Science Concentrates : ACS Meeting News SYNTHESIS
Flow process streamlines assembly of essential antibiotic O
O
O
Continuous synthesis produces ciprofloxacin salt in nine minutes 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 give the ciprofloxacin hydrochloride salt in 60% yield. 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
This antibioticproducing reaction contains the longest linear sequence of telescoped flow steps, researchers say.
N(CH3)2
F
Cl
+ F
F
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 batch process for making ciprofloxacin in comparable yield takes more than 100 hours. Hongkun Lin, a postdoctoral researcher in the Jensen lab, disclosed the synthesis last 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,”
Six steps in Filtration, nine minutes via crystallization continuous flow steps
O
F
OH N
N H2N+
O
Cl–
Ciprofloxacin hydrochloride
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 various 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.—TIEN NGUYEN
MICROFLUIDICS
Watching proteins diffuse through lymph nodes Proteins called cytokines that are secreted by cells within the lymph nodes are often used as drugs to manipulate immune responses. But something so basic as how these proteins travel through lymph node tissue is poorly understood. At last week’s ACS national meeting in Washington, D.C., in a Division of Analytical Chemistry symposium, Ashley E. Ross of the University of Cincinnati described a microfluidic platform for studying the diffusion of cytokines through mouse lymph node tissue. She did the work while still a postdoc with Rebecca R. Pompano at the University of Virginia. The device is a simplified version of one they published earlier this year (Analyst 2017, DOI: 10.1039/ c6an02042a). Ross studied the diffusion of fluores-
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C&EN | CEN.ACS.ORG | AUGUST 28, 2017
A microfluidic device allows spatially resolved delivery cently labeled cytokines in of fluorescently labeled cytokines to lymph node parts of the lymph node and tissue. Shown here is an image of IFN-γ (red) on measured how it differed in mouse lymph node tissue with labeled B cells (green). normal and inflamed tissue. These measurements are much better off with a microfluidic deenabled Ross to calculate diffusion coefvice than with mice,” especially for studyficients for various cytokines through the ing multiple cytokines at a time, Altan-Bontissue. By combining the measured values net told C&EN. “We can inject stuff into with the diffusion coefficients of the cytokines in solution, she was able to determine blood, but in terms of spatial, temporal, the so-called tortuosity of the tissue, which and quantity control, it will never compare to what we can do in a microfluidic device.” was slightly less than that of brain tissue. “The next thing we want to do is to “That explains the extent of hindrance that proteins experience in the tissue,” she said. study actual drugs in lymph node tissue,” Ross said. Understanding how Grégoire Altan-Bonnet, head of the imtherapies transport through diseased munodynamics group at the U.S. National versus healthy tissue, she added, may Institutes of Health, has studied cytokine aid the development of more effective diffusion in mice (Immunity 2017, DOI: immunotherapies.—CELIA ARNAUD 10.1016/j.immuni.2017.03.011). “You really
C RE D IT: AS H LE Y RO S S
Microfluidic device provides easy way to monitor migration
