Flubendiamide structure

Resistance has often been a problem or a potential problem for insecticides and this is one of the most important reasons why the insecticides with a new mode of action have been always desired, though it is quite a difficult task to find such molecules. Flubendiamide, discovered by Nihon Nohyaku (NNC), is a novel insecticide belonging to the new chemical class of 1,2-benzenedicarboxamides or phfhalic diamides, having a unique chemical structure (Figure 1) [1-3], Flubendiamide is co-developed by NNC and Bayer CropScience globally [4], The structure-activity relationships, the chemistry, including topics in process research, the mode of action and the biological profiles are described. 

Figure 1. The chemical structure of flubendiamide, 3-iodo-N -(2-mesyl-l, 1 -dimethylethyl)-N- 4-[l, 2,2,2-tetrafluoro-l -(trifluoromethyl)ethyl]-o-tolyl phthalamide.

Figure 2 shows the early phase of research for flubendiamide. In 1989, Dr. T. Tsuda, at Osaka Prefecture University in Japan, reported that some pyrazinedicarbox-amide derivatives showed moderate herbicidal activity [5]. From 1990, the research for herbicide discovery was conducted at NNC Research Center. In the course of this research, a lead compound for an insecticide was discovered in 1993 from the class of benzenedicarboxamides as shown in Figure 2. This compound provided insecticidal activity on lepidoptera at the relatively high dose of 50-500 mg a.i./L. Moreover, it did not show activity against other species such as Hemiptera or Aca-rina. Although the level of activity was not satisfactory, this compound attracted the attention of researchers for both the novelty of its chemical structure and the characteristic insecticidal symptoms such as gradual contractions of the insect body. We therefore started the study for further optimization of this lead compound.

The weak insecticidal activity was found in the lead compound its structure was quite new as an insecticide. However, there were various points to be improved for practical use such as increased insecticidal activity, reduced phytotoxicity to crops and instability of the compound. Two thousand derivatives were synthesized with the general formula shown in Figure 3. Many studies on the improvement of the activity were conducted, and flubendiamide was finally discovered in 1998. 

The last section shows the effect of substituents (Rj, R2) on the aliphatic amide moiety. As for the aliphatic side chain, it was found that the alpha-branched alkyl side chain was essential for stabilizing the diamide structure. In the case of non-branched alkyl, the diamide derivatives tend to decompose to the corresponding phfhalimides. A variety of substituents were examined to improve the activity. As shown in Table I, the introduction of a heteroatom or a functional group increased the insecticidal activity especially a sulfur atom within the alkyl side chain markedly increased the activity. This sulfonylalkylamine is also novel as an amine residue in pesticide chemistry. In summary, flubendiamide has unique substituents as essential parts of the structure in three adjacent positions on the benzene ring, which characterizes the chemical structare of flubendiamide as totally novel. 

Flubendiamide represents a novel class of insecticide having a unique chemical structure, and provides a new mode of action, which acts as a RyR modulator. This activity is highly selective to insect RyR, and no cross-resistance to existing insecticides is observed. Flubendiamide will also be very suitable for Insecticide Resistant Management. Furthermore, flubendiamide shows a broad insecticidal spectrum against lepidopterous insect pests, excellent efficacy in field evaluations, and excellent safety against various beneficial arthropods and natural enemies. It will be suitable for 1PM programs. 

The second reason why we define flubendiamide as a new generation insecticide is its chemical structure compared with known insecticidal compound classes. This section summarizes the historical basis of improvement in chemical research. 

Details of structure-activity relationships for the three parts of benzenedicarbox-amides (Fig. 31.5) used to select flubendiamide are quoted from the literature [8]. 

For the aromatic amide moiety, the heptafluoroisopropyl group is very unusual since it has never been reported as a substituent in the chemical structure of conventional pesticides. After flubendiamide was found, the substituent of the 2-position on aniline was verified. As expected the methyl substituent gave the best... 

The unique substituents described above account not only for the high activity of flubendiamide but also for its categorization as a totally new chemical structure. 

Benzenedicarboxamide compounds, including flubendiamide, were found through original research at NNC. However, notably, anthranilic diamides, structurally very different from benzenedicarboxamides, were discovered by DuPont [20] to have the same mode of action [21] and a couple of companies are following with patent applications Nissan Chemical [41] and Takeda Pharmaceutical Company [42] have applied for patents of the related compounds of benzenedicarboxamides, and Ishihara Sangyo Kaisha [43] has applied for patent of the related compounds of anthranilic diamides. The market entry of insecticides from this new generation could intensify competition with conventional insecticides in the future. 

Figure I. Structures of the Phthalic Acid Diamides Employed in the Current Study (I, flubendiamide II, flubendiamide-sulfoxide)...

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