Recent trends of Flow Chemistry #memo #chemistry #technology

I enjoyed reading the article in my lunch break. Researchers at Abbie published nice review about the flow chemistry in the pharmaceutical industry. The URL is below.

https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01760

The review describes wide range of the flow chemistry from large scale synthesis to lab scale synthesis.

Flow chemistry can run the reaction under high temperature and high pressure reaction conditions. Photo redox reaction is also available. I like rearrangement reactions because the reaction is atom economic and stereo selective I feel it is elegant. But theres reactions often requires high temperature condition. In scheme 10 shows example of Overman Rearrangement with flow. The example shows >95Kg scale synthesis in 84hr! Continuous synthesis is powerful tool for production.

One of the strong point of flow reaction is flush chemistry that can conduct reaction in very short time. It means the method can handle unstable(reactive) intermediates. In scheme 15 shows flow synthesis example of Eribulin intermediate. You know Eribulin is a laboratory-made form of halichondrin B, a substance. It has very complex structure. The researchers conducted DIBAL-H reduction of ester to aldehyde and then conducted julia coupling type anion addition. To use flow reaction reaction temperature was raise up from -70 deg to 10 deg.

There many examples are described in the article and scheme35 Flow diazomethane chemistry seems very useful. Diazomethane is useful reagent but sometime it is difficult to use in lab for safety reason so TMS-diazomethane was used. But TMS-diazomethane is not cost effective. The Scheme35 shows example tube-in-tube reactor. What is tube-in-tube reactor? I would like to draw the image below. The inner tube is made with teflon AF-2400 which is gas-permeable tube. The tube can through diazomethane only so outer layer trap CH2N2 and generate pure CH2N2/THF solution. I have not known the technology. It is cool. Reader who has interest, pls read the article.

___________________________________________________ outer tube
THF>>>>>>>> CH2N2/THF
___________________________________________________ AF2400
Diazald+KOH >>> CH2N2 aq + side products >> side products
___________________________________________________ AF-2400
TFH>>>>>>> CH2N2/THF
___________________________________________________ outer tube

Above examples are production. BTW, how about parallel chemistry?

According to the article, Abbie was developed SWIFT (synthesis with integrated flow technology, nice naming sense!). The system integrates flow reactor and HPLC/MS and be able to synthesize 6 pure compound per hour in 10 ~ 20mg scale! It is very productive I think. Even if I use parallel reactor such as miniblock, it is difficult to synthesis pure compounds such speed. Fig 24 shows SWIFT platform. It seems not so large. And there are some examples continuous synthesis and assay cycles. In Japan there are few examples of parallel chemistry with flow I think.

If we can run DMTA cycle within few hours, what will be task of medicinal chemists.

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