Fluxapyroxad | Fungicides | Succinate Dehydrogenase Inhibitors (SDHIs) | Treatment for Seeds

Fluxapyroxad [3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide] is a new broad-spectrum fungicide developed and launched by BASF Corporation in 2012. It has both excellent preventative and curative activity through the inhibition of fungi at several stages of the fungal lifecycle including spore germination, germ tube growth, appresoria formation and mycelial growth. Research has demonstrated fluxapyroxad is highly active on several major plant pathogens from the Ascomycete, Basidiomycete, Deuteromycete and Zygomycete classes of fungi [1].

Fluxapyroxad: 2D and 3D Structure

Fluxapyroxad inhibits respiration of fungi by blocking production of succinate dehydrogenase (SDH) and is effective for use on a wide variety of crops, including cereals, corn, soybean, fruiting vegetables, tuberous and corm vegetables, pome fruits and stone fruits with excellent crop safety.

Fluxapyroxad is formulated as an emulsifiable concentrate (EC) or suspension concentrate (SC) and is foliar appield or used as a seed treatement. As with many other succinate dehydrogenase inhibitors (SDHI), Fluxapyroxad can be applied in different crops to prevent a broad range of fungal plant diseases, and is especially efficacious against leaf spot diseases caused by Ascomycetes species. The compound is reported to have a favorable toxicological and ecotoxicological profile. The active ingredient trade name for fluxapyroxad is Xemium® Fungicide. EPA registration is expected in 2012.

Mechanism for Activity

Succinate dehydrogenase (SDH, complex II) or succinate:ubiquinone oxidoreductase (SQR) is an enzyme complex, bound to the inner mitochondrial membrane of mammalian mitochondria and many bacterial cells. SDH is the only enzyme involved in both respiratory chain and tricarboxylic acid (TCA) or Krebs cycle. In the inner mitochondrial membrane, SDH catalyzes the oxidation of succinate to fumarate, coupled with the reduction of ubiquinone to ubiquinol.

In agrochemical research, SDH was identified as a significant target for structurally diverse fungicides and acaricides. The fungicidal effect of nearly all SDH inhibitors relies on the disruption of the TCA cycle.

Fluxapyroxad is an inhibitor of the mitochondrial succinate-dehydrogenase (SDH). It economically controls important diseases of the classes Basidiomycetes, Ascomycetes and Deuteromycetes. After being applied to the crop, the molecule is systemically (acropetally) distributed in the plant. In addition to its preventative and long lasting activities, Fluxapyroxad also provides high curative activity [1].

Developer

Fluxapyroxad is the result of BASFs ongoing research on succinate dehydrogenase inhibitors (SDHIs) having started with benodanil, a carboxamide fungicide introduced in the early 70s of the last century, which mainly provides control of rusts (Puccinia spp.)

Reported Activities for Fluxapyroxad

Fluxapyroxad has been tested in more than 20 crops against more than 60 pathogens worldwide including key cereal diseases, Sclerotinia spp., Cercospora spp., Botrytis spp., Alternaria spp., Venturia spp., and Colletotricum spp..

Activities for Fluxapyroxad

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Summary

Common name: Fluxapyroxad; BAS 70001F; BAS 700F

Trademarks: Xemium

Molecular Formula: C18H12F5N3O

CAS Registry Number: 907204-31-3

CAS Name: 3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

Molecular Weight: 381.30

SMILES:FC1=C(F)C(F)=CC(C2=CC=CC=C2NC(C3=CN(C)N=C3C(F)F)=O)=C1

InChI Key: SXSGXWCSHSVPGB-UHFFFAOYSA-N

InChI: InChI=1S/C18H12F5N3O/c1-26-8-11(16(25-26)17(22)23)18(27)24-14-5-3-2-4-10(14)9-6-12(19)15(21)13(20)7-9/h2-8,17H,1H3,(H,24,27)

Mechanism of Action: Succinate Dehydrogenase Inhibitors (SDHIs)

Activity: Fungicides; Treatment of Seeds

Status: Launched 2012

Chemical Class: Amides; Small-molecules; Benzene containing; Ethyl 3-(difluoromethyl)-1- methyl-1H-pyrazole-4-carboxylate (DFMMP) derivatives; Flouro containing; Difluoro molecules; Trifluoro molecules; Pentafluoro molecules; Anilines

Originator: BASF Cooperation

Fluxapyroxad Synthesis

US20130225833A1: The patent reports synthesis for Fluxapyroxad and derivatives. The process appears to be an industrial one. Yields are 70% and more.

1.37 g 3',4',5'-trifluorobiphenyl-2-amine (1 eq.; 6.1 mmol) in 5 ml THF and 1.25 g (6.1 mmol) ethyl 1-methyl-3-difluoromethyl-pyrazole-4-carboxylate (DFMMP) in 5 ml THF were added to a suspension of 1.03 g (1.5 eq.; 9.2 mmol) KOtBu in 15 ml THF at 0 °C. After stirring at room temperature over night the reaction mixture was poured out in water and extracted twice with acetic ether. The purified organic extracts were washed with water and saturated NaCl solution, dried, filtered and concentrated over sodium sulphate. The residue was filtered through a silicagel column (SiO₂; hexane/acetic ether 1:1); and the desired product 3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide (Fluxapyroxad) was obtained with 70% purity (1.8 g).

US8008232B2: The patents reports synthesis of Fluxapyroxad and many of its derivatives. It is one of earliest work where an economical synthetic route was being attempted. The patent also reports fungicidal activities for the molecules synthesized.

At room temperature, a solution of 10.20 g of ethyl 1-methyl-3-difluoromethyl-pyrazole-4-carboxylate (DFMMP) in 20 ml of tetrahydrofuran was added dropwise to a mixture of 5.13 g of potassium trimethylsilanolate and 100 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 12 hours. The precipitate was filtered off with suction, washed with tetrahydrofuran and dried under reduced pressure. The resulting solid was dissolved in 200 ml of ice-water, and the solution was adjusted to pH 2 using 10% strength hydrochloric acid. The precipitate was extracted twice with methyl tert-butyl ether, and the combined organic phases were washed with saturated aqueous sodium chloride solution, to give the corresponding 4-pyrazole carboxylic acid.

A mixture of 5.3 g of 3-difluoromethyl-1-methyl-4-pyrazolecarboxylic acid and 27.8 g of thionyl chloride in DMF was heated at reflux for 2 hours. The reaction mixture was then concentrated using a rotary evaporator and twice co-distilled with 50 ml of toluene. The isolated oil (acid chloride) was directly reacted further, without further purification. 0.37 g of the oil was added dropwise to a solution of 0.36 g of 3',4',5'-trifluorobiphenyl-2-amine and 0.18 g of pyridine in 10 ml of toluene, and the reaction mixture was stirred at room temperature for 16 hours. 10 ml of tetrahydrofuran and 30 ml of methyl tert-butyl ether were then added. The organic phase was washed successively with 2% strength hydrochloric acid, twice with aqueous sodium bicarbonate solution and with dilute aqueous sodium chloride solution. The organic phase was dried and concentrated under reduced pressure. The crude product was triturated with 10 ml of diisopropyl ether, and the solid that remained was filtered off with suction and dried. This gave the desired product as a white powder of Fluxapyroxad (m.p. 157 ⁰C).

Starting materials:

1. Route to prepare Ethyl 1-methyl-3-difluoromethyl-pyrazole-4-carboxylate (DFMMP): Here

2. Route to prepare 3',4',5'-trifluorobiphenyl-2-amine:  Many routes are available in literature. Following two routes are reported here : Route 1 involves Gomberg-Bachmann-type regioselective radical arylation of anilines with arylhydrazines [Ref. 4] and Route 2 involves Negishi cross-coupling of a trifluorophenylzinc species generated in situ from its corresponding Grignard, with the 2- chloroaniline Schiff base [Ref. 5].

Identifications:

1H NMR (Estimated) for Fluxapyroxad

Experimental: ¹H NMR (360 MHz, CDCl₃) δ 3.92 (s, 3 H), 6.65 (t, JHF = 54.2 Hz, 1 H), 6.92-7.06 (m, 2 H), 7.19-7.25 (m, 2 H), 7.38-7.47 (m, 1 H), 7.81 (bs, 1 H), 7.95 (s, 1 H), 8.19 (d, J = 8.2 Hz, 1 H).

13C NMR (Estimated) for Fluxapyroxad

Experimental: ¹³C NMR (151 MHz, CDCl₃) δ 39.5 (CH₃), 111.6 (t, J_CF = 232.9 Hz, CH), 113.7 (dd, J_CF = 4.7 Hz, J_CF = 16.6 Hz, 2 × CH), 116.5 (C_q), 123.4 (CH), 125.2 (CH), 129.2 (CH), 130.0 (CH), 131.2 (C_q), 134.1 (dt, J_CF = 4.9 Hz, J_CF = 7.9 Hz, C_q), 134.5 (CH), 136.1 (C_q), 139.5 (td, J_CF = 15.3 Hz, J_CF = 252.5 Hz, C_q), 142.3 (t, J_CF = 29.3 Hz, C_q), 151.2 (ddd, J_CF = 4.3 Hz, J_CF = 10.0 Hz, J_CF = 251.2 Hz, 2 × C_q), 159.4 (C_q).

Adverse Reports:

Available data suggest that Fluxapyroxad is free from issues related to carcinogenicity, mutagenicity and sensitization. Moreover, it has no embryotoxic and/or teratogenic potential.

Others:

Fluxapyroxad very effectively controls economically important pathogens from the classes of Ascomycetes, Basidiomycetes and Deuteromycetes. This broad spectrum is particularly useful in crops that are threatened by several pathogens simultaneously, for example grapes, fruits, vegetables or cereals. Although SDHIs are a class of fungicides mainly known for their preventative properties, Fluxapyroxad shows in addition excellent curative and long lasting efficacy. These effects are clearly observed when Fluxapyroxad is applied against the most important pathogen in European wheat production, S. tritici..

Acute oral toxicity (rat) LD₅₀ = greater than 2000 mg/kg

Acute dermal toxicity (rat) LD₅₀ = greater than 2000 mg/kg

Bird acute oral, LD₅₀, = greater than 2000 mg/kg

Honeybee, contact, LD₅₀ = greater than100 ug per bee

The readers are welcome to share their views.

References:

1. Semar, M.; et. al. Xemium – the BASF Fungicide Innovation. Chap. 9 in Modern Fungicides and Antifungal Compounds VI.  Deutsche Phytomedizinische Gesellschaft, Braunschweig, Germany, 2011. (FMO only)

2. Braun, M. J. Process for the preparation of pyrazole-4-carboxamides. US20130225833A1

3. Gewehr, M.; et. al. Pyrazolecarboxanilides, process for their preparation and compositions comprising them for controlling harmful fungi. US8008232B2

4. Heinrich, M. R.; et. al. Regioselective Radical Arylation of Anilines with Arylhydrazines. J Org Chem 2012, 77(23), 10699 – 10706. (FMO only)

5. Heinrich, M.; et. al. Method for synthesising aminobiphenyls using aryl hydrazines. WO2013132006A1

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Fluopicolide | Fungicides | Anti-oomycetes | Cellular Delocalization of Spectrin-like Protein(s)

Fluopicolide [2,6-Dichloro-N-{[3-chloro-5-(trifluoromethyl)-2- pyridinyl]methyl}benzamide] is an oomycete-specific fungicide with a novel mode of action. Fluopicolide has both systemic and translaminar activities. Chemically it is a member of acylpicolides chemical class of fungicides, and blessed with a high antifungal activity against a broad spectrum of Oomycetes, such as Phytophthora infestans, Plasmopora viticola, and various Pythium species [1, 2].

Fluopicolide: 2D and 3D Structure

It shows no cross-resistance to other commercially anti-Oomycete fungicides, and can inhibit the development of strains that are resistant to phenylamides, strobilurins, or dimethomorph, and iprovalicarb. Fluopicolide exhibits excellent activity against oomycetes in vivo as well as antifungal activity in vitro; indeed, the ability is related to its translocation toward the stem tips via the xylem.

The activity of Fluopicolide is expected to be via a mechanism of cellular delocalization of spectrin-like protein(s) in oomycetes, from the plasma membrane to the cytoplasm.

Mechanism for Activity

Oomycota or oomycetes form a distinct phylogenetic lineage of fungus-like eukaryotic microorganisms. Even if oomycetes seem to share some morphological, physiological and biochemical features with fungi, they are phylogenetically distant. They are filamentous, microscopic, absorptive organisms that reproduce both sexually and asexually. Oomycetes occupy both saprophytic and pathogenic lifestyles, and include some of the most notorious pathogens of plants, causing devastating diseases such as late blight of potato and sudden oak death.

Fluopicolide affects several stages of the life cycle of the different Oomycetes studied, such as the release and the motility of zoospores, the germination of cysts, the growth of the mycelium, and sporulation.

The rapidly induced effects of fluopicolide led to the investigation in greater detail of proteins known to be associated with the cytoskeleton. Fluopicolide does not inhibit respiration, has no direct effect on membrane composition, and does not significantly alter tubulin polymerization or the tubulin and actin contents of the cell.

One such candidate here was spectrin, which is known to play a crucial role in membrane stability by anchoring to other cytoskeletal proteins in animal cells. Upon Fluopicolide treatment, a complete loss of plasma membrane localization of these spectrin-like protein(s) was observed, such that they became distributed as spherical spots in the cytoplasm of the hyphae cells. The kinetics of this effect revealed that such spectrin-like protein delocalization occurred very rapidly, within 3 min of Fluopicolide treatment. Notably, such delocalization was maintained with longer treatment times. Clearly, the action of Fluopicolide was to induce a cellular delocalization of spectrin-like protein(s), from the plasma membrane to the cytoplasm.

Developer

Flucopicolide was discovered by Aventis Cropscience, which later became Bayer Cropscience. Bayer launched this unique fungicide in 2006, and as of 2007, Flucopicolide was only available commercially as a co-formulation with Fosetyl-Al for use in vines (as Profiler) and as a co-formulation with propamocarb for use on potatoes and vegetables (as Infinito).

Reported Activities for Fluopicolide

Fluopicolide, when applied to the zoospores of P. infestan at a concentration of only 1 µg/ml, caused the zoospores to stop swimming within 1 min; the zoospores subsequently swelled and burst within a few minutes.

In vitro, Fluopicolide strongly inhibited the mycelial growth of P. infestans, with an 80% inhibition being observed at a concentration as low as 0.1 µg/ml over four to seven days.

A publication in 2012 [1], quoted the following crops and pathogens on which Fluopicolide has been tested successfully:

Potato (Phytophthora infestans)  

Tomato (Phytophthora infestans)

Peppers (Phytophthora capsici)  

Leek (Phytophthora porri)   

Vines (Plasmopara viticola)

Brassicas (Peronospora parasitica)      

Tobacco (Peronospora tabacina)

Cucurbits (Pseudoperonospora cubensis)    

Lettuce (Bremia lactucae)   

Roses (Peronospora sparsa)       

Activities for Fluopicolide

%Inhibition (mycelial growth of P. infestans @ 0.1 ug/ml Fluopicolide) = 80%

Summary

Common name: Fluopicolide; AE C638206; AEC638206; AE-C638206

Trademarks: Profiler; Infinito

Molecular Formula: C14H8Cl3F3N2O

CAS Registry Number: 330459-31-9

CAS Name: 2,6-Dichloro-N-{[3-chloro-5-(trifluoromethyl)- 2-pyridinyl]methyl}benzamide

Molecular Weight: 383.58

SMILES: O=C(NCC1=NC=C(C(F)(F)F)C=C1Cl)C2=C(Cl)C=CC=C2Cl

InChI Key: GBOYJIHYACSLGN-UHFFFAOYSA-N

InChI: InChI=1S/C14H8Cl3F3N2O/c15-8-2-1-3-9(16)12(8)13(23)22-6-11-10(17)4-7(5-21-11)14(18,19)20/h1-5H,6H2,(H,22,23)

Mechanism of Action: Cellular Delocalization of Spectrin-like Protein(s)

Activity: Anti-oomycetes; Fungicides

Status: Launched 2006

Chemical Class: Amides; Small-molecules; Benzene containing; Pyridines; Acylpicolides; Fluoro containing; Chloro containing; Trifluoro molecules

Originator: Aventis Cropscience/Bayer Cropscience

Fluopicolide Synthesis

US6828441B2: The patent reports synthesis for Fluopicolide and derivatives. The process appears to be an industrial one. Yields are not disclosed.

Ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate: To a stirred solution of sodium hydride (0.445 g) in dry dimethylformamide (4 ml) at 0° C. was added ethyl N-(diphenylmethylene)glycinate (1.485 g) in dry dimethylformamide (3 ml) and stirring was continued for 20 minutes. 2,3-Dichloro-5-(trifluoromethyl)pyridine (1.58 g) in dry dimethylformamide (4 ml) was then added dropwise over 10 mins at 5° C. and the reaction mixture was stirred for 2 hours at room temperature. 2M hydrochloric acid (25 ml) was added and stirring continued for 2 hours. The solution was washed with diethyl ether and the layers were separated. The aqueous phase was neutralised with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine (×2), dried (MgSO₄), filtered and the solvent removed to leave a residue which was purified by silica gel chromatography eluting with ethyl acetate/light petroleum (40-60° C.) to give the title product.

(3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine: A mixture of the product from stage a) (0.24 g) and 3M hydrochloric acid (20 ml) was heated under reflux for 4 hours. On cooling the mixture was washed with diethyl ether and the layers separated. Water was removed from the aqueous phase by azeotropic evaporation with toluene (×3) to give the title product.

A solution of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine (0.35 g) in dry ether (2 ml) was added to a solution of 2,6-Dichlorobenzoyl chloride (0.39 g) and triethylamine (0.27 ml) in dry ether (5 ml) and the mixture stirred overnight. Water (20 ml) and ethyl acetate (10 ml) were added and the organic phase was separated and washed with aqueous sodium hydrogen carbonate, dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give Fluopicolide [2,6-Dichloro-N-{[3-chloro-5-(trifluoromethyl)- 2-pyridinyl]methyl}benzamide], m.p. 127-30° C.

Identifications:

1H NMR (Estimated) for Fluopicolide

Adverse Reports:

Available data suggest that Fluopicolide is free from issues related to carcinogenicity, mutagenicity and sensitization. Moreover, it has no embryotoxic and/or teratogenic potential.

Others:

Acute oral toxicity (rat) LD₅₀ = greater than 5000 mg/kg

Acute dermal toxicity (rat) LD₅₀ = greater than 5000 mg/kg

Bird (quail), acute oral, LD₅₀, = greater than 2250 mg/kg

Honeybee, contact, LD₅₀ = greater than100 ug per bee

The readers are welcome to share their views.

References:

1. Toquin, V.; et. al. Fluopicolide: A New Anti-Oomycetes Fungicide? Chap. 21: Modern Crop Protection Compounds, Second Edition. Wiley-VCH Verlag GmbH & Co. KGaA. 2012 (FMO only)

2. Moloney, B. A.; et. al. 2-pyridylmethylamine derivatives useful as fungicides. US6828441B2

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Tioxazafen | Nematicides | Treatment of Seeds

Tioxazafen [3-phenyl-5-(thiophen- 2-yl)-1,2,4-oxadiazole] is a new broad-spectrum seed treatment nematicide that is designed to provide consistent broad-spectrum control of nematodes in corn, soy, and cotton [1].

Tioxazafen exhibits excellent activity against soybean cyst, root knot, and reniform nematodes in soy; lesion, root knot, and needle nematodes in corn; as well as reniform and root knot nematodes in cotton.

Tioxazafen: 2D and 3D Structure

Tioxazafen is a disubstituted oxadiazole, which represents a new class of nematicidal chemistry demonstrating equal or better performance in greenhouse and field trial evaluations when compared with commercial treatments.