Products Cited in Publications Worldwide 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

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; III; Justina M. Burns; Sarah L. Aleshire; David R. Snead; Fengrui Qu; Ken Belmore; Saeed Ahmad; Toolika Agrawal; Joshua D. Sieber; Kai Oliver Donsbach

DOI: PMID:

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.

Keywords

tuberculosis ; TBI-223 ; azaspiro[3.3]heptane ; spiroamine

Purchased from AmBeed

A1157852402-83-795% (stabilized with Cu+MgO)

3,3-Bis(bromomethyl)oxetane

23.0/25g

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A150827369-35-797%

2-Fluoro-4-nitroaniline

10.0/1g

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A2458731522-92-598%

3-Bromo-2,2-bis(bromomethyl)propanol

13.0/25g

Detail

A15420211975218-55-398%

6-(2-Fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane

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