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.
Org Process Res Dev
; 27(7): 1390-1399, 2023 Jul 21.
Article
em En
| MEDLINE
| ID: mdl-37496954
ABSTRACT
A low-cost, protecting group-free route to 6-(2-fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (1), the starting material for the in-development tuberculosis treatment TBI-223, is described. The key bond forming step in this route is the creation of the azetidine ring through a hydroxide-facilitated alkylation of 2-fluoro-4-nitroaniline (2) with 3,3-bis(bromomethyl)oxetane (BBMO, 3). After optimization, this ring formation reaction was demonstrated at 100 g scale with isolated yield of 87% and final product purity of >99%. The alkylating agent 3 was synthesized using an optimized procedure that starts from tribromoneopentyl alcohol (TBNPA, 4), a commercially available flame retardant. Treatment of 4 with sodium hydroxide under Schotten-Baumann conditions closed the oxetane ring, and after distillation, 3 was recovered in 72% yield and >95% purity. This new approach to compound 1 avoids the previous drawbacks associated with the synthesis of 2-oxa-6-azaspiro[3,3]heptane (5), the major cost driver used in previous routes to TBI-223. The optimization and multigram scale-up results for this new route are reported herein.
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MEDLINE
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En
Ano de publicação:
2023
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Article