Continuous flow strategies for the upgrading of bio-based molecules

In the current context of fossil resources depletion and global warming, the upgrading of biomass-derived molecules for the manufacture of fuels and chemicals sustains major research interests. Continuous flow technology holds great potential for the development of chemical facilities with low footprint, improved performance and reduced hazards. This PhD dissertation gathers our results for the upgrading of a selection of low molecular weight bio-based molecules into higher value-added chemicals. Continuous flow procedures were developed to provide robust, versatile, sustainable and scalable technologies for the preparation of chemicals of high industrial relevance

Multistep Continuous-Flow Processes for the Preparation of Heterocyclic Active Pharmaceutical Ingredients

peer reviewedFlow chemistry has many fascinating facets, among which the most challenging is arguably the implementation of complex multistep processes within one uninterrupted fluidic network. This document provides a thorough overview of some of the most representative examples of multistep continuous-flow strategies in the specific context of preparing heterocyclic active pharmaceuticals. Selected examples emphasizing the implementation of multistep sequences, including various combinations of chemical transformations, purifications, or in-line analysis, are discussed

A Safe and Reliable Continuous-Flow System towards Methylphenidate Hydrochloride

The batch-to-flow translation of a carbene-based strategy for the diastereoselective preparation of the active pharmaceutical ingredient threo-methylphenidate hydrochloride is presented. The continuous-flow system implies the generation of an explosive organic azide, its consumption in a diazo transfer reaction, an intermediate purification step followed by a Rh(II)-catalyzed carbene C-H insertion reaction that produces threo-enriched N-Boc-methylphenidate. Boc-deprotection is carried out off-line and provides methylphenidate hydrochloride in 19% isolated yield (3 steps fully telescoped) or 38% isolated yield (sequential)

Preparation, Reactivity, and Synthetic Utility of Simple Benzotriazole Derivatives

peer reviewedThe benzotriazole fragment is known to behave as (1) an excellent leaving group, (2) an electron-donating or an electron-withdrawing group, (3) an anion precursor, and (4) a radical precursor. It confers unique physicochemical properties to its immediate vicinity on various molecular scaffolds. This review covers the preparation and synthetic utility of versatile benzotriazole derivatives. The selected compounds are conveniently prepared from 1H-benzotriazole and are characterized by a huge synthetic potential. Their specific reactivity is discussed and illustrated with various examples ranging from methodology in organic chemistry to the total synthesis of complex structures

Organocatalytic continuous flow strategies for the upgrading of biobased molecules

Organocatalyzed transformations for the upgrading of biomass-derived molecules are studied under continuous flow conditions. Both on- and off-line analytical tools are implemented for reaction monitoring and product quantification. We will first present our efforts for the development of a continuous process for the carbonation of 3-butene-1,2-diol toward vinyl ethylene carbonate. Both homogeneous and polymer-supported 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are studied as organocatalysts. The carbonation reaction is amenable to both purified or crude 3-butene-1,2-diol derived from erythritol. Aiming at a broader substrate scope, the carbonation procedure is next extended to glycerol and other biobased diols. Libraries of homogeneous and heterogeneous organocatalysts are screened, emphasizing that homogeneous and polymer-supported phosphazene and guanidine superbases are efficient catalysts under solvent-free conditions. To further improve cost-efficiency, cheap organic salts such as ammoniums and phosphoniums are assessed as well, giving slightly improved yields by comparison to organic superbases, although requiring more drastic process conditions. In the last part of this lecture, we will illustrate our efforts in photocatalytic continuous flow procedures for the upgrading of biobased fumaric and itaconic acids. γ-Butyrolactones, including spiro derivatives, are produced in good yields under 365 nm LED irradiation and in the presence of benzophenone as a cheap photosensitizer

Expanding chemistry’s horizon with continuous-flow reactors

peer reviewedContinuous-flow micro- and mesofluidic reactors come with inherent properties that can be advantageously utilized for expanding the horizon of preparative chemistry. Accurate control over local process parameters, even under extreme conditions, inherent safety, production homogeneity and seamless scale-up are amongst the most important assets of continuous-flow chemistry. Besides, flow chemistry enables the design of efficient multistep processes with significantly reduced footprints. In this note, we discuss some of the most fascinating aspects of continuous-flow micro- and mesofluidic reactors in the specific context of preparative organic chemistry

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

Assessing Inter-and Intramolecular Continuous-Flow Strategies towards Methylphenidate Hydrochloride

The batch-to-flow translation of inter- and intramolecular strategies for the diastereoselective preparation of the active pharmaceutical ingredient threo-methylphenidate hydrochloride is presented. Both inter- and intramolecular strategies imply the telescoping of multiple processing steps and the generation of unstable diazospecies under continuous-flow conditions. The intermolecular strategy relies on an unprecedented continuous-flow Rh-catalyzed intermolecular C-H carbene insertion, providing enriched threo-N-Boc methylphenidate in 38% or 19% isolated yield according to sequential or fully telescoped processes, respectively. Quantitative Boc-deprotection is carried out off-line. The intramolecular strategy relies on a continuous-flow thermal intramolecular C-H carbene insertion, providing enriched threo-methylphenidate hydrochloride in 70% isolated yield. A continuous-flow photochemical alternative is also presented. The critical step of the most promising intramolecular strategy is implemented on mesoscale in a pilot-scale continuous-flow reactor

Intramolecular continuous-flow strategy towards methylphenidate (Ritalin) hydrochloride

threo-Methylphenidate hydrochloride is the most widely prescribed drug to treat attention deficit hyperactivity disorder (ADHD). Herein we present the batch-to-flow translation of a carbene-based intramolecular strategy for the diastereoselective preparation of this active pharmaceutical ingredient. The process relies on the thermal generation and decomposition of a hazardous diazospecies, its thermal intramolecular C-H insertion reaction yielding an intermediate β-lactam, and its subsequent acidic methanolysis, giving enriched threo-methylphenidate hydrochloride in 70% isolated yield. The automated microfluidic setup telescopes 2 chemical transformations, 1 intermediate in-line purification and sustains a daily productivity of 20.4 g/day of methylphenidate hydrochloride. The preparation of the β-lactam is implemented on mesoscale in a pilot-scale continuous-flow reactor, providing 4.25 kg of this key intermediate per day