This thesis aims to investigate the use of additive manufacturing (AM) as a novel manufacturing process for the production of milli-scale chemical reaction systems. Five well developed additive manufacturing techniques; stereolithography (SL), selective laser melting (SLM), fused deposition modelling (FDM), ultrasonic additive manufacture (UAM) and selective laser sintering (SLS) were used to manufacture a number of miniaturised flow devices which were tested using a range of organic and inorganic reactions. SL was used to manufacture a range of functioning milli-scale flow devices from Accura 60 photoresin, with both simple and complex internal channel networks. These devices were used to perform a range of organic and inorganic reactions, including aldehyde and ketone functional group interconversions. Conversion of products within these reactors, were shown to be comparable to commercially available milli-scale coil reactors. More complex designs, which allowed SL parts to be integrated to existing flow and analytical instrumentation, allowed us to develop an automated reaction analysis and optimisation platform. This platform allowed precise control over the reaction conditions, including flow rate, temperature and reagent composition. We also designed a simplex type reaction optimisation software package that could input data in the form of reaction conversions, peak intensities, and thermocouple data, and generate a new set of optimal reaction conditions. SL parts which incorporated embedded analytical components were also manufactured, which allowed us to perform inline reaction analysis as a feedback method for input into the optimisation platform. Stereolithography was shown to be a highly versatile manufacturing method for designing and producing these flow devices, however the process was shown to be still limited by the range of processable materials currently commercially available. SLM was also used to manufacture a number of functioning milli-scale flow devices from stainless steel and titanium, which had simplistic internal channel designs of diameters ranging from 1 to 3 mm. Again, SLM parts were manufactured which incorporated embedded analytical components, which could be integrated into an automated reaction platform. These devices, unlike parts produced via SL, could be attached to heating platforms to allow us to perform high temperature reactions. This control over the reaction temperature formed an essential part of the reaction optimisation platform. These parts were again used to perform a ketone functional group interconversion. Internal structures of these SLM parts were also visualised via micro computed tomography (μCT or microCT) scanning as well as optical microscopy. FDM was used throughout the project as an inexpensive method of prototyping parts which were to be manufactured via more expensive manufacturing processes. This prototyping allowed the optimisation of intricate design features, such as the manufacture of an inline spectroscopic flow cell for integration with a commercially available LC system. FDM was also proposed as a customisable approach to designing and manufacturing flow devices with embedded components, however the current limitations in build resolution and materials choices severely limited the use of FDM for this application. UAM was also proposed as a novel manufacturing process whereby the build process would allow discrete components to be embedded directly into a flow channel. This was demonstrated by embedding a type-k thermocouple across a 2 mm channel. The data from this thermocouple was monitored during a heated reaction, and used as a method of determining the exact reaction conditions the reaction medium was being exposed to. SLS was also proposed as a possible manufacturing method for milli-scale flow devices, however it proved difficult to remove un-sintered powder from parts with internal channel diameters as high as 5 mm. It was shown that this powder was forming a dense semi solid, due to the large degree of shrinkage upon cooling of the SLS parts, which was compressing the powder. More research into optimum processing conditions is required before SLS could be used for the production of intricate channel networks.

No description available.

To make chemical analysis available both practically and economically, one approach is to miniaturise the equipment needed for the analysis. High-performance liquid chromatography (HPLC) is an example of a flow chemistry analysis system where active work is performed to achieve miniaturised systems. In this thesis, the focus is on creating a miniatyrised pump system constructed of pressurised CO2 (PCO) and a microfluidic chip with a restriction channel. The assignment of the PCO is to force a separate medium, which in this case is water, through the remaining system. The pump system will therefore be defined as pressure-driven, which has advantages as pulse-free flows. Utilising the latent energy from the PCO also reduces the need for electrical power, hence allowing a smaller battery. However, the pressure from the carbon dioxide source will gradually decrease as the content is consumed. To obtain continuous pressure, heaters have been integrated into the chip, and thus, the pressure drop can be controlled by changing the viscosity and density of the through-flowing fluid. A cooling table was also used to enable the cooling of the chip and thus further increase the pressure drop. PID control was implemented for the temperature to be adjusted to maintain a constant pressure downstream of the chip. By using this technology, runs of just over 80 minutes have been achieved with a pressure of 60 bar and a flow of 100 µl/min downstream, with a maximal error of around 0.03 bar. Then a chip adapted for water was used to control the water flow. Chips adapted for carbon dioxide placed right after the carbon dioxide source were also tested andruns of just over 10 minutes at 75 bar and 100 µl/min could be achieved with a maximal error closer to 1 bar. The pressure vessel used held a maximum of 100 ml of CO2 at 60 bar. The idea is that the pump system, in the end, will be applied for portable HPLC, and the PCO will then be stored in a cartridge, but in the experiments, a turned-off ISCO pump functioned as a carbon dioxide source.

<p dir="ltr">The present work seeks to use High Throughput Experimentation (HTE) and continuous flow chemistry as tools to guide drug discovery and development. HTE allows for the grouping, miniaturization and automation of common operations so that hundreds of experiments can be done simultaneously employing less reagents and less time and promoting faster reaction optimization. Continuous flow chemistry provides a greater surface-area-to-volume ratio relative to batch synthesis, promoting greater mixing and heat transfer. Furthermore, it is a complete closed system protected from air exposure and light, ideal for the synthesis of light and oxygen sensitive, as well as toxic compounds. In this context, two themes on this work are Stargardt disease and the use of HTE and continuous flow for the green synthesis of small molecules. Chapter One introduces Stargardt disease and its key culprit, A2E. Through Chapter Two, we revisited the synthesis of A2E and utilized HTE and continuous flow to optimize the classical synthesis from 48 h to a residence time of 33 min, and yield from 49 to 78%. On Chapter Three, we studied the design and synthesis of IRE1 inhibitors for potential treatment of Stargardt disease. Our molecular docking approach afforded us the design of 66 compounds that were synthesized with the aid of HTE for reaction optimization and were evaluated by RT-qPCR and viability assays. Our studies indicated that three of our inhibitors have lower IC_50s than KIRA6 at inhibiting IRE1 activity in retinal cells. On Chapter Four we introduced the use continuous flow chemistry to make a process greener by revisiting the synthesis of Lomustine. Our method substituted DCM for a mixture of two green solvents, 2MeTHF and acetic acid as well as improved the yield and productivity of the reaction by increasing the solubility of the reaction intermediate produced. Finally, in Chapter Five, we studied the use of HTE to guide catalyst and solvent selection for development of a green synthesis of benzamides. Our method was further optimized by the use of microwave heating and was able to convert sterically hindered amines and carboxylic acids into the corresponding benzamides.</p>

L’attrait des compagnies pharmaceutiques pour des structures cycliques possédant des propriétés biologiques intéressantes par les compagnies pharmaceutiques a orienté les projets décrits dans ce mémoire. La synthèse rapide, efficace, verte et économique de ces structures suscite de plus en plus d’attention dans la littérature en raison des cibles biologiques visées qui deviennent de plus en plus complexes. Ce mémoire se divise en deux projets ciblant la synthèse de deux structures aromatiques importantes dans le monde de la chimie médicinale. Dans un premier temps, l’amélioration de la synthèse de dérivés phénoliques a été réalisée. L’apport de la chimie en flux continu dans le développement de voies synthétiques plus vertes et efficaces sera tout d’abord discuté. Ensuite, une revue des antécédents concernant l’hydroxylation d’halogénure d’aryle sera effectuée. Finalement, le développement d’une nouvelle approche rapide de synthèse des phénols utilisant la chimie en flux continu sera présenté, suivi d’un survol de ses avantages et ses limitations. Dans un deuxième temps, le développement d’une nouvelle méthodologie pour la formation de 3-aminoindazoles a été réalisé. Tout d’abord, un résumé de la littérature sur la synthèse de différents indazoles sera présenté. Ensuite, une présentation de deux méthodes efficaces d’activation de liens sera effectuée, soit l’activation d’amides par l’anhydride triflique et l’activation de liens C–H catalysée par des métaux de transition. Finalement, le développement d’une nouvelle méthodologie pour la synthèse de 3-aminoindazole utilisant ces deux approches sera discuté. / The continuous attraction towards accessing cyclic structures that possess interesting biological properties by pharmaceutical companies has guided the projects described in this M.Sc. thesis. Due to the increasing complexity of drug targets, methodologies encompassing efficient, rapid, economical and environmentally friendly syntheses are highly sought in the organic chemistry literature. The present work consists of two projects targeting the synthesis of two important aromatic structures in the field of medicinal chemistry. The first part of the thesis will present an improved synthesis of phenol derivatives. The recent chemical contributions in the continuous development of greener and efficient synthetic routes will be discussed, followed by a quick review of the literature on the hydroxylation of aryl halides. Then, the development of a new approach for rapid synthesis of phenol derivatives using continuous flow chemistry will be presented, including an overview of its benefits and limitations. The second part of the thesis will put forward the development of a novel methodology for the formation of 3-aminoindazoles. A summary of the literature on the synthesis of various indazoles will be presented, followed by an overview of two effective bond activation methods: the amide activation using triflic anhydride and transition metal catalyzed C–H activation. Finally, the evolution of a new method for the synthesis of 3-aminoindazole using the previously mentioned two approaches will be discussed.

No description available.

No description available.

La réaction de macrocyclisation est une transformation fondamentale en chimie organique de synthèse. Le principal défi associcé à la formation de macrocycles est la compétition inhérente avec la réaction d’oligomérisation qui mène à la formation de sousproduits indésirables. De plus, l’utilisation de conditions de dilutions élevées qui sont nécessaires afin d’obtenir une cyclisation “sélective”, sont souvent décourageantes pour les applications à l’échelle industrielle. Malgré cet intérêt pour les macrocycles, la recherche visant à développer des stratégies environnementalement bénignes, qui permettent d’utiliser des concentrations normales pour leur synthèse, sont encore rares. Cette thèse décrit le développement d’une nouvelle approche générale visant à améliorer l’efficacité des réactions de macrocyclisation en utilisant le contrôle des effets de dilution. Une stratégie de “séparation de phase” qui permet de réaliser des réactions à des concentrations plus élevées a été developpée. Elle se base sur un mélange de solvant aggrégé contrôlé par les propriétés du poly(éthylène glycol) (PEG). Des études de tension de surface, spectroscopie UV et tagging chimique ont été réalisées afin d’élucider le mécanisme de “séparation de phase”. Il est proposé que celui-ci fonctionne par diffusion lente du substrat organique vers la phase ou le catalyseur est actif. La nature du polymère co-solvant joue donc un rôle crutial dans le contrôle de l’aggrégation et de la catalyse La stratégie de “séparation de phase” a initiallement été étudiée en utilisant le couplage oxidatif d’alcynes de type Glaser-Hay co-catalysé par un complexe de cuivre et de nickel puis a été transposée à la chimie en flux continu. Elle fut ensuite appliquée à la cycloaddition d’alcynes et d’azotures catalysée par un complexe de cuivre en “batch” ainsi qu’en flux continu. / Macrocyclization is a fundamentally important transformation in organic synthetic chemistry. The main challenge associated with the synthesis of large ring compounds is the competing oligomerization processes that lead to unwanted side-products. Moreover, the high dilution conditions needed to achieved “selective” cyclization are often daunting for industrial applications. Despite the level of interest in macrocycles, research aimed at developing sustainable strategies that focus on catalysis at high concentrations in macrocyclization are still rare. The following thesis describes the development of a novel approach aimed at improving the efficiency of macrocyclization reactions through the control of dilution effects. A “phase separation” strategy that allows for macrocyclization to be conducted at higher concentrations was developped. It relies on an aggregated solvent mixture controlled by a poly(ethylene glycol) (PEG) co-solvent. Insight into the mechanism of “phase separation” was probed using surface tension measurments, UV spectroscopy and chemical tagging. It was proposed to function by allowing slow diffusion of an organic substrate to the phase where the catalyst is active. Consequently, the nature of the polymer co-solvent plays a role in controlling both aggregation and catalysis. The “phase separation” strategy was initially developed using the copper and nickel co-catalyzed Glaser-Hay oxidative coupling of terminal alkynes in batch and was also transposed to continuous flow conditions. The “phase separation” strategy was then applied to the copper-catalyzed alkyne-azide cycloaddition in both batch and continuous flow.

Les composés aminés représentent une grande part des substances actives en chimie médicinale. Les travaux rapportés dans cette thèse décrivent les efforts consacrés au développement d’une nouvelle méthode d’amination de liens C-H propargyliques. Notre groupe de recherche a développé depuis quelques années un nouveau précurseur de nitrène métallique, les N-mésyloxycarbamates, permettant d’effectuer des réactions d’amination de liaisons C-H diversement activées. Au cours du développement de notre méthodologie, la synthèse du N-mésyloxycarbamate a fait l’objet de nombreuses optimisations, notamment en améliorant l’échelle globale de la synthèse ainsi que son efficacité. De même, des efforts ont été consacrés pour diminuer le nombre d’étapes nécessaires à la synthèse du réactif en développant la synthèse d’un des intermédiaires de manière énantiosélective. Enfin, la synthèse de ce réactif a également été envisagée à l’aide de la chimie en flux continu. Au cours du développement de la méthode de synthèse d’amines propargyliques, nous avons constaté que l’acide acétique jouait un rôle déterminant dans la conservation de bonnes sélectivités et réactivités de la réaction. Ces différentes observations ont permis de mettre au point un procédé diastéréosélectif efficace permettant d’obtenir des amines propargyliques avec des rendements allant de moyens à bons et avec d’excellentes diastéréosélectivités. A la suite de l’étude de l’étendue de notre procédé, nous avons tenté de déterminer les mécanismes réactionnels qui régissaient la réactivité et la sélectivité de celui-ci. Nous avons ainsi montré que l’espèce réactive du système catalytique était bel et bien un nitrène métallique, et que l’étape cinétiquement déterminante était celle d’insertion. Des expériences faites en oxydant l’espèce catalytique de rhodium ont suggéré que plusieurs états d’oxydation de cette espèce peuvent être présents et actifs dans le système catalytique. / The nitrogen containing compounds represent a large portion of the active substances in medicinal chemistry. The work reported in this manuscript describe the efforts devoted to the development of a new method of amination of propargylic C-H bonds. Our research group has developed recently a new metal nitrene precursor, N-mesyloxycarbamates, to perform amination reactions on various C-H bonds. During the development of our methodology, the synthesis of N-mesyloxycarbamate has undergone many improvements, including improved global scale synthesis and effectiveness. Similarly, efforts were devoted to reduce the number of steps required for the synthesis of the reagent by developing the synthesis of an intermediate enantioselectively. Finally, the synthesis of this reagent was also considered using continuous flow chemistry. During development of the method of synthesis of propargylic amines, we have found that acetic acid plays a key role in the conservation of good selectivity and reactivity of the reaction. These observations allowed to develop an efficient diastereoselective process in order to obtain propargylic amines with moderate to good yields and with excellent diastereoselectivities. Following the study of the scope of our process, we tried to determine the reaction mechanisms governing the reactivity and selectivity. We have shown that the reactive species of the catalyst system was indeed a metal nitrene, and that the rate-determining step was the insertion. Experiments made by oxidizing the rhodium catalytic species suggested that several oxidation states of this species may be present and active in the catalytic system.