to safely produce essential cardiovascular medications and chemotherapeutics, critical polymeric assemblies with biomedical and flame-retardancy applications and privileged ligands for asymmetric catalysis using continuous flow systems.Ces dernières années, l'évolution au sein de l’industrie chimique a conduit à l'interdiction de réactions chimiques considérablement dangereuses afin d'éviter des accidents graves, en particulier pour les procédés à grande échelle. L'émergence actuelle des technologies relatives à la chimie en flux continu a complètement redéfini la façon dont sont abordés ce type de procédures et a permis la renaissance de réactions autrefois considérées comme trop dangereuses en permettant le développement de procédés plus sûrs. Dans le cadre de ce travail, nous nous sommes attaqués à la valorisation de divers dérivés (poly)alcools avec des réactifs ou des intermédiaires particulièrement sensibles, corrosifs et/ou toxiques en mettant en œuvre, au sein des procédés, des outils et des protocoles plus sûrs qui permettent la production efficace et rapide de divers produits finaux à haute valeur ajoutée. Deux thèmes principaux sont abordés ici, à savoir la valorisation de molécules biosourcées et l’emploi d’espèces organophosphorées (et eventuellement chlorées). Les différents programmes de recherche portant sur ces deux thèmes ont permis de produire en toute sécurité des médicaments cardiovasculaires et chimiothérapeutiques essentiels, des polymères ayant des applications biomédicales et ignifuges et d’importants ligands employés en catalyse asymétrique en utilisant des réacteurs à flux continu.IN FLOW9. Industry, innovation and infrastructur

Valorization of glycerol: Continuous flow synthesis of value-added oxirane building blocks

The progressive depletion of fossil resources and a global environmental awareness stimulates research toward a transition for more sustainable resources. The last three decades have witnessed developments for the valorization of biomass, and various chemicals of industrial interest can nowadays be derived from bioresources. A wide range of specific molecules named “biobased platforms” can be obtained from raw biomass through biotechnological, chemical or physical treatments. These platforms are compounds of low molecular mass and complexity that can be used as potential building blocks for the synthesis of value-added chemicals. Among them, glycerol occupies a special place: it is widely available as a by-product of the biodiesel production and can readily be transformed into a large variety of value-added products. We present herein a synthetic pathway starting from biobased glycerol toward useful oxirane building blocks traditionally produced from petrobased propene

A Semi-Continuous Flow Platform for the Direct Preparation of Novel Cyclic Phosphate Monomers from Bulk Chemicals and Their Further Polymerization Toward Functional Polyphosphoesters

Polyphosphoesters have recently emerged as new materials for biomedical applications thanks to their biocompatibility and biodegradability properties that can be finely tuned by varying their functional side-chains linked to a pentavalent phosphorus. The preparation of polyphosphoesters frequently relies on the ring-opening polymerization of 5-membered cyclic phosphate monomers (CPMs), which are generally synthetized through a 3-step procedure. Starting from bulk chemicals the preparation of such monomers by a batch process is time-consuming, difficult to scale-up and involves safety concerns such as the uncontrolled generation of HCl by-product and the handling of sensitive and corrosive intermediates. To this end, we developed a semi-continuous flow platform allowing the direct preparation of CPMs starting from PCl3 and a 1,2-diol derivative without isolation of the intermediates. The first step involved the preparation of cyclic chlorophosphite derivatives by reacting a neat diol with a highly concentrated organic solution of PCl3 at room temperature with an associated residence time of 1 minute in a compact coil reactor. This procedure allowed to produce a wide range of novel cyclic chlorophosphites starting from various diols in moderate to high yields and with a daily productivity of up to ~500 g. The scope was also extended to thioalcohol, dithiol, aminoalcohol and diamine derivatives and the process was eventually adapted to a base-involving procedure allowing the conversion of more demanding substrates such as highly hindered pinacol-type diols. The next oxidation step toward cyclic chlorophosphates was directly concatenated with the upstream production of chlorophosphites in a single continuous flow system. A high pressure and an improved mixing capacity allowed to perform the oxidation using 4 equivalents of molecular oxygen in only 21 seconds of residence time at 65 °C toward a quantitative conversion while batch procedures usually require tens of hours or days of reaction time. A final functionalization of chlorophosphates toward various CPMs was subsequently integrated in a semi-continuous flow platform where the effluent coming from the oxidation step is directly reacted in a batch reactor. The system allowed to produce the CPMs directly from PCl3 in an extremely shortened time by a single process without purification and isolation of the sensitive intermediates while mitigating the hazards linked the corrosive derivatives produced. Among the novel monomers prepared, a bifunctional derivative was successfully copolymerized by ring-opening polymerization allowing the introduction of a typical alkoxy pendant group linked to a pentavalent phosphorus and an additional convertible chloromethyl function directly linked to a main-chain carbon. The introduction of such functionalizations opens new opportunities for the preparation of novel materials with various properties which could be time-dependent through the quick (P-linked group) or slower (C-linked group) degradation of the polyphosphoester linkages.In Flo

Valorization of glycerol: A robust flow procedure toward oxirane building blocks and active pharmaceutical ingredients from a biobased platform

The progressive depletion of fossil resources and a global environmental awareness stimulates research toward a transition for more sustainable supplies Glycerol, which is nowadays obtained as a by product of the biodiesel production, presents a significant industrial potential and can be upgraded in a large variety of value added building blocks We present herein a robust multi module continuous flow procedure for the valorization of glycerol towards active pharmaceutical ingredients (through the intermediate formation of epichlorohydrin The first module is dedicated to the valorization of glycerol into oxiranes by a hydrochlorination dechlorination concatenated sequence involving economically and environmentally favorable conditions, an organocatalyst and an in line separation of the two products Finally, biobased epichlorohydrin is further utilized for the preparation of β-amino alcohol APIs including propranolol (WHO essential), naftopidil (prostatic hyperplasia) and alprenolol (angina pectoris) within a concatenable Williamson/ aminolysis sequence using a FDA class 3 solvent (DMSO)

Continuous Flow Upgrading of Glycerol toward Oxiranes and Active Pharmaceutical Ingredients thereof

The progressive depletion of fossil resources and a global environmental awareness stimulates research toward a transition for more sustainable supplies. Glycerol, which is nowadays obtained as a by product of the biodiesel production, presents a significant industrial potential and can be upgraded in a large variety of value added building blocks. We present herein a robust multi module continuous flow procedure for the valorization of glycerol towards active pharmaceutical ingredients (through the intermediate formation of epichlorohydrin). The first module is dedicated to the valorization of glycerol into oxiranes by a hydrochlorination dechlorination concatenated sequence involving economically and environmentally favorable conditions, an organocatalyst and an in line separation of the two products. Finally, biobased epichlorohydrin is further utilized for the preparation of β-amino alcohol APIs including propranolol (WHO essential), naftopidil (prostatic hyperplasia) and alprenolol (angina pectoris) within a concatenable Williamson/ aminolysis sequence using a FDA class 3 solvent (DMSO).Fluidic upgrading of biobased platform

End-to-End Production and Polymerization of Cyclic Phosphate Monomers from Bulk Chemicals in a Semi-Continuous Flow System

IN FLO

Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof

peer reviewedA robust continuous flow procedure for the transformation of biobased glycerol into high value-added oxiranes (epichlorohydrin and glycidol) is presented. The flow procedure features a central hydrochlorination/dechlorination sequence and provides economically and environmentally favorable conditions involving an organocatalyst and aqueous solutions of hydrochloric acid and sodium hydroxide. Pimelic acid (10 mol%) shows an exceptional catalytic activity (99% conversion of glycerol, a high selectivity toward 1,3-dichloro-2-propanol and 81% cumulated yield toward intermediate chlorohydrins) for the hydrochlorination of glycerol (140 °C) with 36 wt.-% aqueous HCl. These conditions are validated on a sample of crude biobased glycerol.The dechlorination step is effective (quantitative conversion based on glycerol) with concentrated aqueous sodium hydroxide (20 °C) and can be directly concatenated to the hydrochlorination step, hence providing a ca. 2:3 separable mixture of glycidol and epichlorohydrin (74% cumulated yield). An in-line membrane separation unit is included downstream, providing usable streams of epichlorohydrin (in MTBE, with an optional concentrator) and glycidol (in water). The scalability of the dechlorination step is then assessed in a commercial pilot-scale continuous flow reactor. Next, biobased epichlorohydrin is further utilized for the continuous flow preparation of β-amino alcohol active pharmaceutical ingredients including propranolol (hypertension, WHO essential), naftopidil (prostatic hyperplasia) and alprenolol (angina pectoris) within a concatenated two-step procedure using a FDA class 3 solvent (DMSO). This work provides the first example of direct upgrading of biobased glycerol into high value-added pharmaceuticals under continuous flow condition

Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof

The progressive depletion of fossil resources and a global environmental awareness stimulates research toward a transition for more sustainable supplies. Glycerol, which is nowadays obtained as a by-product of the biodiesel production, presents a significant industrial potential and can be upgraded in a large variety of value-added building blocks. We present herein a robust multi-module continuous flow procedure for the valorization of glycerol towards active pharmaceutical ingredients (APIs) through the intermediate formation of epichlorohydrin. The first module is dedicated to the valorization of glycerol into oxiranes by a hydrochlorination/dechlorination concatenated sequence involving economically and environmentally favorable conditions, an organocatalyst and an in-line separation of the two products. Finally, biobased epichlorohydrin is further utilized for the preparation of β-amino alcohol APIs including propranolol (hypertension, WHO essential), naftopidil (prostatic hyperplasia) and alprenolol (angina pectoris) within a concatenable Williamson/aminolysis sequence using a FDA class 3 solvent (DMSO)

Biodegradable aliphatic polyphosphoester-based particles — green production by batch and flow processes

Nano- and microparticles are used as carriers for the controlled delivery of an active ingredient with a high potential for applications for, among others, the health care and personal care industry. Particles made up of aliphatic polylactones, typically, polylactide, polyglycolide and polycaprolactone are very well-known since many years. Aliphatic polyphosphoesters less popular even though they this class of polymers has witnessed a renewed interest. This communication aims at comparing the potential of aliphatic polylactones and aliphatic polyphophoesters with a special attention paid on particles, based on the recent developments carried out in the Center of Education and Research of Macromolecules of the University of Liège. Ring-opening polymerization of 5-membered cyclic polyphosphoesters is very efficient for the synthesis of high molar mass aliphatic polyphosphoesters. As far as cyclic 5-memberd phosphates are concerned, their extremely high sensitivity to hydrolysis remains a strong limitation at the time being. In this context, efficient processes allowing the synthesis of a wide range of aliphatic polyphosphoesters, functionalized or not, will be reported based on: (1) flow technologies, (2) organocatalysis and (3) chemical modification of the polymers. Advantages and drawbacks of aliphatic polyphosphoesters compared to polyesters will be detailed with a special attention on both the synthesis of these polymers and their properties, to assess their potential for future applications. Particles made up of biodegradable poly(phospho)esters will be shown to be prepared by the self-assembly of amphiphilic polymers or by nanoprecipitation in batch or in flow reactors. Depending on the preparation process and the chemical structure of the polyesters, the size and size-dispersity of particles as well as the loading content, loading efficiency and release rate of a model active ingredient will be discussed. Acknowlegements: Philippe Lecomte is research associate by the belgian FNRS. The authors thanks all the partners of the IN-Flow project carried out under the Interreg V-A Euregio Meuse-Rhine Programme, with €2.1 million from the European Regional Development Fund (ERDF). By investing EU funds in Interreg projects, the European Union invests directly in economic development, innovation, territorial development, social inclusion, and education in the Euregio Meuse-Rhine

Sustaining the Transition from a Petrobased to a Biobased Chemical Industry with Flow Chemistry

In the current context of transitioning to more sustainable chemical processes, the upgrading of biobased platform molecules (i.e., the chemical transformation of widely available low molecular weight entities from biomass) is attracting significant attention, in particular when combined with enabling continuous flow conditions. The success of this combination is largely due to the ability to explore new process conditions and the perspective of facilitating seamless scalability while maintaining a small overall footprint. This review considers representative continuous flow processes which utilize a selection of currently popular platform molecules that target industrially relevant building blocks, including (a) commodity chemicals, (b) specialty and fine chemicals, and (c) fuels and fuel additives