Microwave to Continuous Flow Tech Transfer

I’m not sure if it was in the generic scheme of the reactions performed, the authors of the work or the title translating microwave methods to flow that got me: truth is it was a bit of all three in a recent publication (Beilstein JOC 2011). The scheme had a para-nitro diaryl ether, which for me means an amine handle with multiple substitution patterns on both rings — reliving my sorafenib days at Bayer ( I did a lot of Ullmann reactions, uugh, although the microwave did prove handy!). The authors of course are front and center of the flow chemistry community and lastly there have been a number of papers taking microwave methods and transferring them into flow methods — and I do believe we will see more of these. It’s meaningful and there are advantages to both.

Although Dr. Watts and Dr. Wiles probably didn’t have kinase inhibitors in mind, the para-amino diaryl, heteroaryl motif and diaryl motif is found bountiful in the literature. So taking an illustration of a microwave model from JD Moseley (Org. Biomol. Chem., 2010) and later work by O. Kappe and JD Moseley (Green Chem 2011), they studied and compared micro-reactor and microwave approaches to the reaction scheme below:

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For a starting point, W/W point to the studies by M/K’s stop flow microwave conditions and point to the lack of energy benefit in using microwave conditions on a larger scale due to the limited penetration depth and lack of energy efficiency. Add to this in both a batch and stop-flow capacity where the heating and cooling in a microwave mode does not help the cause. All true, although I would point out that with auto-sampler and improved cooling in many of the latest microwave developments (Anton Paar, CEM), the man hours to make libraries of compounds would be the more efficient technology.

To perform the flow experiments, W/W used a Labtrix S1 (Chemtrix) (shown below). The system consists of a glass micro-reactor that is positioned on a thermally regulated stage, which enables reactions to be performed between −15 and 195 °C. Reagent solutions are delivered to the reactor through a series of syringe pumps (0.1 to 25 µL·min−1) and the system is maintained under a back pressure of 25 bar, which enables reactants and solvents to be heated above their atmospheric boiling point whilst staying in the liquid phase. The reactant flow rates, reactor temperature and sample collection point is automated and the system has an in-line pressure sensor that monitors the system pressure throughout the course of an investigation. The software enables the effect of reaction time, temperature and reactant stoichiometry to be investigated in an automated manner whilst the system is operated, unattended, within a fumehood — the software is something where the flow manufacturers have developed a much more extensive data retrieval and display compared to their microwave counterparts – although I do like the onboard screens on the microwave for daily operation.

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Using a two-feed system they are able to control the reactants, temperature, flow-rate and stoichiometry of the reagents and base during the studies with a reaction time of 10 minutes to compare to the microwave method. The first set of results were nearly identical to that of the mw method. While it is a side note, it is fair to mention that one of the positives of flow is that nearly all solvents can be used for experimentation and for microwaves, one has to choose how to handle the situation. Not all solvents absorb microwave energy….and with that, a choice of absorbing material or vessel will need to be made for the reaction conditions. The nice thing if you look at the conditions used, 195C with a max of 25 bar of pressure will allow most organic solvents as an option under these conditions (hexane, CH2Cl2, toluene, EtOH, EtOAc, Dioxane, MeCN, DMA) in a microwave set-up.

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Following the initial set of experiments, they found a reduction in reaction time for this reaction from 10 minutes to that of about 1 min to complete the reaction. In addition, MeCN was a suitable replacement for DMA — which will work for either technology. In addition, with the feedlines separating organic base for the other reactants, they screened a number of bases to identify the best choice with some striking differences in bases used. Although we can all probably decide in retrospect which bases would have or did provide the best results, the ability to screen and scope reactions provides an excellent way to move from small to large scale methods in a data driven format.

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Now that I talked about some of the basic features in the paper, I will leave the rest for you to dive into — there are additional efforts made to understand the reaction with several different substitution patterns, a move from organic bases to inorganic bases — a nice added value with biphasic aqueous inorganic bases used, where mixing can be employed in microfluid development of reaction conditions. This was a nice example of a transfer of technology from microwave to micro-reactor conditions with pluses in a number of areas — and some things to think about where microwave conditions can be used as the preferred method on small scale. Overall I think these are the things that should be discussed at length as a strategy is being developed for a particular project — both showing the capability as an enabling technology depending on the application need. Happy Reading!

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