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

被引：1

作者：

Cardoso, Flavio S. P. ^{[1
]}

Kadam, Appasaheb L. ^{[1
]}

Nelson, Ryan C. ^{[1
]}

Tomlin, John W. ^{[1
]}

Dahal, Dipendra ^{[2
]}

Kuehner, Christopher S. ^{[2
]}

Gudvangen, Gard ^{[2
]}

Arduengo, Anthony J. ^{[2
]}

Burns, Justina M. ^{[1
]}

Aleshire, Sarah L. ^{[1
]}

Snead, David R. ^{[1
]}

Qu, Fengrui ^{[3
]}

Belmore, Ken ^{[3
]}

Ahmad, Saeed ^{[1
]}

Agrawal, Toolika ^{[4
]}

Sieber, Joshua D. ^{[4
]}

Donsbach, Kai Oliver ^{[1
]}

机构：

[1] Virginia Commonwealth Univ, Med All Inst, Richmond, VA 23298 USA

[2] Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA

[3] Univ Alabama, Dept Chem & Biochem, Tuscaloosa, AL 35487 USA

[4] Virginia Commonwealth Univ, Dept Chem, Richmond, VA 23284 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2023年 / 27卷 / 07期

关键词：

tuberculosis; TBI-223; azaspiro[3; 3]heptane; spiroamine; NUCLEAR-MAGNETIC-RESONANCE; REACTIVITY; AMINES;

D O I：

10.1021/acs.oprd.3c00148

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

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.

引用

页码：1390 / 1399

页数：10