3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

Last updated
3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
Pyrazole SDHI intermediate.svg
Names
Preferred IUPAC name
3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
Other names
CSAA798670, NOA449410
Identifiers
3D model (JSmol)
11698637
ChemSpider
ECHA InfoCard 100.117.460 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 700-093-4
PubChem CID
UNII
  • InChI=1S/C6H6F2N2O2/c1-10-2-3(6(11)12)4(9-10)5(7)8/h2,5H,1H3,(H,11,12) Yes check.svgY
    Key: RLOHOBNEYHBZID-UHFFFAOYSA-N Yes check.svgY
  • CN1C=C(C(=N1)C(F)F)C(=O)O
Properties [1]
C6H6F2N2O2
Molar mass 176.12
Melting point 200–201°C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid is a chemical compound which is used commercially as an intermediate to seven fungicides which act by inhibition of succinate dehydrogenase (SDHI). [2] It consists of a pyrazole ring with difluoromethyl, methyl and carboxylic acid groups attached in specific positions.

Contents

Background

Inhibition of succinate dehydrogenase, the complex II in the mitochondrial respiration chain, has been known as a fungicidal mechanism of action since the first examples were marketed in the 1960s. [2] [3] By 2016, at least 18 examples were developed by crop protection companies, with the market leader being boscalid, owing to its broad spectrum of fungal species controlled. However, it lacked full control of important cereal diseases, especially septoria leaf blotch Zymoseptoria tritici . [2]

A group of compounds which did control septoria were 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic amides, as shown below, [2] [4] [5] ordered by year of their first registration. [6]

Synthesis

The first reported synthesis of the pyrazole acid was in 1993, by chemists at Monsanto. [7]

Pyrazole synthesis.svg

The ethyl ester of difluoroacetoacetic acid is treated with triethyl orthoformate in the presence of acetic anhydride [8] and then with methyl hydrazine, which forms mainly the required pyrazole ring, in addition to its isomer with the methyl group on the alternative nitrogen atom. This ester is then hydrolysed with sodium hydroxide to give the pyrazole acid. [7] [2] : 410 

Manufacture of the acid at large scale has been optimised by chemists at Syngenta, Bayer Crop Science and BASF. [2] : 409–11 

Uses

As of 2023, amides of the acid were commercialised in seven SDHI fungicides. [2] : 406–409, 422  [6] : Table 3  [9] : 371–3  The US Geological Survey for 2018 reported that the most heavily used there were fluxapyroxad, at 400,000 pounds (180,000 kg), [10] followed by benzovindiflupyr at 200,000 pounds (91,000 kg). [11] The acid has been reported as a metabolite of fluxapyroxad and pydiflumetofen and thus may be present in the environment where these materials are used. [12] [13] The most recently registered example of this class is Sumitomo's inpyrfluxam. [14] Two further compounds, pyrapropoyne (Nissan Chemical Corporation) and flubeneteram (Dongguan Hec Tech) are under development. [6]

This group of pyrazole carboxamide fungicides are very effective against major crop pests such as Alternaria species, including early blight of tomato and potato. [2] : 416–8  [12] However, none display commercial levels of activity against oomycetes, fungal-related organisms which include important diseases like Phytophthora infestans , late blight of potato. [2] : 418  [15] [16]

Related Research Articles

Fungicides are pesticides used to kill parasitic fungi or their spores. Fungi can cause serious damage in agriculture, resulting in critical losses of yield, quality, and profit. Fungicides are used both in agriculture and to fight fungal infections in animals. Fungicides are also used to control oomycetes, which are not taxonomically/genetically fungi, although sharing similar methods of infecting plants. Fungicides can either be contact, translaminar or systemic. Contact fungicides are not taken up into the plant tissue and protect only the plant where the spray is deposited. Translaminar fungicides redistribute the fungicide from the upper, sprayed leaf surface to the lower, unsprayed surface. Systemic fungicides are taken up and redistributed through the xylem vessels. Few fungicides move to all parts of a plant. Some are locally systemic, and some move upward. Most fungicides that can be bought retail are sold in liquid form, the active ingredient being present at 0.08% in weaker concentrates, and as high as 0.5% for more potent fungicides. Fungicides in powdered form are usually around 90% sulfur.

<span class="mw-page-title-main">Succinate dehydrogenase</span> Enzyme

Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates in both the citric acid cycle and the electron transport chain. Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential.

The Japp–Klingemann reaction is a chemical reaction used to synthesize hydrazones from β-keto-acids and aryl diazonium salts. The reaction is named after the chemists Francis Robert Japp and Felix Klingemann.

Pyrazole is an organic compound of azole group with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in ortho-substitution. Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugate acid 2.49 at 25 °C). Pyrazoles are also a class of compounds that have the ring C3N2 with adjacent nitrogen atoms. Notable drugs containing a pyrazole ring are celecoxib (celebrex) and the anabolic steroid stanozolol.

The cereal grain wheat is subject to numerous wheat diseases, including bacterial, viral and fungal diseases, as well as parasitic infestations.

Acibenzolar-<i>S</i>-methyl Chemical compound

Acibenzolar-S-methyl is the ISO common name for an organic compound that is used as a fungicide. Unusually, it is not directly toxic to fungi but works by inducing systemic acquired resistance, the natural defence system of plants.

<span class="mw-page-title-main">Azoxystrobin</span> Chemical compound

Azoxystrobin is a broad spectrum systemic fungicide widely used in agriculture to protect crops from fungal diseases. It was first marketed in 1996 using the brand name Amistar and by 1999 it had been registered in 48 countries on more than 50 crops. In the year 2000 it was announced that it had been granted UK Millennium product status.

<span class="mw-page-title-main">Saflufenacil</span> Chemical compound

Saflufenacil is the ISO common name for an organic compound of the pyrimidinedione chemical class used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase to control broadleaf weeds in crops including soybeans and corn.

<span class="mw-page-title-main">O-1269</span> Chemical compound

O-1269 is a drug that is a diarylpyrazole derivative, related to potent cannabinoid antagonist drugs such as rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full or partial agonists at the cannabinoid receptors rather than antagonists, and so produce the usual effects expected of cannabinoid agonists in animal tests, such as sedation and analgesic effects. The N-heptyl homolog O-1270 and the N-propyl homolog O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker binding affinity at cannabinoid receptors compared to the pentyl homolog O-1269. Agonist-like and atypical cannabinoid activity has also been observed with a number of related compounds.

<span class="mw-page-title-main">Imazaquin</span> Chemical compound

Imazaquin is an imidazolinone herbicide, so named because it contains an imidazolinone core. This organic compound is used to control a broad spectrum of weed species. It is a colorless or white solid, although commercial samples can appear brown or tan.

Early twenty-first century pesticide research has focused on developing molecules that combine low use rates and that are more selective, safer, resistance-breaking and cost-effective. Obstacles include increasing pesticide resistance and an increasingly stringent regulatory environment.

<span class="mw-page-title-main">Fluxapyroxad</span> Chemical compound

Fluxapyroxad is a broad-spectrum pyrazole-carboxamide fungicide used on a large variety of commercial crops. It stunts fungus growth by inhibiting the succinate dehydrogenase (SQR) enzyme. Application of fluxapyroxad helps prevent many wilts and other fungal infections from taking hold. As with other systemic pesticides that have a long chemical half-life, there are concerns about keeping fluxapyroxad out of the groundwater, especially when combined with pyraclostrobin. There is also concern that some fungi may develop resistance to fluxapyroxad.

<span class="mw-page-title-main">AB-CHFUPYCA</span> Chemical compound

AB-CHFUPYCA is a compound that was first identified as a component of synthetic cannabis products in Japan in 2015. The name "AB-CHFUPYCA" is an acronym of its systematic name N-(1-Amino-3-methyl-1-oxoButan-2-yl)-1-(CycloHexylmethyl)-3-(4-FlUorophenyl)-1H-PYrazole-5-CarboxAmide. There are two known regioisomers of AB-CHFUPYCA: 3,5-AB-CHMFUPPYCA (pictured) and 5,3-AB-CHMFUPPYCA. The article[1] refers to both 3,5-AB-CHMFUPPYCA and 5,3-AB-CHMFUPPYCA as AB-CHMFUPPYCA isomers, so AB-CHMFUPPYCA and AB-CHFUPYCA are not names for a unique chemical structure.

<span class="mw-page-title-main">Fluopyram</span> Chemical compound

Fluopyram is a fungicide and nematicide used in agriculture. It is used to control fungal diseases such as gray mold, powdery mildew, apple scab, Alternaria, Sclerotinia, and Monilinia. It is an inhibitor of succinate dehydrogenase.

<span class="mw-page-title-main">Oxycarboxin</span> Chemical compound

Oxycarboxin is an organic chemical used in agriculture to protect crops from fungal diseases. It was first marketed by Uniroyal in 1969 using their brand name Plantvax. The compound is an anilide which combines a heterocyclic acid with aniline to give an inhibitor of succinate dehydrogenase (SDHI).

<span class="mw-page-title-main">Sedaxane</span> Chemical compound

Sedaxane is a broad spectrum fungicide used as a seed treatment in agriculture to protect crops from fungal diseases. It was first marketed by Syngenta in 2011 using their brand name Vibrance. The compound is an amide which combines a pyrazole acid with an aryl amine to give an inhibitor of succinate dehydrogenase.

<span class="mw-page-title-main">Carboxin</span> Chemical compound used to kill fungi

Carboxin is a narrow-spectrum fungicide used as a seed treatment in agriculture to protect crops from fungal diseases. It was first marketed by Uniroyal in 1969 using their brand name Vitavax. The compound is an anilide which combines a heterocyclic acid with aniline to give an inhibitor of succinate dehydrogenase (SDHI).

<span class="mw-page-title-main">Boscalid</span> Chemical compound used to kill fungi

Boscalid is a broad spectrum fungicide used in agriculture to protect crops from fungal diseases. It was first marketed by BASF in 2002 using their brand name Endura. The compound is an biphenyl amide derived inhibitor of succinate dehydrogenase.

<span class="mw-page-title-main">Pydiflumetofen</span> Chemical compound used to kill fungi

Pydiflumetofen is a broad spectrum fungicide used in agriculture to protect crops from fungal diseases. It was first marketed by Syngenta in 2016 using their brand name Miravis. The compound is an amide which combines a pyrazole acid with a substituted phenethylamine to give an inhibitor of succinate dehydrogenase.

References

  1. ↑ "3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid". pubchem.ncbi.nlm.nih.gov. 2023-07-22. Retrieved 2023-07-27.
  2. 1 2 3 4 5 6 7 8 9 Walter, Harald (2016). "Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides". In Lamberth, Clemens; Dinges, Jürgen (eds.). Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals. Wiley. pp. 405–425. doi:10.1002/9783527693931.ch31. ISBN   9783527339471.
  3. ↑ "History of SDHI-fungicides". frac.info. Retrieved 2023-07-26.
  4. ↑ "Pyrazolecarboxamide fungicides". BCPC . Retrieved 2023-07-27.
  5. ↑ Walter, Harald; Lamberth, Clemens; Corsi, Camilla (2018). "Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel difluoromethylated heterocyclic acid moieties". Monatshefte für Chemie - Chemical Monthly. 149 (4): 791–799. doi:10.1007/s00706-017-2101-y. S2CID   103548298.
  6. 1 2 3 Umetsu, Noriharu; Shirai, Yuichi (2020). "Development of novel pesticides in the 21st century". Journal of Pesticide Science. 45 (2): 54–74. doi:10.1584/jpestics.D20-201. PMC   7581488 . PMID   33132734.
  7. 1 2 USpatent 5223526,McLoughlin, J I&Metz, S,"Pyrazole carboxanilide fungicides and use",published 1993-06-29, assigned to Monsanto Co
  8. ↑ Jones, Reuben G. (1951). "The Synthesis of Ethyl Ethoxymethyleneoxalacetate and Related Compounds". Journal of the American Chemical Society. 73 (8): 3684–3686. doi:10.1021/ja01152a034.
  9. ↑ Jeschke, Peter (2021). "Current Trends in the Design of Fluorine-Containing Agrochemicals". In Szabó, Kálmán; Selander, Nicklas (eds.). Organofluorine Chemistry. Wiley. pp. 363–395. doi:10.1002/9783527825158.ch11. ISBN   9783527347117. S2CID   234149806.
  10. ↑ US Geological Survey (2021-10-12). "Estimated Agricultural Use for fluxapyroxad, 2018" . Retrieved 2023-07-30.
  11. ↑ US Geological Survey (2021-10-12). "Estimated Agricultural Use for benzovindiflupyr, 2018" . Retrieved 2023-07-30.
  12. 1 2 Pesticide Properties Database. "Fluxapyroxad". University of Hertfordshire. Retrieved 2023-07-30.
  13. ↑ Arena, Maria; Auteri, Domenica; Brancato, Alba; et al. (2019). "Peer review of the pesticide risk assessment of the active substance pydiflumetofen". EFSA Journal. 17 (10): e05821. doi: 10.2903/j.efsa.2019.5821 . PMC   7008818 . PMID   32626121.
  14. ↑ Kiguchi, So; Inoue, Takuya; Matsuzaki, Yuichi; Iwahashi, Fukumatsu; Sakaguchi, Hiroshi (2021). "Discovery and biological profile of inpyrfluxam: A new broad-spectrum succinate dehydrogenase inhibitor fungicide". Recent Highlights in the Discovery and Optimization of Crop Protection Products. pp. 381–389. doi:10.1016/B978-0-12-821035-2.00026-7. ISBN   9780128210352. S2CID   234160975.
  15. ↑ Pan, Yuemin; Ye, Tao; Gao, Zhimou (2017). "Cloning and functional analysis of succinate dehydrogenase gene PsSDHA in Phytophthora sojae". Microbial Pathogenesis. 108: 40–48. doi:10.1016/j.micpath.2017.03.012. PMID   28438637.
  16. ↑ Wang, Minlong; Du, Ying; Ling, Chen; et al. (2021). "Design, synthesis and antifungal/anti-oomycete activity of pyrazolyl oxime ethers as novel potential succinate dehydrogenase inhibitors". Pest Management Science. 77 (9): 3910–3920. doi:10.1002/ps.6418. PMID   33871901. S2CID   233298456.
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