In recent years, chemistry in flowing systems has become more prominent as a method of carrying out chemical transformations, ranging in scale from analytical-scale (microchemistry) through to kilogram-scale synthesis (macrochemistry). The advantages are readily apparentincreased control of conditions leading to greater reproducibility, scaleability, and increased safety/reduced lossalthough its acceptance as a viable synthesis technique has been limited due to its drawbacks, primarily precipitation, liquid handling, and diffusion of the reaction within the reactor. Here, we present details of a system which bridges the gap between micro- and macroreactors and has enabled fast reaction optimisation (using small amounts of reagents) and subsequent multigram scale-up using a commercial reactor.

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Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provide small amounts of pharmaceutically interesting fragments via a safe and scalable route, which would enable the rapid synthesis of multigram quantities on demand. Here we report a general and versatile route which utilises flow chemistry to deliver a range of known and novel indazoles, including 3-amino and 3-hydroxy analogues. ' INTRODUCTIONAs part of an ongoing medicinal chemistry program, we were interested in synthesising a range of 5-and 6-substituted N-methylindazoles (1), which can be synthesised via the condensation of methylhydrazine with the corresponding 2-fluorobenzaldehyde (scheme 1). This approach was particularly attractive to us due to the relatively large set of commercial 2-fluorobenzaldehydes available, but we were surprised to find the reaction is not widely precedented, and we were only able to locate isolated examples in the literature. 1 Condensations with hydrazine are slightly more common, and although recent publications by Lukin 2 and Slade 3 demonstrate the versatility of the reaction, the yields are variable (0-82% and 38-66%, respectively) and the reaction times long (3-36 h). We also reasoned that this approach could be applied to give 3-aminoindazoles (2) and 3-hydroxyindazoles (3) from 2-fluorobenzonitriles and benzoates respectively (scheme 1). Once again, we were surprised to learn that, although the S N Ar condensation between hydrazines and 2-fluorobenzonitriles is fairly well reported, 4 there are very few reported procedures for the synthesis of 3-hydroxyindazoles from 2-fluorobenzoates. 5 Additionally, we hoped to identify a generic route which would utilise unsubstituted hydrazine, thus enabling us to diversify around the 1-position at a later date. However, the hazards with using hydrazines under forcing conditions are well-known, 6 and this issue, together with the long reaction times cited in the literature, pointed towards a potentially scale-limited route.We therefore considered utilising flow chemistry techniques as a means of providing a safe, scalable alternative in order to deliver the small quantities of monomers required, and also to facilitate scale-up on-demand. Flow chemistry reactions are now widely documented in the literature, 7,8 and the technology is becoming increasingly prominent in the pharmaceutical industry. 9 Our group has previously demonstrated the use of flow reactors to safely control reaction exotherms, 10 and also the use of flow microwaves to achieve selective bromination of a substituted benzene. 11 Indeed, one of the perceived advantages of flow chemistry is the ability to safely perform reactions at elevated temperatures and pressures, and as such it is often compared to microwave synthesis. 12 We aimed to exploit this appro...

Microwave-assisted organic synthesis in a laboratory-scale monomodal microwave reactor is investigated for continuous flow applications using fluorous spacer technology. The benchtop continuous flow microwave described allows sequential processing of multiple plugs using small amounts of reagents for reaction optimization, scale-up and array synthesis. The system features online monitoring of temperature, pressure and microwave power. Several different reactions have been scaled up, including a Suzuki-Miyaura cross-coupling reaction and nucleophilic substitutions. In all cases it was possible to optimize the reaction conditions on a small scale (∼300 µL processing volume), and achieve similar conversions on an intermediate scale (∼30 mL), offering the potential for further scale-up without modifying the optimized conditions (direct scalability) producing similar isolated yields in the C-C bond formation reaction.

This paper reports a novel evaporator and its integration with an automated sample handling system to create a high throughput evaporation platform. The Vaportec V-10 evaporator uses a high speed rotation motor ( approximately 6000 rpm) to spin the vial containing a sample, creating a thin film of solvent which can be readily evaporated by the application of heat to the vial, while the consequent centrifugal force prevents "bumping". An intelligent algorithm controls pressure and temperature for optimum solvent removal conditions and end of run detection, critical for automation. The system allows the option of evaporation directly from a sample source vial, or alternatively, integrated liquid handling facilities provide the capability of transferring samples portionwise from a (large) source vial or bottle to a (small) daughter container, enabling efficient sample reformatting, with minimum user intervention. The open access system makes significant advances over current vacuum centrifugal evaporators in terms of evaporation rate and ease of automation. The evaporator's main features, the integration of robotics to provide automation, and examples of evaporation rates of a wide range of solvents from a variety of containers are described.