Development of a novel class of pharmacodynamic hybrids/no donors that targets cox-2 selectively and a machine-assisted flow procedure for the synthesis of meclinertant, a neurotensin receptor probe

The work described below is divided into two parts. In the first chapter, the development of a novel class of pharmacodynamic hybrids is discussed. These compounds are endowed with analgesic/anti-inflammatory properties along with their ability to release nitric oxide which makes them an important contribution to the development of effective COX-Inhibiting Nitric Oxide Donors. In the second chapter, the synthesis of an important neurotensin receptor antagonist (SR 48692, Meclinertant) is described. The synthesis of Meclinertant is achieved with the use of machine-assisted flow protocols through a robust, reliable and scalable route

Development of a novel class of pharmacodynamic hybrids/no donors that targets cox-2 selectively and a machine-assisted flow procedure for the synthesis of meclinertant, a neurotensin receptor probe

The work described below is divided into two parts. In the first chapter, the development of a novel class of pharmacodynamic hybrids is discussed. These compounds are endowed with analgesic/anti-inflammatory properties along with their ability to release nitric oxide which makes them an important contribution to the development of effective COX-Inhibiting Nitric Oxide Donors. In the second chapter, the synthesis of an important neurotensin receptor antagonist (SR 48692, Meclinertant) is described. The synthesis of Meclinertant is achieved with the use of machine-assisted flow protocols through a robust, reliable and scalable route

Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry.

When considering life's aetiology, the first questions that must be addressed are "how?" and "where?" were ostensibly complex molecules, considered necessary for life's beginning, constructed from simpler, more abundant feedstock molecules on primitive Earth. Previously, we have used multiple clues from the prebiotic synthetic requirements of (proto)biomolecules to pinpoint a set of closely related geochemical scenarios that are suggestive of flow and semi-batch chemistries. We now wish to report a multistep, uninterrupted synthesis of a key heterocycle (2-aminooxazole) en route to activated nucleotides starting from highly plausible, prebiotic feedstock molecules under conditions which mimic this scenario. Further consideration of the scenario has uncovered additional pertinent and novel aspects of prebiotic chemistry, which greatly enhance the efficiency and plausibility of the synthesis

Machine-Assisted Organic Synthesis.

In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies

Direct Oxidation of Csp3 -H bonds using in Situ Generated Trifluoromethylated Dioxirane in Flow.

A fast, scalable, and safer Csp 3 -H oxidation of activated and un-activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp3 -H bonds. The process exhibits a broad scope and good functional group compatibility (28 examples, 8-99 %). The scalability of this methodology is demonstrated on 2.5 g scale oxidation of adamantane.The authors gratefully acknowledge the Walloon region (Bel-gium)-DG06 (Convention no. 7240) for fundin

A multicomponent approach for the preparation of homoallylic alcohols.

Here we report the in situ generation of transient allylic boronic species, by reacting TMSCHN2 and E-vinyl boronic acids, followed by their subsequent trapping with aldehydes as electrophiles to yield homoallylic alcohols. This metal-free reaction was initially discovered by the use of a flow chemistry approach to generate a variety of homoallylic alcohols in a straightforward fashion and then transferred to a batch protocol.We are grateful to the Cambridge Home and European Scholarship Scheme (J. S. P.), Croucher Foundation (S. H. L.), the Swiss National Science Foundation (D. N. T.), Pfizer Worldwide Research & Development (C. B.), and the Engineering and Physical Sciences Research Council (S. V. L. grant no. EP/K0099494/1 and EP/K039520/1) for financial support.This is the final version of the article. It first appeared from RSC at http://dx.doi.org/10.1039/C6SC02581A

Solvent-Free Continuous Operations Using Small Footprint Reactors: A Key Approach for Process Intensification

A solvent-free approach to intensification of chemical processes is reported. This concept, in which reactions are carried out solvent-free, without the need for further downstream processing, was highlighted first with a full reduction of ethyl nicotinate to ethylpiperidine-3-carboxylate under continuous flow conditions. Using a small footprint reactor, a throughput of 26.4 g h–1 was achieved. Similarly, this approach was used for the telescoped two-step synthesis of 2-propyl phenol (productivity 120 g h–1) and 2-propyl cyclohexanone (productivity 30 g h–1), starting from the commercially available allyl phenol ether via Claisen rearrangement and subsequent reduction.We would like to thank Pfizer Worldwide Research & Development (CB), the EPSRC (RJM, SVL, Grant Codes EP/K009494/1, EP/M004120/1 and EP/K039520/1) and the Woolf Fisher Trust (DEF) for financial support.This is the final version of the article. It first appeared from the American Chemical Society via https://doi.org/10.1021/acssuschemeng.6b0028

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions.

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.We are grateful to the Swiss National Science Foundation (DNT), the Ralph Raphael fellowship (RJI), the German Academic Exchange Service DAAD (SF), the Royal Society Newton International Fellowship (ZEW), Pfizer Worldwide Research and Development (CB) and the EPSRC (SVL, SF and ZEW, grant nº EP/K0099494/1) for financial support. The Labtrix Start was kindly loaned by Chemtrix BV and the liquid-liquid phase separator by Zaiput Flow Technologies (we are grateful to Dr Andrea Adamo for technical support with this device).This is the final version. It was first published by the Royal Society of Chemistry at http://dx.doi.org/10.1039/C4OB02105

Cyclopropanation using flow-generated diazo compounds.

We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.We are grateful to Pfizer Worldwide Research and Development (CB, RJI and JMH), the Swiss National Science Foundation (DNT), CAPES (RL, no 9865/13-6) and the EPSRC (SVL, grant no EP/K0099494/1 and no EP/K039520/1) for financial support.This is the final published article, originally published in Organic & Biomolecular Chemistry, 2015,13, 2550-2554 DOI: 10.1039/C5OB00019