posted on 2021-06-25, 17:36authored byCameron Armstrong, Yuma Miyai, Anna Formosa, Dale Thomas, Esther Chen, Travis Hart, Victor Schultz, Bimbisar K. Desai, Angela Y. Cai, Alexandra Almasy, Klavs Jensen, Luke Rogers, Tom Roper
The
experimental approach taken and challenges overcome in developing
a high-purity production (>100 g) scale process for the telescoped
synthesis of the antibiotic ciprofloxacin is outlined. The process
was first optimized for each step sequentially with regard to purity
and yield, with necessary process changes identified and implemented
before scaling for longer runs. These changes included implementing
a continuous liquid–liquid extraction (CLLE) step and eliminating
and replacing the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) initially
used in the ring-closure step due to DBU plausibly forming a decomposition
side product that negatively impacted the final product purity. Process
conditions were scaled 1.5–2-fold in order to enable the ultimate
project goal of producing enough crude ciprofloxacin within 24 h to
manufacture 1000 250 mg tablets. Working toward this goal, several
production-scale runs were carried out to assess the reproducibility
and robustness of the finalized process conditions, with the first
three steps being run continuously up to 22 h and the last two steps
being run continuously up to 10 h. The end result is a process with
a throughput of ∼29 g/h (∼700 g/24 h) with a crude product
stream profile of 94 ± 2% and 34 ± 3 mg/mL after five chemical
transformations across four reactors and one continuous CLLE unit
operation with each intermediate step maintaining a purity >95%
by
HPLC.