Flow process streamlines assembly of essential antibiotic

Flow chemistry—in which reagents course through a series of reactors to form new compounds—allows chemists to build molecules in a fast and efficient assembly-line-like way. But with each additional step, the reaction becomes more challenging: Solubility issues with intermediate compounds arise, and unwanted by-products can clog the reactor tubing.

Researchers have now overcome some of these limitations to engineer a flow process for making ciprofloxacin, an essential antibiotic. The overall reaction consists of six telescoped steps followed by a filtration and crystallization step to yield a ciprofloxacin hydrochloride salt. Telescoped steps are those in which the flow isn’t paused for offline purifications. According to the team, this is the longest linear sequence of telescoped flow steps so far achieved (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201703812).

The flow sequence takes nine minutes. Batch chemistry, a more traditional process that produces molecules in discrete amounts, rarely generates product molecules within minutes, according to Timothy Jamison, whose group developed the new ciprofloxacin process in collaboration with Klavs Jensen’s lab at Massachusetts Institute of Technology. A current patented batch process for making ciprofloxacin takes more than 100 hours and has a comparable overall yield around 60%.

Hongkun Lin, a postdoctoral researcher in the Jensen lab, disclosed the synthesis earlier this week during a Division of Organic Chemistry poster session at the ACS national meeting in Washington, D.C.

The method “illustrates how to overcome many of flow chemistry’s problems,” said Christopher Smith, an organic chemist now at the University of Reading who formerly conducted work in the Jensen lab as a postdoc. For instance, the team addressed the low solubility of multiple intermediate reaction steps by screening multiple solvent systems and engineering the system to heat up to 180 °C then rapidly cool back to room temperature.

The team also sidelined an amine by-product in one step that would have interfered with a subsequent step by introducing acyl chloride. The compound reacted with the excess by-product to keep it from impeding the process, a very “clever” move, said Eindhoven University of Technology’s Timothy Noël, who is an associate editor of the Journal of Flow Chemistry.

The authors told C&EN that early efforts to scale up their process have yielded promising results.