Ask the experts: the challenges and benefits of flow chemistry to optimize drug development.

Against a backdrop of a struggling economic and regulatory climate, pharmaceutical companies have recently been forced to develop new ways to provide more efficient technology to meet the demands of a competitive drug industry. This issue, coupled with an increase in patent legislation and a rising generics market, makes these themes common issues in the growth of drug development. As a consequence, the importance of process chemistry and scale-up has never been more under the spotlight. Future Medicinal Chemistry wishes to share the thoughts and opinions of a variety of experts from this field, discussing issues concerning the use of flow chemistry to optimize drug development, the potential regulatory and environmental challenges faced with this, and whether the academic and industrial sectors could benefit from a more harmonized system relevant to process chemistry.

Solid-supported gallium triflate: an efficient catalyst for the three-component ketonic Strecker reaction.

In light of the growing interest in the use of rare earth metal triflates as water-tolerant Lewis acid catalysts, we embarked upon the development of a solid-supported gallium triflate (PS-Ga(OTf)(2) ) derivative as a means of increasing the cleanliness and cost effectiveness of using these increasingly expensive catalytic materials in synthetic processes. Having previously highlighted the advantages associated with coupling solid-supported catalysis and the emerging area of micro-reaction technology, we screened PS-Ga(OTf)(2) for activity towards the ketonic Strecker reaction, in which the target α-aminonitriles were obtained in higher yield and purity compared to reactions reported in literature, in which the analogous homogeneous catalyst was used.

Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated S(N)Ar reaction.

Whilst microwave heating has been widely demonstrated as a synthetically useful tool for rapid reaction screening, a microwave-absorbing solvent is often required in order to achieve efficient reactant heating. In comparison, microreactors can be readily heated and pressurised in order to "super-heat" the reaction mixture, meaning that microwave-transparent solvents can also be employed. To demonstrate the advantages associated with microreaction technology a series of S(N)Ar reactions were performed under continuous flow by following previously developed microwave protocols as a starting point for the investigation. By this approach, an automated microreaction platform (Labtrix(®) S1) was employed for the continuous flow synthesis of diaryl ethers at 195 °C and 25 bar, affording a reduction in reaction time from tens of minutes to 60 s when compared with a stopped-flow microwave reactor.

Recent advances in micro reaction technology.

It is the intention of this review to provide the reader with a survey of the current literature pertaining to the use of micro reactors in synthetic chemistry; recent advances are briefly discussed, with references provided to assist with further reading on this rapidly growing research topic.

Improved method for kinetic studies in microreactors using flow manipulation and noninvasive Raman spectrometry.

A novel method has been devised to derive kinetic information about reactions in microfluidic systems. Advantages have been demonstrated over conventional procedures for a Knoevenagel condensation reaction in terms of the time required to obtain the data (fivefold reduction) and the efficient use of reagents (tenfold reduction). The procedure is based on a step change from a low (e.g., 0.6 µL min(-1)) to a high (e.g., 14 µL min(-1)) flow rate and real-time noninvasive Raman measurements at the end of the flow line, which allows location-specific information to be obtained without the need to move the measurement probe along the microreactor channel. To validate the method, values of the effective reaction order n were obtained employing two different experimental methodologies. Using these values of n, rate constants k were calculated and compared. The values of k derived from the proposed method at 10 and 40 °C were 0.0356 ± 0.0008 mol(-0.3) dm(0.9) s(-1) (n = 1.3) and 0.24 ± 0.018 mol(-0.1) dm(0.3) s(-1) (n = 1.1), respectively, whereas the values obtained using a more laborious conventional methodology were 0.0335 ± 0.0032 mol(-0.4) dm(1.2) s(-1) (n = 1.4) at 10 °C and 0.244 ± 0.032 mol(-0.3) dm(0.9) s(-1) (n = 1.3) at 40 °C. The new approach is not limited to analysis by Raman spectrometry and can be used with different techniques that can be incorporated into the end of the flow path to provide rapid measurements.

The development and evaluation of a continuous flow process for the lipase-mediated oxidation of alkenes.

We report the use of an immobilised form of Candida antarctica lipase B, Novozym((R)) 435, in a preliminary investigation into the development of a continuous flow reactor capable of performing the chemo-enzymatic oxidation of alkenes in high yield and purity, utilising the commercially available oxidant hydrogen peroxide (100 volumes). Initial investigations focussed on the lipase-mediated oxidation of 1-methylcyclohexene, with the optimised reaction conditions subsequently employed for the epoxidation of an array of aromatic and aliphatic alkenes in 97.6 to 99.5% yield and quantitative purity.

A microreactor for the study of biotransformations by a cross-linked gamma-lactamase enzyme.

A (+)-gamma-lactamase was precipitated, cross-linked and the resulting solid crushed prior to immobilisation within a capillary column microreactor. The microreactor was subsequently used to study enzyme stability, activity, kinetics and substrate specificity. The thermophilic (+)-gamma-lactamase retained 100% of its initial activity at the assay temperature, 80 degrees C, for 6 h and retained 52% activity after 10 h, indicating the advantage of immobilisation. This high stability of the immobilised enzyme provided the advantage that it could be utilised to screen many compounds in the microreactor system. This advantage overcame the fact that the immobilisation process affected enzyme kinetics and activity, which was reduced (by 70%) compared to the free enzyme. In general, the enzyme displayed similar substrate specificity to that found in a previous study for the free enzyme; however, enhanced activity was seen towards one substrate, acrylamide. The system developed correlates well with the free enzyme in batch assay and indicates the suitability of the system for enzyme substrate screening, allowing a significant reduction in cost, due to the reduced amounts of enzyme, substrates and other assay constituents required.

Continuous-flow organic synthesis: a tool for the modern medicinal chemist.

Medicinal chemists are under increasing pressure, not only to identify lead compounds and optimize them into clinical candidates, but also to produce materials in sufficient quantities for subsequent investigation. With this in mind, continuous-flow methodology presents an opportunity to reduce the time taken to, first, identify the compound and, second, scale the process for evaluation and, where necessary, production. It is therefore the aim of this review to provide the reader with an insight into the advantages associated with the use of continuous-flow chemistry through the use of strategically selected literature examples.

An optical sensor for reactive oxygen species: encapsulation of functionalised silica nanoparticles into silicate nanoprobes to reduce fluorophore leaching.

Sol-gel nanoprobes, also known as Photonic Explorer for Bioanalysis with Biologically Localised Embedding (PEBBLE), capable of performing in-vitro intracellular monitoring of reactive oxygen species have been developed using a modified form of 5(6)-carboxyfluorescein diacetate. A sol-gel matrix was selected for the design of the probes as it is photostable, optically transparent and chemically inert, and to minimise leaching of the dye from the porous matrix it was covalently immobilised to silica nanoparticles (15 nm). Using this approach, 0.1% of the dye was found to leach over a typical analysis time of 5 h and minimal photobleaching was observed. In addition, the nanoprobes were shown to respond to hydrogen peroxide, hydroxyl anions, nitric oxide, peroxynitrile and superoxide anions, obtaining limits of detection of 2.2, 1.1, 3.2, 1.1 and 1.1 nM respectively. The nanoprobes were subsequently introduced into bovine oviducts using a lipid transfection reagent (Escort IV) and fluorescence was observed.

The use of solid-supported reagents for the multi-step synthesis of analytically pure alpha,beta-unsaturated compounds in miniaturized flow reactors.

Micro reaction technology offers a safe, controllable and information rich technique suitable for the long-term production of pharmaceutical agents and fine chemicals. To date however, few of the syntheses performed using this technology have addressed the problems associated with product purification. With this in mind, we report herein the incorporation of multiple supported reagents into EOF-based miniaturized flow reactors for the two-step synthesis of analytically pure compounds. Using this approach, the successful synthesis of 20 alpha,beta-unsaturated compounds in excellent yields (>99.1%) and purities (>99.9%) has been achieved, illustrating significant improvements compared to traditional batch techniques.

The use of electroosmotic flow as a pumping mechanism for semi-preparative scale continuous flow synthesis.

By employing a series of reactions we demonstrate the use of electroosmotic flow as a continuous pumping mechanism suitable for semi-preparative scale synthesis, affording an array of small organic compounds, of analytical purity, with yields ranging from 0.57-1.71 g h(-1).

Micro reactors: a new tool for the synthetic chemist.

This review focuses on the use of micro reactors as tools in synthetic organic chemistry, aiming to highlight the many advantages associated with their use, in particular their ability to synthesise products in high yield, purity and, where relevant, selectivity.

Recent advances in synthetic micro reaction technology.

Although in its infancy, the field of micro reaction technology is growing rapidly, with many research groups investigating the practical advantages associated with reaction miniaturisation. With this in mind, the following Feature Article aims to provide an overview of the progress made in the past decade, paying particular attention to the field of synthetic organic chemistry.

Parallel synthesis in an EOF-based micro reactor.

We present herein a micro reactor set-up that enables parallel syntheses to be performed under electroosmotic flow conditions.

Improving chemical synthesis using flow reactors.

Owing to the competitive nature of the pharmaceutical industry, researchers involved in lead compound generation are under continued pressure to identify and develop promising programmes of research in order to secure intellectual property. The potential of a compound for therapeutic development depends not only on structural complexity, but also on the identification of synthetic strategies that will enable the compound to be prepared on the desired scale. One approach that is of present interest to the pharmaceutical industry is the use of continuous flow reactors, with the flexible nature of the technology being particularly attractive as it bridges the changes in scale required between the initial identification of a target compound and its subsequent production. Based on these factors, a significant programme of research is presently underway into the development of flow reactors as tools for the synthetic chemist, with the transfer of many classes of reaction successfully reported to date. This article focuses on the application of continuous flow methodology to drug discovery and the subsequent production of pharmaceuticals.

Stereoselective alkylation of an Evans auxiliary derivative within a pressure-driven micro reactor.

A simple technique for the diastereoselective alkylation of a metal stabilised enolate is demonstrated within a pressure-driven micro reactor whereby enhanced diastereoselectivities were obtained compared to batch.

The regioselective preparation of 1,3-diketones within a micro reactor.

We demonstrate a simple method for the regioselective preparation of 1,3-diketones within a micro reactor from silyl enol ethers where the products are free from both competing O-acylation and diacylation products.

Investigation of racemisation in peptide synthesis within a micro reactor.

We demonstrate that peptides derived from alpha-amino acids may be prepared in a micro reactor. The peptides were prepared in 20 min with quantitative conversion, compared to batch reactions which require prolonged reaction times. We illustrate that by using dilute reagent concentrations and short reaction times, less racemisation is observed in micro reactions than in bulk reactions.

1,4-addition of enolates to alpha,beta-unsaturated ketones within a micro reactor.

We demonstrate the formation of a series of diketone enolates and their subsequent reaction with alpha,beta-unsaturated carbonyl compounds in order to prepare a variety of Michael adducts. In all cases, the conversions observed within a micro reactor were greater than those obtained in batch.