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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Isofetamid I Fungicides | Succinate Dehydrogenase Inhibitors (SDHIs)

Isofetamid [N-[1,1-dimethyl-2-(4-isopropoxy-o-tolyl)-2-oxoethyl]-3-methylthiophene-2-carboxamide] is a thiophene-carboxamide based succinate dehydrogenase inhibitor (SDHI)  fungicide launched in 2012 by Ishihara Sangyo Kaisha [1].

Isofetamid: 2D and 3D Structure

Isofetamid has been shown to be highly effective against Botrytis cinerea (grey mold) on grape. It is registered for the control of different Botrytis and Sclerotinia spp. on grape, lettuce, rapeseed, low growing berry, and turfgrass on golf courses.

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 [2].

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.

Isofetamid is a new succinate dehydrogenase inhibitor (SDHI) fungicide with a single-site of action that inhibits cellular respiration and appears to be a new option in the chemical treatment against gray mold.

Gray mold is an important disease in grapevines, and its control depends primarily on the use of fungicides with a single-site mode of action. Botrytis cinerea has a high risk of developing resistance against such fungicides. Therefore, novel chemical options are needed to achieve satisfactory control of gray mold where Isofetamid fits the bill perfectly.

Developer

It is developed by Ishihara Sangyo Kaisha and was launched in 2012.

Reported Activities for Isofetamid

EC₅₀ (Inhibition of Botrytis allii growth ) = 0.22 ug/ml

EC₅₀ (Inhibition of Botrytis cinerea growth ) = 0.1 ug/ml

EC₅₀ (Inhibition of Botrytis squamosa growth ) = 0.74 ug/ml

EC₅₀ (Inhibition of Botrytis tulipae growth ) = 0.36 ug/ml

Summary

Common name: Isofetamid; IKF-5411; IKF5411; IKF 5411

Trademarks: KENJA (36% SC)

Molecular Formula: C20H25NO3S

CAS Registry Number: 875915-78-9

CAS Name: N-[1,1-dimethyl-2-(4-isopropoxy-o-tolyl)-2-oxoethyl]-3-methylthiophene-2-carboxamide

Molecular Weight: 359.48

SMILES: O=C(C1=C(C)C=CS1)NC(C)(C)C(C2=CC=C(OC(C)C)C=C2C)=O

InChI Key: WMKZDPFZIZQROT-UHFFFAOYSA-N

InChI: InChI=1S/C20H25NO3S/c1-12(2)24-15-7-8-16(14(4)11-15)18(22)20(5,6)21-19(23)17-13(3)9-10-25-17/h7-12H,1-6H3,(H,21,23)

Mechanism of Action: Succinate Dehydrogenase Inhibitors (SDHIs)

Activity: Fungicide

Status: Launched 2012 (Japan)

Chemical Class: Amides containing; Sulphur containing; Thio containing; Thiophene containing; Small-molecules

Originator: Ishihara Sangyo Kaisha (ISK)

Isofetamid Synthesis

WO2006016708A1: The patent reports synthesis for Isofetamid and its various derivatives.

The first strategy to Isofetamid synthesis starts with Fridel Crafts acylation of m-cresol. The phenol end of cresol is esterified in the next step with iso-propyl bromide. Subsequent bromination of intermediate with phenyltrimethyl-ammonium tribromide gave the bromo intermediate compound, which reacted with sodium azide to yield intermediate azide. Finally, reduction of azide with H₂ yielded intermediate isofetamid amine, followed by a coupling reaction with 3-methylthiophene-2-carbonylchloride to give the title product, Isofetamid.

The second strategy starts with addition of 4-isopropoxy-2-methylbenzonitrile with isopropyl magnesium bromide forming the ester intermediate. Subsequent steps are same as reported above.

Identifications:

1H NMR (Estimated) for Isofetamid 

Adverse Reports:

Nothing available.

Others:

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

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

Carp LC₅₀ (96 hr) = greater than 7.1 mg/L

Mutagenicity = Negative

The readers are welcome to share their views.

References:

1. Tsukuda, S. Developing trend of SDHI fungicide and studies on a novel fungicide, isofetamid. Japanese Journal of Pesticide Science 2014, 39(1), 89-95. (free article) {text in Japanese}

2. Yang, G. -F.; et. al. Succinate Dehydrogenase: An Ideal Target for Fungicide Discovery. Chap 13 In Discovery and Synthesis of Crop Protection Products; ACS Symposium Series; American Chemical Society: Washington, DC, 2015. (FMO only)

3. Nakamura, Y.; et. al. Fungicidal composition containing acid amide derivative. WO2006016708A1

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