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

Flavio S P Cardoso; Appasaheb L Kadam; Ryan C Nelson; John W Tomlin; Dipendra Dahal; Christopher S Kuehner; Gard Gudvangen; Anthony J Arduengo 3rd; Justina M Burns; Sarah L Aleshire; David R Snead; Fengrui Qu; Ken Belmore; Saeed Ahmad; Toolika Agrawal; Joshua D Sieber; Kai Oliver Donsbach

doi:10.1021/acs.oprd.3c00148

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. 2023 Jul 12;27(7):1390-1399. doi: 10.1021/acs.oprd.3c00148. eCollection 2023 Jul 21.

Authors

Flavio S P Cardoso¹, Appasaheb L Kadam¹, Ryan C Nelson¹, John W Tomlin¹, Dipendra Dahal², Christopher S Kuehner², Gard Gudvangen², Anthony J Arduengo 3rd², Justina M Burns¹, Sarah L Aleshire¹, David R Snead¹, Fengrui Qu³, Ken Belmore³, Saeed Ahmad¹, Toolika Agrawal⁴, Joshua D Sieber⁴, Kai Oliver Donsbach¹

Affiliations

¹ Medicines for All Institute, Virginia Commonwealth University, 737 N. 5th St., Box 980100, Richmond, Virginia 23298, United States.
² School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, United States.
³ Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States.
⁴ Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, Virginia 23284-3208, United States.

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.