Na primeira parte deste trabalho apresentamos uma forma eficiente para sintetizar quinze novos compostos α-amino-1,3-dicarbonílicos através da reação multicomponente de Ugi. Para estas sínteses foi utilizado o microrreator de fluxo contínuo, um aparelho que possibilita uma excelente transferência de calor, de massa e alta relação superfície / volume. Algumas das vantagens em se utilizar um microrreator de fluxo contínuo na síntese são: redução do tempo de reação, aumento de rendimento, seletividade das reações e menor geração de resíduos. Foi possível assim estudar as reações químicas em condições inéditas, variando parâmetros como: temperatura, pressão, tempo de residência e relação estequiométrica. Um comparativo de rendimento da síntese de quatro moléculas foi realizado e pôde-se notar a eficiência do equipamento utilizado, pois os rendimentos obtidos foram superiores quando as mesmas moléculas foram sintetizadas através da reação one-pot. Um scale-up da reação de Ugi também foi realizado e apresentou um resultado satisfatório. Na segunda parte alguns destes compostos foram utilizados como intermediários na formação de uma ligação amídica e também aplicamos a metodologia relacionada à cicloadição catalisada por cobre entre alquinos e azidas na síntese de cinco novos compostos 1,2,3-triazóis. Este foi o primeiro trabalho realizado no Laboratório de Compostos Heterocíclicos da Faculdade de Ciências Farmacêuticas utilizando o microrreator de fluxo contínuo e este equipamento atendeu as necessidades deste trabalho com efetividade. / The first part of this work we present an efficient way to synthesize fifteen new α-amino-1,3-dicarbonyl compounds through the multicomponent Ugi reaction. For these syntheses was used the continuous flow micro-reactor, an equipment that allows an excellent transfer of heat, mass and high surface / volume ratio. Some of the advantages of using a continuous flow micro-reactor in the synthesis are: reduction of reaction time, increase of yield, selectivity of reactions and less generation of residues. It was possible to study the chemical reactions under new conditions, varying parameters such as: temperature, pressure, residence time and stoichiometric ratio. A yield comparison of the synthesis of four molecules was carried out and it was possible to note the efficiency of the equipment used, because the obtained yields were superior when the same molecules were synthesized through the one-pot reaction. A scale-up of the Ugi reaction was also performed and presented a satisfactory result. In the second part some of these compounds were used as intermediates in the formation of an amide bond and we also apply the methodology related to the copper catalyzed cycloaddition between alkynes and azides in the synthesis of five new 1,2,3-triazoles compounds. It was the first work performed in the Laboratory of Heterocyclic Compounds of the Faculty of Pharmaceutical Sciences using the continuous flow micro-reactor and this equipment met the needs of this work with effectiveness.

Le présent mémoire décrit le développement d’une méthode de synthèse des hélicènes catalysée par la lumière visible. Les conditions pour la formation de [5]hélicène ont été établies par une optimisation du photocatalyseur, du solvant, du système d’oxydation et du temps réactionnel. Suite aux études mécanistiques préliminaires, un mécanisme oxydatif est proposé. Les conditions optimisées ont été appliquées à la synthèse de [6]hélicènes pour laquelle la régiosélectivité a été améliorée en ajoutant des substituants sur la colonne hélicale. La synthèse de thiohélicènes a aussi été testée en utilisant les mêmes conditions sous irradiation par la lumière visible. La méthode a été inefficace pour la formation de benzodithiophènes et de naphtothiophènes, par contre elle permet la formation du phenanthro[3,4-b]thiophène avec un rendement acceptable. En prolongeant la surface-π de la colonne hélicale, le pyrène a été fusionné aux motifs de [4]- et [5]hélicène. Trois dérivés de pyrène-hélicène ont été synthétisés en utilisant les conditions optimisées pour la photocyclisation et leurs caractéristiques physiques ont été étudiées. La méthode de cyclisation sous l’action de la lumière visible a aussi été étudiée en flux continu. Une optimisation du montage expérimental ainsi que de la source lumineuse a été effectuée et les meilleures conditions ont été appliquées à la formation de [5]hélicène et des trois dérivés du pyrène-hélicène. Une amélioration ou conservation des rendements a été observée pour la plupart des produits formés en flux continu comparativement à la synthèse en batch. La concentration de la réaction a aussi été conservée et le temps réactionnel a été réduit par un facteur de dix toujours en comparaison avec la synthèse en batch. / The present work describes the development of a visible-light-mediated method for the synthesis of helicenes. The conditions for the formation of [5]helicene were established in a batch process as a result of an extensive optimization of the photosensitizer, solvent, oxidant system and reaction time. Following preliminary mechanistic studies, an oxidative reaction mechanism was proposed. The optimized conditions were applied to the synthesis of [6]helicenes and the regioselectivity of the reaction was improved through substitution along the helicene backbone. Synthesis of thiohelicenes was also explored under the same conditions and although ineffective for the formation of benzodithiophenes and naphthothiophene, it did provide phenanthro[3,4-b]thiophene in a moderate yield. In an effort to extend the π-surface of the helical backbone, a pyrene moiety was fused to the [4]- and [5]helicene core. Three pyrene-helicene hybrid derivatives were synthesized under the visible-light-mediated cyclization conditions and their physical properties investigated. The visible-light-mediated method for the formation of helicenes was also explored using the continuous flow method. An optimization of the reaction set up, the reaction medium as well as the light source was conducted with the [5]helicene model system. The optimal conditions were applied to the formation of various pyrene-helicene derivatives. In most cases the reaction yields were maintained or significantly improved when compared with the batch process. Also, the reaction concentration was conserved while the reaction time was decreased tenfold from the batch method to the continuous flow process.

This thesis is centered around the use of flow chemistry to enable cycles in order to increase reaction or process efficiency. Chapter two describes the development of a pseudo-catalytic cycle in space; a strategy to achieve formal sub-stoichiometric loading of a chiral auxiliary. By telescoping auxiliary attachment, asymmetric transformation and auxiliary cleavage into one continuous flow process, coupled with separation of product and recovery of auxiliary, the reuse of the auxiliary can be automated by returning the recovered auxiliary back to the start of the process to achieve ‘turn-over.’ An asymmetric hydrogenation mediated by Oppolzer’s sultam is used to demonstrate this concept. In order to achieve cycles such as the one discussed in Chapter two, the ability to telescope reactions in flow is paramount. However, solid handling challenges are frequent when transitioning to flow, leading to limitations in potential solvents or conditions in order to achieve homogeneity. This complicates the ability to telescope reactions, and to address this challenge the work in Chapter three focuses on the development of a general and simple solution to negate precipitation problems arising from precipitation of base·HX salts, a frequent reaction by-product of common reactions. By using bases that form low- to moderate-melting salts upon protonation, precipitation is precluded while reactions are performed above the melting point of the base·HX salt. This is shown to be applicable for a wide variety of substitution reactions and allow facile reaction telescoping. Chapter four focus on overcoming severe scope limitations in palladium catalyzed transformations that result when rapid background reactions deplete the nucleophilic coupling partner faster than catalyst turnover. This work starts with real-time MS investigations to investigate why slow addition of Grignard or organolithium nucleophiles facilitates substantial scope expansion in Kumada-Corriu or Murahashi cross-couplings, and then uses the information gleaned from these studies to significantly expand the accessible scope of palladium catalyzed aryl halide–diazo cross-coupling, through controlled addition of the diazo reagent at a rate that approximates aryl halide oxidative addition, in combination with on-demand flow synthesis of non-stabilized diazo reagents. Chapter five focuses on improving efficiency in the collection of kinetic data in flow, by developing a reaction cycling reactor. Conversion over time data is obtained by passing a discrete reaction slug back-and-forth between two residence coils, with analysis performed each time the solution passes from one coil to the other. In contrast to a traditional steady state flow system, which requires >5 X the total reaction time to collect data, this reactor design collects all the data during a single reaction. Multiple reactions can also be monitored at the same time by performing multiple reactions as sequential slugs in the reactor. The reactor is demonstrated by application to a wide variety of transformations and different methods of kinetic analysis.

<p>A significant number of resources are allocated to maintaining the resiliency of pharmaceutical supply chain as failure to do so thoroughly can result in drug shortages of essential medicines. Recently, the effects of COVID-19 exacerbated flaws in the current system causing the pharmaceutical industry and government organizations and to reassess relief strategies that could also strengthen the supply chain. Flow chemistry has become an attractive and prominent platform enabling continuous manufacturing (CM) technologies to synthesize active pharmaceutical ingredients (API) quickly according to demand. Compared to traditional batch chemistry, flow chemistry has demonstrated to be more robust in terms of throughput, scalability, and hazard reduction while maintaining a high degree of control and product quality. This work demonstrates these capabilities in reaction optimization and discovery with the overarching goal of domesticating CM to make essential medicines more affordable. A two-step process for the synthesis in diazepam was developed using a Chemtrix Labtrix S1 and Start microfluidic systems where purities as high as 98% were achieved. The system was successfully scaled up to a larger system that was able to produce 96% pure diazepam at a 91% yield. </p>

Cinnamic acids and their derivatives are building blocks for cyclobutanes in many natural products. In nature, dimerization of these derivatives is thought to occur through a [2+2] photocycloaddition. Experimentally, efficient dimerization of these substrates using UV irradiation has predominantly been achieved in the solid state and is thought to be a result of stringent requirements for distance and orientation of the participating olefins. In the following pages a new strategy is presented which achieves [2+2] dimerization of these substrates in solution through the use of a bis-thiourea catalyst that induces proximity via hydrogen bonding while exploiting novel flow technology. Using these platforms, we demonstrate the ability to perform the [2+2] photocycloaddition on a variety of electron rich and poor cinnamates to yield two major truxinic ester products in good yields and regioselectivity. The methodology is also readily scalable to a decagram scale and has enabled access to large quantities of a variety of truxinic ester products. Using a liquid-liquid slug flow strategy greatly accelerated reactivity by nearly four-fold in most cases and has allowed for an expansion of the substrate scope to include historically unreactive substrates such as cinnamamide dimers. This rate increase is attributed to improved mixing and an organic thin film known to occur within these systems. More recently, this flow methodology has been further developed to enable access to various heterodimers similar to those found in various bioactive natural products in a simple and efficient manner by using a cinnamic acid monomer in combination with an excess of cinnamic ester or amide monomer. The heterodimer can be easily separated from the homodimers and unreacted ester or amide monomers through an acid-base workup. Finally, to demonstrate the utility of these methodologies for biological exploration, a small library of truxinic amides was synthesized and underwent biological testing in breast cancer cell lines. Single dose inhibition data showed promising anti-cancer activity. Lastly, this methodology has also been applied to the synthesis of two interesting bioactive natural products, eucommicin A and piperarborenine D in an efficient modular fashion in both cases. These syntheses open the doors to future SAR studies which have yet to be performed on these and most truxinic and truxillic acid derived natural products. / 2020-02-15T00:00:00Z

No description available.

No description available.

<p>Continuous flow synthesis provides an efficient, rapidly scalable, safer, and improved synthetic route over traditional batch synthesis owing to enhanced heat and mass transfer. High throughput experimentation (HTE) is a powerful tool to discover novel reaction conditions and optimize challenging transformations in significantly small amount of time and by exploring multiple arrays of reactions. The utilization of desorption electrospray ionization mass spectrometry (DESI-MS) couple to HTE enables the exploration of 384 unique reaction conditions in just ~7 minutes. Chapter 1 highlights the different organic transformations and the target-based synthesis that have been studied using the HTE in the literature. Validation of the HTE-DESI-MS was investigated by performing a large set of aldol reactions on triacetic acid lactone (TAL), a compound well studied for use as a bio-based platform molecule which can be transformed to a range of valuable agrochemicals, commodity chemicals and intermediates for pharmaceutical industry. Two different active pharmaceutical ingredients namely, HSN-608 and Lorazepam have been synthesized using continuous manufacturing. HTE-DESI MS tools were utilized for rapid reaction screening for Sonogashira couplings for the development of telescoped continuous flow synthesis of an alkynyl naphthyridine anti-cancer agent, HSN-608. It is a fms-like tyrosine kinase 3 (FLT-3) inhibitor, a drug-lead compound for potential treatment of acute myeloid leukemia. Furthermore, a 5-step continuous flow synthesis involving N-acylation, cyclization, N-oxidation, polonovski-type rearrangement, and hydrolysis has been developed for Lorazepam, an essential generic active pharmaceutical ingredient under shortage. Different synthetic routes scouting, and impurity profiling was done to propose the novel route that was further developed under continuous flow conditions with optimization of each step.</p>

Les mousses polymères appartiennent à la famille des mousses solides qui sont des matériaux polyvalents, largement utilisés dans un grand nombre d'applications telles que l'automobile, l'emballage, produits de sport, isolants thermiques et acoustiques ou l'ingénierie tissulaire. Composé de bulles d'air piégées dans un réseau continu solide, elles allient les propriétés du polymère avec ceux de la mousse pour créer un matériau intéressant et complexe. L'intégration d'une mousse dans un réseau de polymère permet non seulement d'utiliser la vaste gamme de propriétés intéressantes offertes par les polymères, mais permet aussi de profiter des propriétés avantageuses des mousse telles que la légèreté, la faible densité, la compressibilité et un rapport surface/volume grande surface élevé. En général, les propriétés des mousses polymères sont fortement liées à leur densité et leur structure (la taille des bulles, l’arrangement des bulles dans l’espace, la structure des cellules ouvertes ou fermées). Le contrôle des propriétés finales de ces mousses est donc régi par le contrôle de sa densité et sa structure.Nous avons développé une technique dans laquelle des mousses solides sont générées essentiellement suivant un processus à deux étapes dans lequel une mousse liquide suffisamment stable ayant des propriétés bien contrôlées est générée dans une première étape, puis solidifiée. Avec une telle approche, la production des mousses solides peut être divisé en un certain nombre de sous-tâches qui peuvent être contrôlées et optimisées séparément.Le passage de l'état liquide à l'état solide est essentiellement composé de trois étapes principales: la production de la mousse, le mélange des réactifs et la solidification de la mousse. Ce dernier nécessite l'optimisation de la stabilité de la mousse et des paramètres expérimentaux tels que le choix du temps de moussage et de solidification. En outre, une bonne homogénéité de la mousse polymère appelle à un bon mélange des différents réactifs impliqués dans la formulation de la mousse et de la polymérisation.Une illustration des avantages de cette approche est donnée par la solidification de mousses liquides monodisperses générées à l’aide de la technique millifluidique. Dans une telle mousse, des bulles de volume égal, s’auto-organisent sous l’effet de la gravité et du confinement pour former des structures cristallines. Ainsi, les mousses monodisperses permettent d’avoir un contrôle simultanément sur la taille et la distribution des bulles du matériau poreux final, ce qui donne lieu à une meilleure compréhension de la corrélation entre sa structure et ses propriétés. L’objectif de cette étude est donc d'explorer le nouveau spectre de propriétés, que des mousses polymère offrent lorsque l’on y introduit une structure ordonnée et de démontrer la faisabilité de cette approche à deux étapes pour différentes classes de polymères (hydrogel, polymère super-absorbant et polyuréthane).La génération de ces mousses polymères structurées a été réalisée à l’aide d’un laboratoire sur puce qui permet le rétrécissement des dispositifs expérimentaux à l'échelle micro / millimétrique. Il permet également l’injection et le mélange divers ingrédients liquides et gazeux de la mousse. / Polymer foams belong to the solid foams family which are versatile materials, extensively used for a large number of applications such as automotive, packaging, sport products, thermal and acoustic insulators, tissue engineering or liquid absorbents. Composed of air bubbles entrapped in a continuous solid network, they combine the properties of the polymer with those of the foam to create an intriguing and complex material. Incorporating a foam into a polymer network not only allows one to use the wide range of interesting properties that the polymer offers, but also permits to profit from the advantageous properties of foam including lightness, low density, compressibility and high surface-to-volume ratio. Generally, the properties of polymer foams are strongly related to their density and their structure (bubble size and size distribution, bubble arrangement, open vs closed cells). Having a good control over foam properties is thus achieved by first controlling its density and structure.We developed a technique in which solid foams are generated essentially in a two-step process: a sufficiently stable liquid foam with well-controlled structural properties is generated in a first step, and then solidified in a second one. With such a two-step approach, the generation of solid foams can be divided into a number of well-separated sub-tasks which can be controlled and optimised separately. The transition from liquid to solid state is a sensitive issue of a great importance and therefore needs to be controlled with sufficient accuracy. It is essentially composed of three key steps: foam generation, mixing of reactants and foam solidification and requires the optimisation of foam stability in conjunction with an appropriate choice of both foaming time and solidification time. Furthermore, a good homogeneity of the polymer foam calls for a good mixing of the different reactants involved in the foaming and the polymerisation.A particularly powerful demonstration of the advantages of this approach is given by solidifying monodisperse liquid foams generated using millifluidic technique, in which all bubbles have the same size. In a liquid foam, equal-volume bubbles self-order into periodic, close-packed structures under gravity or confinement. As such, monodisperse foams provide simultaneous control over the size and the organisation of the pores in the final solid with an accuracy which is expected to give rise to a better understanding of the structure-property relationship of porous solids and to the development of new porous materials.We therefore aim to explore the new spectrum of properties, which polymer foams offer when we introduce an ordered structure into them since the most widely used polymer foams nowadays have disordered structures. The goal of our study is to demonstrate the feasibility of this two-step approach for different classes of polymers, including biomolecular hydrogel, superabsorbent polymer and polyurethane.For the generation of the structured polymer foams we use Lab-on-a-Chip technologies which allow the “shrinking” of large-scale set-ups to micro/millimetic scale. It permits also to perform “flow chemistry” in which the various liquid and gaseous ingredients of the foam are injected and mixed in a purpose-designed network of the micro- and millifluidic Lab-on-a-Chip. We adjust this approach according to the requirements of each polymer system, i.e. the foaming and the mixing techniques are chosen to fit the properties of each system, and can be exchanged to fit the properties of the studied systems.

Over the last two centuries, the discovery and application of catalysts has had a substantial impact on how and what chemicals are produced.Given their broad significance, our group has focused on developing new catalyst systems that are recoverable and reusable, in an attempt to reduce concomitant costs. Our efforts have centered on constructing a recyclable chiral heterogeneous catalyst capable of effecting asymmetric hydrogenations of olefins with high stereoselectivity. A class of phosphinoimidazoline ligands, developed by researchers at Boehringer-Ingelheim, known as BIPI ligands, have proven efficacious in the asymmetric reduction of alkenes. However, these chiral ligands are homogeneous and coordinated to precious metals, rendering them irrecoverable and expensive. To address these issues, our group has derivatized the BIPI ligand-metal complex and immobilized it to the surface of graphene oxide as well as polystyrene. Their efficacy and recyclability toward the asymmetric hydrogenation of a functionalized olefin have been evaluated. Another facet of our work has included developing a cost effective synthetic process to artemisinin, the gold standard drug in the treatment of malaria.As a natural product, artemisinin’s worldwide supply remains highly unpredictable, contributing to great price volatility.Combining the benefits of catalysis and the advantages of continuous flow chemistry, our research has sought to develop an economical approach to convert a biosynthetic precursor, artemisinic acid, to artemisinin in three chemical transformations. High-throughput experimentation allowed us to screen a prodigious number of catalysts and identify those effective in the asymmetric hydrogenation artemisinic acid to dihydroartemisinic acid, the first step in the transformation. This screening directed us to an inexpensive, heterogeneous ruthenium catalyst. The second step of the process includes the photooxygenation of dihydroartemisinic acid, which involves photochemically generated singlet oxygen. We have evaluated a commercially available heterogeneous photocatalyst packed in a transparent bed, surrounded by light emitting diodes in the continuous photooxygenation of dihydroartemisinic acid to dihydroartemisinic acid hydroperoxide. The third and final step, an acid induced hock cleavage, initiates an intricate cascading reaction that installs an endoperoxide bridge to deliver artemisinin. Our process afforded a 57% yield from dihydroartemisinic acid to artemisinin.