2848-94-4Relevant academic research and scientific papers
Multistep Flow Synthesis of Diazepam Guided by Droplet-Accelerated Reaction Screening with Mechanistic Insights from Rapid Mass Spectrometry Analysis
Ewan, H. Samuel,Iyer, Kiran,Hyun, Seok-Hee,Wleklinski, Michael,Cooks, R. Graham,Thompson, David H.
, p. 1566 - 1570 (2017)
Electrospray and Leidenfrost droplet accelerated reactions were used as a predictive tool for estimating the outcome of microfluidic synthesis as demonstrated by Wleklinski et al. Rapid analysis by electrospray-mass spectrometry (ESI-MS) also provided immediate feedback on reaction outcomes in flow reactions. Significant reaction acceleration was observed in electrospray relative to the corresponding bulk reaction. This rapid reaction screening and analysis method has allowed for the detection of previously unreported outcomes in the reaction between 5-chloro-2-(methylamino)benzophenone and haloacetyl chloride (halo = Cl or Br) in the continuous synthesis of diazepam. In our current study, a more detailed extension of the previous work, we report acceleration factors that are solvent dependent; additional byproducts that were observed on the microfluidic scale that were absent in the droplet reactions. Gaining insight from this combined droplet and microfluidic screening/rapid ESI-MS analysis approach, we have helped guide the synthesis of diazepam and showcased the potential of this method as a reaction optimization and discovery tool. Informed by these new insights, diazepam was synthesized in a high-yield two-step continuous flow process.
Can Accelerated Reactions in Droplets Guide Chemistry at Scale?
Wleklinski, Michael,Falcone, Caitlin E.,Loren, Bradley P.,Jaman, Zinia,Iyer, Kiran,Ewan, H. Samuel,Hyun, Seok-Hee,Thompson, David H.,Cooks, R. Graham
, p. 5480 - 5484 (2016)
Mass spectrometry (MS) is used to monitor chemical reactions in droplets. In almost all cases, such reactions are accelerated relative to the corresponding reactions in bulk, even after correction for concentration effects, and they serve to predict the likely success of scaled-up reactions performed in microfluidic systems. The particular chemical targets used in these test studies are diazepam, atropine and diphenhydramine. In addition to a yes/no prediction of whether scaled-up reaction is possible, in some cases valuable information was obtained that helped in optimization of reaction conditions, minimization of by-products, and choice of catalyst. In a variant on the spray-based charged droplet experiment, the Leidenfrost effect was used to generate larger, uncharged droplets and the same reactions were studied in this medium. These reactions were also accelerated but to smaller extents than in microdroplets, and they gave results that correspond even more closely to microfluidics data. The fact that MS was also used for online reaction monitoring in the microfluidic systems further enhances the potential role of MS in exploratory organic synthesis.
