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Controlled Flow Precipitation as a Valuable Tool for Synthesis

Ian Baxendale recently published a paper(1) in Organic Process Research & Development detailing the use of a Coflore ATR system to produce a free-flowing suspension of a product with a solids content of 46% v/v

AMT.2015.11 OPRD Durham ATRProf. Ian Baxendale, University of Durham, has used a Coflore ATR-1L to great effect, taking advantage of its flexibility and solids handling capabilities. The process involved multistep synthesis with the first being the fast formation of a diazonium salt in a simple coil reactor. This was then fed into the first segment of an ATR-1L together with an second reactant to make a key building block. Subsequent work and and isolation steps were carried out in additional ATR1L tube segments which included a two-stage pH change, an extractive work up and final acidification, all in flow.

(1) ‘Controlled Flow Precipitation as a Valuable Tool for Synthesis’, Paolo Filipponi, Antimo Gioiello, and Ian R. Baxendale, Org. Process Res. Dev., 2016, 20 (2), pp 371–375 DOI: 10.1021/acs.oprd.5b00331

Controlled Flow Precipitation as a Valuable Tool for Synthesis

Paolo Filipponi†, Antimo Gioiello‡, and Ian Baxendale*†
†Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK
‡Department of Pharmaceutical Science, University of Perugia, Via del Liceo, 1, I-06123 Perugia, Italy

ABSTRACT: In most standard flow process, the formation of solids represents a major problem often leading to obstruction of the flow device and reactor shutdown. However, many reactions produce solid products, and therefore finding ways to process these materials is an important area of research. In this article we demonstrate how a dynamically agitated flow reactor can be a powerful tool to facilitate workup and processing of biphasic solid−liquid flow streams at scale.




Two aqueous solutions, one comprising NaNO2 and the other 4-bromoaniline solubilized in aqueous HCl, were combined at a T-piece mixer and then processed through a 20 mL flow coil. […] The output was mixed with a feed of the pyranone 1 dissolved in aqueous K2CO3 before entering the first reaction chamber of the Coflore system (agitator frequency 4 Hz) (Scheme 3). The chamber was maintained at room temperature and resulted in the immediate generation of a thick yellow precipitate consisting of intermediate 12 which formed in almost quantitative conversion. Under mechanical agitation the material was easily progressed as a free-flowing suspension (Figure 3; solid content of 46% v/v) and was not hindered by the production of CO2 resulting from the partial neutralization of the acidic diazonium stream. Indeed, the agitation facilitated the efficient degassing of the flow stream circumventing the previously encountered foaming problem. […] Under the derived basic conditions and at a temperature of 85 °C, the transformation of hydrazone 12 into the final desired pyridazone 2 proceeded efficiently. The reaction required a residence time of 50−55 min which could be easily serviced by connecting 8 of the remaining 100 mL ATR reaction chambers in series. The final ATR chamber was used to facilitate purification by extractive workup through toluene addition leading to partitioning of any organic soluble impurities. The resulting biphasic output was discharged from the ATR reactor into a settling tank which allowed the organic phase to be removed to waste and the lower aqueous layer to be drained. Isolation of the target compound 2 was achieved through acidification of the aqueous phase. […] The extracted aqueous solution was blended with a flow stream of conc. HCl (37% to attain pH 5.5) mixing within the Coflore ATR reactor which was regulated at 0 °C (agitator frequency 4 Hz). The flow was progressed through two sequentially linked reactor chambers and then directed onto a filtration bed set under constant vacuum suction. The pale orange solid collected was periodically removed, washed with cold water (0 °C), and dried overnight in a vacuum oven at 30 °C. The isolated material was pure as determined by NMR and HPLC analysis. […] Overall, this multistep sequence allowed the successful continuous processing of 2 with a productivity of over 9.6 g/h (excluding drying) of pure final product isolated in 73% yield operating at steady state.

Reprinted (adapted) with permission from Org. Process Res. Dev.2016, 20 (2), pp 371–375. Copyright 2016 American Chemical Society.

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