Synthesis of a Library of Ciprofloxacin Analogues By Means of Sequential Organic Synthesis in Microreactors

Abstract

The realm of combinatorial chemistry is strongly based on the concept of parallel chemistry and its ease of automation. Although this batch-type approach in general may be considered a success story, some limitations remain rarely addressable by conventional approaches. Particularly, scaling-up problems such as the re-synthesis of multigram amounts of active compounds as well as the synthesis of building blocks and scaffolds in large amounts may prove to be problematic. Our expertise in continuous chemistry prompted us to develop a microreaction system for sequential organic synthesis that should overcome these limitations. In the present contribution we describe this system as well as its application to the first library approach towards fluoro-quinolone antibiotics such as Ciprofloxacin solely using microreaction technology. A known one-pot batch procedure for the synthesis of this compound class was split in its individual reaction steps, which were successfully adapted to a continuous conduct. After some optimisation studies the overall sequence was suitable for chemical diversification. Particularly it was shown, that the first step of the synthesis -the acylation reaction of a b-dimethylamino acrylate with trifluoro-benzoic acid chloride -was accessible to synthesis of high quantities without any difficulties to yield a primary building block suitable for subsequent library synthesis. In a first diversification step, the Michael addition of a set of primary amines was followed by nucleophilic ring closure providing the difluoroquinolone system, which was subjected to a second diversification step by means of a nucleophilic aromatic substitution reaction. Thus, a number of Ciprofloxacin analogues could be synthesised in good overall yield and purity. Isolated yields ranged from 71 to 85% in the first diversification step and from 59 to 99% in the second step.

Combinatorially-generated library of 6-fluoroquinolone analogs as potential novel antitubercular agents: a chemometric and molecular modeling assessment

“…CombiChem add-on modul available in ChemBioOffice Ultra was used for in silico generation of 6-fluoroquinolone structural analogs [22]. For this purpose we employed the original synthetic pathways of three well known 6-FQ antibiotics: ciprofloxacin, moxifloxacin, and ofloxacin [23][24][25]. Using a building-blocks commercial dataset (Bionet Fragment Library of 6995 "Rule of 3" filtered lead-like fragments) [26], and SAR-based structural modifications at positions 1 and 7 of the main 6-FQ scaffold, we built six different subsets of combinatorially-generated 6-fluoroquinolone analogs.…”

Continuous‐flow syntheses of heterocycles

“…Schwalbe et al developed a multistep microreactor library approach toward fluoroquinolone antibiotics such as Ciprofloxacin (Scheme 34) [58]. Five sequential microreactor transformations were required to generate the desired products.…”

Micro reactor and flow chemistry for industrial applications in drug discovery and development

“…Thus, 28 ciprofl oxacin analogs could be synthesized at good overall yield and purity. The isolated yields ranged from 71 % to 85 % in the fi rst diversifi cation step and from 59 % to 99 % in the second step [52] .…”

“…The known Bayer approach for the synthesis of the drug is based on a one-pot batch procedure without isolation of intermediate compounds [52] .…”