Development of an Efficient Synthetic Process for Broflanilide

Article abstract of DOI:10.1021/acs.oprd.0c00028

This article describes the development of an efficient and scalable synthetic route to the novel insecticide broflanilide (1). This redesigned synthetic sequence starts from 2-fluoro-3-nitrobenzoic acid and 4-(perfluoropropan-2-yl)-2-(trifluoromethyl) ani

Full text of DOI:10.1021/acs.oprd.0c00028

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Development of an Efficient Synthetic Process for Broflanilide
Chunyan Luo, Qiong Xu, Chaoqun Huang, Liangming Luo,
Jintao Zhu, Rong Zhang, Geng Huang, and Du-Lin Yin
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00028 • Publication Date (Web): 07 Apr 2020
Downloaded from pubs.acs.org on April 8, 2020
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Development of an Efficient Synthetic Process
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‡
‡
Chunyan Luo,†, Qiong Xu,*,† Chaoqun Huang,*, Liangming Luo,‡ Jintao Zhu,‡ Rong
Zhang,‡ Geng Huang,† Dulin Yin*,†
† National & Local Joint Engineering Laboratory for New Petro-chemical Materials and
Fine Utilization of Resources, College of Chemistry and Chemical Engineering, Hunan
Normal University, 36 Lushan Rd., Changsha 410081, Hunan, P. R. China
‡ChangSha Jiaqiao Biological Technology Co. Ltd., 186 Guyuan Rd., Changsha 410205,
Hunan, P. R. China
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ABSTRACT: This article describes the development of an efficient and scalable
synthetic route to the novel insecticide broflanilide (1). This redesigned synthetic
sequence
starts
from
2-fluoro-3-nitrobenzoic
acid
and
8
4-(perfluoropropan-2-yl)-2-(trifluoromethyl) aniline and provides the target product in a
high overall yield through condensation, nitro group reduction, N-methylation, amidation
and subsequent bromination steps. The desired amide moiety is established under mild
conditions, and imide generation is avoided. Using paraformaldehyde and Pt/C for
N-methylation and NaBr-NaClO for bromination increased the industrial suitability of
this route. Unlike existing routes, this new route requires isolation at only six steps
(including the heptafluorination), and the overall yield was 60.3%, representing a
significant improvement. Broflanilide (1) crystals were obtained from recrystallization in
98% aqueous CH3OH, and the structure was confirmed by X-ray analysis. This work
provides a reliable strategy for the large-scale manufacturing of broflanilide (1).
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KEYWORDS: broflanilide, insecticides, synthesis, crystal structure
INTRODUCTION
Insects are one of the most important causes of crop yield reduction in recent decades,
and the annual economic loss caused by arthropod pests alone exceeds 400 billion USD.1
With the development of insecticide resistance, this situation will worsen.2 Thus, to
facilitate insecticide resistance management in agriculture and meet the food demands of
the rapidly growing population (expected to reach 9 billion by 2050), new insecticides
with unique modes of action are essential.3 Broflanilide (1; Fig. 1), discovered by Mitsui
Chemicals, is an efficient broad-spectrum meta-diamide insecticide.4 Its active metabolite,
desmethyl-broflanilide, acts on or close to G336, a novel site in the M3 region of
drosophila resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor, inhibiting
the permeation of chloride ions and GABA-induced neuroactivity and thus resulting in
hyperexcitation and death. The binding site is different from that of conventional
noncompetitive antagonists (NCAs), making 1 active against cyclodiene-resistant and
fipronil-resistant pests. In addition, the selectivity of desmethyl-broflanilide for pests over
mammals makes it safer.5 Accordingly, 1 is one of most promising insecticides in recent
decade, and it is sure to be a powerful pest control agent after its commercialization in
2020. To accelerate its practical application in agriculture, an economical, efficient and
scalable synthetic process is required. Herein, a new synthetic route to 1 was designed
and optimized, including the synthesis of intermediates as well as the drug substance.
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