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Department of Chemistry & Biochemistry

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Browsing Department of Chemistry & Biochemistry by Author "Aleshire, Sarah L."

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    Practical and Scalable Two-Step Process for 6-(2-Fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane: A Key Intermediate of the Potent Antibiotic Drug Candidate TBI-223
    (American Chemical Society, 2023) Cardoso, Flavio S. P.; Kadam, Appasaheb L.; Nelson, Ryan C.; Tomlin, John W.; Dahal, Dipendra; Kuehner, Christopher S.; Gudvangen, Gard; Arduengo, Anthony J.; Burns, Justina M.; Aleshire, Sarah L.; Snead, David R.; Qu, Fengrui; Belmore, Ken; Ahmad, Saeed; Agrawal, Toolika; Sieber, Joshua D.; Donsbach, Kai Oliver; Virginia Commonwealth University; Georgia Institute of Technology; University of Alabama Tuscaloosa
    A low-cost, protectinggroup-free route to 6-(2-fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane(1), the starting material for the in-development tuberculosistreatment TBI-223, is described. The key bond forming step in thisroute is the creation of the azetidine ring through a hydroxide-facilitatedalkylation of 2-fluoro-4-nitroaniline (2) with 3,3-bis(bromomethyl)oxetane(BBMO, 3). After optimization, this ring formation reactionwas demonstrated at 100 g scale with isolated yield of 87% and finalproduct purity of >99%. The alkylating agent 3 wassynthesizedusing an optimized procedure that starts from tribromoneopentyl alcohol(TBNPA, 4), a commercially available flame retardant.Treatment of 4 with sodium hydroxide under Schotten-Baumannconditions closed the oxetane ring, and after distillation, 3 was recovered in 72% yield and >95% purity. This newapproachto compound 1 avoids the previous drawbacks associatedwith the synthesis of 2-oxa-6-azaspiro[3,3]heptane (5), the major cost driver used in previous routes to TBI-223. Theoptimization and multigram scale-up results for this new route arereported herein.