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Keywords:

  • diamides;
  • ryanodine receptors;
  • insecticides;
  • anthranilamides;
  • phthalamides

Abstract

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. References

This paper describes the story of the invention of the diamides, a novel chemical class of insecticides. It starts with the pioneering work by Nihon Nohyaku researchers, who developed a herbicide lead with weak insecticidal activity to flubendiamide, a highly potent lepidoptericide. The journey continues with Nissan's isoxazolines and the invention of the anthranilamides by DuPont, culminating in the discovery of the blockbuster chlorantraniliprole and its analogue cyantraniliprole. The next steps are Syngenta's sulfoximines and bicyclic anthranilamides, Ishihara Sangyo Kaisha's cyclopropylamides, Sumitomo's hydrazides, Bayer's pyrazoles and tetrazoles, BASF's sulfoximines and more recent contributions from Chinese agrochemical companies and academic institutions. The diamides affect calcium homeostasis by binding to ryanodine receptors and releasing calcium from the intracellular stores. Investigations at Nihon Nohyaku, DuPont and Bayer on the action of the diamides on ryanodine receptors will be briefly reported.

During the last century, a large number of insecticides have been introduced to the market. Interestingly, each decade has seen the introduction of at least one new major chemical class. For example, the organophosphates, the carbamates, the organochlorines, the synthetic pyrethroids and the neonicotinoids have helped farmers to protect their crops, even though some of these chemicals have brought with them undesired environmental and health problems.[1] It is the miracle of organic chemistry that, after decades of research, new classes of small molecules are still discovered, with novel modes of action and with environmental profiles addressing both the issues of resistance and highly demanding registration criteria.[2] This account will describe industrial research leading to the discovery of one of the most recent class of insecticides, the diamides (IRAC group 28) from the late 1990s to the present time.

Most of the major industrial companies involved in agrochemical research in the 1980s had a programme devoted to protoporphyrinogen-IX-oxidase inhibitors, at that time a new class of herbicides.[3] Some analogues made in this context had not only herbicidal activity but also weak insecticidal activity. The Japanese company Nihon Nohyaku started an insecticidal programme with a weak lead in 1993 and made a major breakthrough in 1998, with phthalamides having an aniline moiety substituted with a perflororoalkyl side chain.[4-7] This new class not only has an extraordinary high activity against lepidopteran pests but also has no sign of phytotoxicity. Their best compound, flubendiamide (1) (Fig. 1), was developed jointly with Bayer Crop Sciences and was brought to the market in 2007. Its chemical structure reveals several interesting features. The heptafluoro-isopropyl side chain confers to flubendiamide its lipophilic character (log P: 4.2) and is required for the very high insecticidal activity. This substituent was originally introduced via a radical reaction of 2-iodo-heptafluoropropane on the aniline moiety. Bayer process chemists proposed an elegant and relatively cheap synthesis of 2-bromo-heptafluoropropane (4), easily available from the commodity chemical hexafluoropropene (2) (Scheme 1).[8][9][10]

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Figure 1. Flubendiamide.

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Scheme 1. Bayer synthesis of the aniline part of flubendiamide.

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The heptafluoro-isopropyl substituent is also found in three recent classes of insecticides. Nihon Nohyaku has introduced pyrifluquinazon (7), a pymetrozine analogue. They have also described a new family of carboxamide acaricides (e.g. 8) (Fig. 2).[11] Mitsui has claimed the insecticidal activity of the meta-diamides (e.g. 9).[12, 13] Flubendiamide has furthermore an iodine substituent, which is very unusual for a crop protection compound and accounts for superior activity by comparison with the cheaper chloro analogue. The introduction of this halogen may be done classically by a Sandmeyer reaction on the corresponding amino phthalic acid 11 (Scheme 2a). Direct introduction via a Pd-catalysed C–H activation was described in the patent literature by Nihon Nohyaku researchers as early as 2001[14] (Scheme 2b), and this constitutes one of the very first reactions of that type, years before it was successfully developed as a new tool in organic synthesis.[15, 16]

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Figure 2. Insecticides with a CF(CF3)2 substituent.

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Scheme 2. Introduction of the iodo substituent into flubendiamide: (a) via the Sandmeyer reaction; (b) via C–H activation.

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The new phthalamides claimed by Nihon Nohyaku dramatically stimulated research activities in this field. Nissan researchers found that the heptafluoro-isopropyl group could be replaced by heterocycles,[17] cycloalkyl substituents,[18] an oxime moiety[19] or a group of the type C(OH)(CF3)-aryl.[20, 21] A typical example, the isoxazoline-substituted phthalamide (13), is depicted in Fig. 3. This class does not seem to have been further pursued; however, this chemistry was developed to a novel important insecticide class, the isoxazolines (14) (Fig. 3), with an enhanced biological spectrum (Lepidoptera, Coleoptera, thrips and mites) but a different mode of action.[22, 23]

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Figure 3. Nissan diamides and isoxazolines.

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DuPont researchers recognised early on the potential of the phthalamide chemistry. In a noteworthy achievement, they were able to transform the phthalamide lead to an original novel chemistry type, the anthranilamides, in less than 2 years. The modifications include the inversion of an amide bond, the replacement of the aniline by a pyrazole ring, the simplification of the heptafluoro-isopropyl group to a simple trifluoromethyl or a halogen and the replacement of a methyl o-substituent by a chloropyridine![24] Chlorantraniliprole[25, 26] (15) (Fig. 4) is a remarkable molecule and is even more potent than flubendiamide. It is active in the field against a wide range of lepidopteran pests, at rates from 5 g AI ha−1 (!) to about 100 g AI ha−1. Following the discovery of chloranthraniliprole, more than 60 patent applications were filed by DuPont, covering novel compounds (25 applications), process chemistry (17 applications) and other topics such as formulation and mixtures, as well as various uses such as animal health. Part of this work has been published.[27-29] Chlorantraniliprole was launched in the market place in 2008. A second molecule is currently in the pipeline: cyantraniliprole (16)[30] has a cyano substituent replacing a chlorine atom on the anthranilic core. This compound has interesting physical properties (log P: 1.9; aqueous solubility: 14 ppm), explaining its insecticidal spectrum, larger than for the classical diamides and including hemipteran pests such as Myzus persicae and hoppers. The key synthetic step towards cyantraniliprole is the cyanation of a bromo or a chloro precursor, and it is claimed in six patent applications.[31-36]

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Figure 4. DuPont diamides chlorantraniliprole and cyantraniliprole.

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One of the first contributions by Syngenta in this field was the discovery of sulfoximine derivatives in the phthalamide[37] as well as in the anthranilamide series.[38] The anthranilic sulfoximines, such as 17 (Fig. 5), show relatively good intrinsic activity in a radioligand binding assay[39] (Spodoptera IC50: 19 nM; chlorantraniliprole IC50: 2 nM) and interesting mobility properties (log P: 1.6; water solubility: 361 ppm). As a consequence, it has a robust activity when applied as seed treatment, although its activity against hemipteran pests is limited. Syngenta also claimed anthranilamides with a bicyclic core ring. For example, the naphthalene derivative 18 (Fig. 5) is one the most potent diamides against Lepidoptera in vitro (Spodoptera IC50: 5 nM; chlorantraniliprole IC50: 2 nM) as well as in the greenhouse (Spodoptera EC80: 0.2 ppm; chlorantraniliprole EC80: 0.8 ppm). Syngenta claimed a wide range of heterocyclic bicyclic core anthranilamides, some of them having exquisite in vivo and in vitro activities (e.g. 19 to 21) (Fig. 5).[40-44]

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Figure 5. Syngenta diamides, sulfoximines and bicyclic anthranilamides.

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Novel anthranilamides with specific functional groups on the aliphatic amine moieties were also claimed by Syngenta (Fig. 6): for example, the cheap Strecker amines 22,[45] the more elaborate oxetanyl or thietanyl derivatives,[46] such as 23 and 24, or the bis-cyclopropyl derivatives, such as 25,[47, 48] easily made by Kulinkovich chemistry.[49] These compounds display activity in the range of the best diamides against Lepidoptera, one drawback being their cost compared with chlorantraniliprole, which has a methyl amide. Some of these derivatives have also been claimed by competitors such as Ishihara Sangyo Kaisha and DuPont[50] at around the same time.

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Figure 6. Syngenta diamides – variation on the aliphatic amide.

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Ishihara Sangyo Kaisha (ISK) was the first company to claim anthranilamides with an aliphatic amide such as alkyl substituted by cycloalkyl.[51] Compound 26 (Fig. 7) is structurally very close to chlorantraniliprole. Its biological profile is similar to chlorantraniliprole and to the bis-cyclopropylamine analogue 25 of Syngenta. Several patent applications claiming chemical process document the skillfulness of ISK researchers to circumvent intermediates claimed by DuPont by introducing the original amine at an early step of the synthesis.[52-55]

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Figure 7. Diamides from Ishihara Sangyo Kaisha and Sumitomo.

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Sumitomo has also been very active in the diamide area. Their main contribution is the discovery of the hydrazide analogues of chlorantraniliprole (Fig. 7).[56, 57] The nitrogen atoms of the hydrazide moiety can be alkylated, and the second nitrogen is mostly acylated or carbamoylated, such as in compound 27. Sumitomo has filed several patent applications[58-60] with a few preferred diamides of the hydrazide type. By analogy with work by DuPont,[61, 62] several patent applications claiming hydrazide diamides with a heterocyclic modified anthranilic core[63] or pyrazole replacements[64] were also filed by Sumitomo. Process chemistry work is the object of several patent applications. In particular, the introduction of the hydrazide moiety at a very early stage in the synthesis sequence allows the design of a process that does not use any key intermediates claimed by DuPont.[65]

Bayer has been very prolific in the area of diamide chemistry. There are at least 76 patent applications in this field, including numerous mixtures of diamides with other insecticides, as well as 11 chemistry process applications (status: April 2012). Since Bayer codeveloped flubendiamide with Nihon-Nohyaku, they have filed several patent applications supporting this chemistry. A particular flubendiamide analogue, called CMP (28) (Fig. 8), already claimed by Nihon Nohyaku,[66] is the subject of more than 18 patent applications![67, 68] The phthalic acid core is substituted by a chloro atom, and the aliphatic side chain contains only one methyl substituent. The enantiopure aliphatic amine can easily be derived from (L)-alanine. CMP (log P: 3.5) is slightly less lipophilic than flubendiamide (log P: 4.2) and may have some advantages owing to better bioavailability properties. Following work at Nihon Nohyaku, the search for a replacement of the C3F7 group was an early focus of Bayer research.[69-73] Groups of the CH2-heterocycle type with the heterocycle itself being substituted by fluoroalkyl groups is one of the preferred motifs (29) (Fig. 8). Based on the DuPont transformation of flubendiamide to chlorantraniliprole,[24] the next step in the Bayer diamide work appears to be logical: position 3 of the pyrazole of chlorantraniliprole should tolerate the best substituents replacing the C3F7 group in the phthalamide series. Indeed, this approach is documented by at least ten patent applications, from which the most promising compounds 30 and 31 are depicted in Fig. 9.[74-78] The most preferred substituents appear to be a CH2-pyrazole substituted by a CF3 group, a CH2-triazole substituted by a CF3 group or a CH2-tetrazole substituted by a CF3 group.[79] The process to prepare the key intermediate 32 is also well described.[80]

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Figure 8. Bayer diamides of the phthalamide type.

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Figure 9. Bayer diamides of the anthranilamide type.

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Contributions from BASF to the diamide chemistry have been limited to date.[81] The aliphatic amide moiety was modified by groups of the type CONHSO2NR1R2, CONHSO2R3, CON=SR4R5 or CON=S(O)R5R7.

In 2008, the first contributions from Chinese institutions appeared in the scientific and patent literature. A large body of patent applications, as well as publications in peer-reviewed journals, has now been published. Many of these anthranilamides are structurally closely related to compounds described in earlier DuPont patents. The company Sinochem and the Shenyang Research Institute of Chemical Industry (SRICI) are quite active in the diamide field. They claimed compounds structurally very close to chlorantraniliprole, sometimes already claimed in DuPont patent applications such as 33 (Fig. 10), as well as process chemistry related to it.[82, 83] Jiangsu Pesticide Research Institute Co. Ltd focused first on hydrazide analogues of the Sumitomo type.[84] In a second step they claimed cyclised versions (oxadiazoles and thiadiazoles,[85, 86] 34) (Fig. 10) that are very close to compounds claimed earlier by DuPont.[87] Mixtures of compound 34 and abamectin are also disclosed.[88] Among the numerous research papers published by Chinese institutions, mention should be made of representative contributions from Nankai University,[89, 90] the China Agricultural University in Beijing,[91] the Wuhan Institute of Technology[92] and Guizhou University.[93]

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Figure 10. Diamides from Sinochem/SRICI and Jiangsu.

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The mode of action of the diamides has been investigated in depth by researchers at Nihon Nohyaku and Bayer,[94-101] as well as at DuPont.[102-105] The diamides are modulators of ryanodine receptors (RyR) which are ubiquitous calcium channels regulating the calcium release from intracellular stores located in the sarcoplasmic reticulum. Under the action of the diamides, the calcium channels remain open and the calcium stores are depleted, inducing gradual muscle contraction and resulting in paralysis.[103] No high-resolution crystal structures of the tetrameric transmembrane RyR are available, and very little is known about the diamide active site. Recent photoaffinity labelling investigations revealed that flubendiamide interacts in the insect transmembrane domain, and that the N-terminus plays an important role in flubendiamide sensitivity.[100] The genes encoding the RyR have been characterised for various species (Heliothis virescens, Myzus persicae, Aphis gossypii, Peregrinus maidis and Drosophila melanogaster),[102] and more recently for Plutella xylostella.[106]

The ryanodine receptor as a target for insecticides and the insecticidal activity of the alkaloid ryanodine have been known for a long time.[107, 108] The diamides bind to a site at the receptor distinct from the site of ryanodine but allosterically related. Radioligand binding assays have shown that the phthalamides and the anthranilamides probably act at the same site in the lepidopteran Spodoptera litorralis (for an assay description, see Gnamm et al.[39]). In this context, the high affinity of compound 35 for the Spodoptera RyR, as shown by a binding assay, is of interest (IC50: 5 nM). This molecule is a hybrid of a Nissan-type phthalamide and a typical anthranilamide. Its high affinity for the RyR was predicted by a pharmacophore analysis (Fig. 11) (Jacob O, Syngenta, unpublished). It shows that a large isoxazole substituent at the pyrazole can be accommodated at the Spodoptera active site.

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Figure 11. Hybrid structure of a Nissan-type phthalamide and a DuPont-type anthranilamide.

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Interestingly enough, the phthalamides are much less potent in a radioligand binding assay in the sucking pest Myzus persicae when compared with the anthranilamides (IC50 values of ∼60 nM, as opposed to ∼2 nM for chlorantraniliprole).[109] This poor intrinsic activity against sucking pests, together with the poor physical properties for plant distribution and translocation, may explain the lack of activity of flubendiamide (log P: 4.2; aqueous solubility: 0.3 ppm) against these species in the field. As such, some pharmacological differences at the RyR diamide receptor over different insect species have to be anticipated. A remarkable feature of the diamides is their high selectivity for the insect ryanodine receptor over the mammalian receptors by a factor larger than 500, an important aspect for understanding their excellent human safety profile.[103]

The diamides have been classified as a new group (28: ryanodine receptor modulators) by the Insecticide Resistance Action Committee (IRAC, www.irac-online.org). This target is attractive for insecticides with no cross-resistance to other known modes of action.[110, 111]

In conclusion, the discovery by Nihon Nohyaku of the phthalamides as a new class of lepidoptericides with exceptional activity and selectivity has stimulated research in all companies active in insecticide discovery. Two compounds have been launched onto the market, and others will follow in the coming years. As this class is already very successful, one major challenge of the future will be to manage the resistance,[112-119] which is already appearing in the field. The research in the field of the diamides has also opened the door to novel classes of insecticides such as the oxazolines (14) (Fig. 3) and the meta-diamides (9) (Fig. 2), which have distinct modes of action and biological spectrum. This is a good starting point for the future discovery of new major classes of insecticides, confirming the creative force of synthetic chemistry in the discovery of new plant protection agents.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Acknowledgements
  4. References

The author would like to thank Christopher RA Godfrey and Roger G Hall for reviewing the manuscript.

References

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  3. Acknowledgements
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