PL229316B1 - Quaternary salts of diphenoconazol with inorganic anion, method for obtaining them and application as fungicides - Google Patents

Abstract

The invention relates to quaternary salts of diphenoconazole with an inorganic anion of general formula I, wherein A- is: an inorganic nitrate (V) or chloride or bisulfate (VI) or tetrafluoroboric anion, a method for their preparation and use as fungicides. The method of their preparation is that the quaternary diphenoconazole chloride or bromide is dissolved in an aliphatic alcohol with a carbon chain length from one to four carbon atoms, or a mixture thereof, mixed with a methanolic solution of sodium, potassium or ammonium hydrochloric acid, nitric (V), or sulfur (VI) or tetrafluoroboric acid, at a concentration of at least 1%, in a molar ratio of difenoconazole hydrochloride to salt from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably at 20 ° C for at least 40 minutes, then the product is isolated and the solvent is then removed. The use of the new inorganic anion quaternary diphenoconazole salts as fungicides has also been disclosed.

Description

Description of the invention

The present invention relates to the quaternary salts of diphenoconazole with an inorganic anion, their preparation and their use as fungicides.

Quaternary ammonium salts were first synthesized in 1890 by Nikolai Menschutkin and described by N. Menschutkin in Zeitschrift fur Physikalische Chemie, 1980, 5, 589. These are compounds of ionic structure which contain four organic groups in the molecule linked to atoms nitrogen. The nitrate cation is hydrophilic and the alkyl chain is hydrophobic. Thanks to this, they reduce the interfacial tension, which was used, among others, in the process of softening fabrics presented by A. Lipińska-Ojrzanowska, J. Walusiak-Skorup in Medycyna Pracy, 2014, 65, 675-682. Those of them that melt at a temperature of less than 100 ° C are called ionic liquids. In 1914, Walden presented them to the world by synthesizing ethyl ammonium nitrate, the melting point of which was 12 ° C. Since then, ionic liquids have become the subject of intense research by scientists. They are usually composed of an unsymmetrical cation and a much smaller anion.

Quaternary ammonium salts have a broad spectrum of activity - they have antibacterial and antifungal properties, they can also fight viruses with a lipid coating. They are components of hair care products, medications and anti-corrosion preparations, as discussed by E. Obłąk, A. Gamian, Progress of Hygiene and Anti-Corrosion Medicine, as discussed by E. Obłąk, A. Gamian, Postęp of Hygiene and Experimental Medicine '}, 2010, 64, 201-211. They are also used as wood preservatives, for example against fungi that cause wood mold (e.g. Chaetomium globosum), presented in the publication of J. Zabielska-Matejuk, i. Pernak, A. Kropacz, M. Kot, A. Stangierska, Wood, 2010 , 184.11-20.

Quaternary triazole salts can also be distinguished, which consist of a positively charged nitrogen atom in the cyclic system and numerous hydrocarbon groups (the polar part of the compound). In the five-membered ring, the triazole derivatives have two carbon atoms and three nitrogen atoms. Thanks to this, they show a strong biological activity. Triazoles are widely used as components of cooling and hydraulic fluids, lubricants and drugs. Thanks to their structure, they are characterized by bactericidal and fungicidal properties. They are effective against various species of fungi: Physalospora piricola Nose or Alternaria solani, as described by HX Song, D.Q. SHi, Journal of Heterocyclic Chemistry, 2014, 51 (5), 1345-1348. Some of them act simultaneously on fungi and bacteria, e.g. they fight against the parasitic yeast found in the human gastrointestinal tract, Candida albicans and Staphylococcus aureus, a bacteria causing food poisoning, presented by S.M. El-Feky, L.A. Abou-Zeid, M, A. Massoud, S.G. Shokrall, H.M. Eisa, Acta Pharmaceutica Sciencia, 2010, 52, 353-364]. Others are a pillar in the treatment of aspergillosis, which causes pulmonary infections, discussed by A. Chowdhary, C. Sharma, S. Kathuria, F. Hagen and JF, Meis, Journal of Antimicrobial Chemotherapy, 2014, 69, 555-557. They are also included in plant protection products, eg fungicides, which is confirmed by J. Pernak, F. Walkiewicz, PL 215 045,2013. Fungicides are composed of a biologically active substance, carrier, activator, stabilizer and wetting agent. Some of them only remain on the surface in the place where they were applied, some spread over this surface, and there are also some that penetrate into tissues and spread in them. The latter, called systemic, include triazole fungicides such as cyproconazole, propiconazole, tebuconazole and difenoconazole. Propiconazole and cyproconazole are components of the Artea 330 EC formulation that fights wheat diseases caused by fungi such as Fusarium culmorum, Fusarium graminearum, Fusarium nivale, published by W. Walkowiak, T, Krzyśko-Łupicka, Progress In Plant Protection, 2014, 54, 127-134.

The only active ingredient in Difo 250 EC, a fungicide commonly used in Poland, is difenoconazole. It is a yellow-brown solid that melts at 78-79 ° C. Studies were conducted to compare the effects of difenoconazole and another known fungicide - iprodine on the growth of Lecaniciltium fungicola. Difenoconazole turned out to be a more potent inhibitor, which fought 76% of the pathogenic fungus, described in the publication of D. Cunha Zieda, J. Santana Nunesb, VF Nicolinic, AP Gimenezd, D. Lee Rinkere, E, Souza Diasb, Scientia Horticulturae, 2015, 190,117- 122. Tests were also carried out against pathogenic fungal species such as Botrytis cinerea, Fusarium oxysporum, and Sclerotium rolfsii. The mixture of difenoconazole and carbendazim turned out to be effective, but comparable to the natural antifungal extracts of the Eucomis autumnalis plant, as confirmed by D, Eksteen, JC Pretorius, TD Nieuwoudt, PC Zietsman, Annals of Applied Biology, 2005, 139, 243-249. Diphenoconazole is also used to preserve wood in synergistic mixtures with metals such as

PL 229 316 Β1 as zinc, lead, copper, as disclosed in the patent by G. Williams, J. A. Cornfield, J. Brown, N. P. Ryan, US 5916356 A, 1991.

Examples of compounds from the group of the quaternary salts of difenoconazole with an inorganic anion of the general formula I can be mentioned:

• Diphenoconazole hydrochloride [DFC] [Cl], • Diphenoconazole nitrate [DFCjfNOS], • Diphenoconazole bisulfate [DFC] [HSO4], • Diphenoconazole tetrafluoroborate [DFC] [BF4j.

The essence of the invention is the quaternary salts of diphenoconazole with an inorganic anion of the general formula 1, in which A is: an inorganic nitrate (V) or chloride or bisulfate (VI) or tetrafluoroboric anion, and the method of their preparation consists in the fact that the quaternary diphenoconazole chloride or bromide of general formula 2, is dissolved in an aliphatic alcohol with a carbon chain length from one to four carbon atoms, or a mixture of them, mixed with a methanolic solution of sodium or potassium or ammonium salt of hydrochloric, nitric (V) or sulfuric (VI) ) or tetrafluoroboric acid, at a concentration of at least 1%, in a molar ratio of difenoconazole hydrochloride to salt from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably at 20 ° C, during which at least 40 minutes, then the product is isolated and the solvent is then removed.

The second method of preparation consists in dissolving the diphenoconazole of the general formula II in an aliphatic alcohol with a carbon chain length of one to four carbon atoms, or a mixture thereof, preferably in ethanol, mixed with the sodium, potassium or ammonium salt of the acid. hydrochloric, or nitric (V), or sulfuric (VI) or tetrafluoroboric dissolved in ethanol at a concentration of at least 1%, in a molar ratio of diphenoconazole quaternary salt to inorganic acid from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably 50 ° C, for at least 40 minutes, after which the solvent is removed.

The third method of preparation consists in dissolving the quaternary diphenoconazole hydroxide of the general formula 2 in propanol, mixed with the sodium or potassium or ammonium salt of hydrochloric, nitric (V), sulfuric (VI) or tetrafluoroboric acid dissolved in propanol, at a concentration of at least 1%, in a molar ratio of diphenoconazole hydroxide to salt from 1: 1 to 1.1.05, preferably 1: 1, at a temperature below 100 ° C, preferably 20 ° C, for at least 40 minutes, then the product is isolated, then the solvent is removed.

Another method of preparation consists in dissolving the quaternary diphenoconazole chloride or bromide of general formula 2 in butanol, mixed with sulfuric (VI), hydrochloric, nitric (V) or tetrafluoroboric acid dissolved in butanol at a concentration of at least 1%, in a molar ratio of diphenoconazole bromide to acid from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably 20 ° C, over a period of at least 40 minutes, then separates the reaction product. then the solvent is removed.

The use of new diphenoconazole quaternary salts with an inorganic anion as fungicides.

It is preferred that the salts are used in pure form.

It is also advantageous when the salts are used in the form of hydroalcoholic solutions.

It is also advantageous when the salts are used in hydroalcoholic solutions with a concentration of at least 0.1%.

Thanks to the solution according to the invention, the following technical and economic effects were obtained:

• a method was developed for the preparation of a new group of compounds - diphenoconazole quaternary salts with an inorganic anion, • reaction yields for the preparation of diphenoconazole quaternary salts with an inorganic anion are high and exceed 87%, • the obtained diphenoconazole quaternary salts are well soluble in many organic solvents, but do not dissolve in water, • the synthesized salts are thermally stable, • the obtained salts are fungicidal, they are new fungicides.

The preparation of diphenoconazole quaternary salts with an inorganic anion is illustrated by the following examples:

PL229 316 Β1

Example I.

Method for the production of diphenoconazole nitrate [DFC] [NO3],

50 cm ³ of methanol was dissolved 44.27 g (0.10 mol) of difenoconazole. Then a stoichiometric amount of potassium nitrate (0.10 mol) dissolved in 30 cm ^{3 of} methanol was added in small portions with constant stirring. After stirring was continued for 50 minutes at room temperature, the filtrate's solvent was evaporated and the reaction product was dried for 24 hours at 50 ° C under reduced pressure.

The product was obtained in 89% yield.

The structure of the compound was confirmed by proton and carbon nuclear magnetic resonance spectra:

Ή NMR (400 MHz DMSO-c / 6) δ [ppm] = 1.05 (dd, J = 8.02; 24.54Hz, 3H); 3.16 (dt, J = 7.53; 7.91 Hz, 1H); 4.07 (m, 2H); 4.90 (m, 2H); 6.95 (td, 2.56; 5.56; 2.56 Hz, 1H); 7.15 (m, 3H); 7.48 (m, 3H); 8.52 (m, 1H); 9.26 (m, 1H). ¹³ C NMR (DMSO-c / 6) δ [ppm] = 157.86; 154.35; 147.25; 144.53; 132.51; 131.02; 130.24; 128.51; 121.35; 120.61; 116.45; 106.35; 72.69; 70.88; 54.45; 17.73.

Example II

Method for producing difenoconazole hydrochloride [DFC] [CI]:

5.15 g of ammonium chloride dissolved in 10 cm ^{3 of} ethanol (0.10 mol) were placed in the flask, to which 40.63 g of an ethanolic solution of difenoconazole (0.10 mol) was added in small portions with constant stirring. The mixture was stirred for 40 minutes at 50 ° C. The solvent was evaporated from the resulting mixture under reduced pressure to give the diphenoconazole quaternary salt, which was thoroughly dried.

The product was obtained in a 92% yield.

The structure of the compound was confirmed by proton and carbon nuclear magnetic resonance spectra:

Ή NMR (400 MHz DMSO-c / 6) δ [ppm] = 1.05 (dd, J = 5.98, 30.71 Hz, 3H); 3.14 (dt, J = 7.52; 7.92 Hz, 1H); 4.07 (m, 2H); 4.81 (m, 2H); 6.94 (m, 1H); 7.14 (m, 3H); 7.49 (m, 3H); 8.32 (d, J = 10.02 Hz, 1H). ¹³ C NMR (DMSO-6) δ [ppm] = 157.72; 154.31; 148.14; 144.63; 132.42; 131.80; 131.13; 130.19; 129.93; 128.40; 121.27; 120.55; 116.38; 106.39; 72.60; 70.80; 54.18; 17.69.

Example III

Process for the production of diphenoconazole bisulfate (DFC] [HSO4]:

50 cm ^{3 of} propanol was dissolved 42.43 g (0.10 mol) of sodium hydroxide difenoconazole. Then a stoichiometric amount of sodium bisulfate (0.10 mol) dissolved in 30 cm ^{3 of} propanol was added in small portions with constant stirring. Stirring was continued for 40 minutes at room temperature, then the solvent was evaporated and the reaction product was dried for 24 hours at 50 ° C under reduced pressure.

The product was obtained in a yield of 90%.

The structure of the compound was confirmed by proton and carbon nuclear magnetic resonance spectra;

Ή NMR (400 MHz DMSO-c / 6) δ [ppm] = 1.05 (dd, J = 6.04; 31.92Hz, 3H); 3.16 (m, 1H); 4.07 (m, 2H); 4.86 (m, 2H); 6.96 (m, 1H); 7.15 (m, 3H); 7.49 (m, 3H); 8.49 (d, J = 13.50 Hz, 1H); 9.23 (s. 1H). ¹³ C NMR (DMSO-6) δ [ppm] = 157.75; 154.31; 147.20; 144.52; 132.51; 131.71; 131.02; 130.28; 130.06; 128.52; 121.39; 120.59; 116.46; 106.35; 72.72; 70.90; 54.46; 17.95

Example IV

Preparation of diphenoconazole tetrafluoroborate [DFC] [BF4):

50 cm ^{3 of} butanol was dissolved 48.71 g (0.10 mol) of difenoconazole. They were then added in small portions with stirring, a stoichiometric amount of tetrafluoroboric acid (0.10 mol) dissolved in 30 cm ^{3 of} butanol. Stirring was continued for 50 minutes at room temperature, then the solvent was evaporated and the reaction product was dried for 24 hours at 50 ° C under reduced pressure.

The product was obtained in a 92% yield.

The structure of the compound was confirmed by proton and carbon nuclear magnetic resonance spectra;

Ή NMR (400 MHz DMSO-c / 6) δ [ppm] = 1.05 (dd, J = 6.02; 32.88Hz, 3H); 2.20 (s, 3H); 3.20 (m, 1H); 4.07 (m, 2H); 4.73 (m, 4H); 6.86 (m, 2H); 7.13 (m, 5H); 7.47 (m, 3H); 7.92 (d, J = 13.55 Hz, 1H); 8.44 (d, J = 5.10 Hz, 1H). ¹³ C NMR (DMSO-6) δ (ppm] = 157.88; 154.34; 147.07; 144.41; 132.50; 131.69; 130.97; 130.24; 130.04; 128 , 52; 121.35; 120.36; 116.30; 106.33; 72.70; 70.88; 54.48; 17.74.

PL 229 316 Β1

Solubility in water and common solvents was established for the synthesized salts. Table 1 shows the solubility of the obtained salts, and Table 2 shows the reaction yields and melting points. The synthesized salts are insoluble in water, but dissolve well in DMSO and methanol.

Table 1 p

; Salt L.

1.

HDFcyiw

PScho) ..........

Solubility | DMF1 HzO L methanol, chloroform and acetone

j [DFC] | HSOaj j f | -] * ϊ $ I ’

L __________________ L ............. L ............ L ...................... .L -............................. i .............. ΐ [DFCMBR ] and · * -; *। + | +

Table 2

No.

Name

[Performance | reaction

mp PCj

(ΝΟ.Ϊ]

[DFCHNO

[DFCHCIJ

Ϊ89

4 ----—., - | 180182.

and Χ57-159 (8h j i [DFC] [BF4 | 92 ΐ 61-62

Application example:

The obtained salts were tested against four fungal species: Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium culmorum and Microdochium nivale (IOR-PIB collection).

The test compounds were dissolved in 4 ml of 98% ethyl alcohol and then added to a sterile medium (PDA - Potato Dextrose Agar, Difco ™), preheated to 50 ° C. The concentration of the preparations in the medium was set at 10, 100 and 1000 ppm (the cation - responsible for the fungistatic action and the active substance contained in the reference product Tebu 250 EW. The liquid medium containing difenconazole derivatives was poured onto petri dishes (50 mm). 4 mm was placed on the center of the plate. On the control plates, the fungi were grown on a medium supplemented with ethyl alcohol. The test preparations were compared to the Tebu 250 EW fungicide containing tebuconazole as active substance. The plates were incubated at room temperature around 21 ° C until the mycelium in the control reached the edge Then the diameter of the mycelium was measured by subtracting from the measurement the initial diameter of the disc with the mushroom 4 mm. 3 replicates were performed for each object.The results were analyzed by Student-Newman-Keuls, determining a significant difference between the control and the samples with the addition of preparations.

Results:

The in vitro fungicidal activity against the perpetrators of plant diseases depended on the preparation used, its concentration, and the species of fungus. For Sclerotinia sclerotiorum, Botrytis cinerea and Microdochium nivale all test liquids used

PL229 316 Β1 in concentrations of 100 and 1000 ppm showed very high fungistatic activity. The fungus Fusarium culmorum turned out to be the least sensitive to the tested ionic liquids, and the fungus Botrytis cinerea was the most sensitive.

Claims (9)

Patent claims CLAIMS 1. Quaternary salts of diphenoconazole with an inorganic anion of general formula I, wherein A is: an inorganic nitrate (V) or chloride or bisulfate or tetrafluoroboric anion. 2. A method for the preparation of the quaternary salts of diphenoconazole and an inorganic anion of the general formula 1 as defined in claims The process of claim 1, wherein the quaternary diphenoconazole chloride or bromide of general formula II is dissolved in an aliphatic alcohol with a carbon chain length of one to four carbon atoms, or a mixture thereof, mixed with a methanolic solution of a sodium, potassium or ammonium salt. hydrochloric, nitric (V), or sulfuric (VI) or tetrafluoroboric acid, at a concentration of at least 1%, in a molar ratio of diphenoconazole hydrochloride to salt from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably at 20 ° C, for at least 40 minutes, then the product is isolated and the solvent is then removed. Method for the preparation of the quaternary salts of diphenoconazole and an inorganic anion of the general formula 1 as defined in claims A process as claimed in claim 1, characterized in that the diphenoconazole of general formula II is dissolved in an aliphatic alcohol with a carbon chain length of one to four carbon atoms, or a mixture thereof, preferably ethanol, mixed with a sodium, potassium or ammonium salt of hydrochloric acid, or nitric (V), or sulfur (VI) or tetrafluoroboric dissolved in ethanol at a concentration of at least 1%, in a molar ratio of diphenoconazole quaternary salt to inorganic acid from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably 50 ° C, for at least 40 minutes, followed by removal of the solvent. Process for the preparation of the quaternary salts of diphenoconazole with an inorganic anion of the general formula 1 as defined in claims A process as claimed in claim 1, characterized in that the diphenoconazole quaternary hydroxide of the general formula 2 is dissolved in propanol, mixed with the sodium or potassium or ammonium salt of hydrochloric, nitric (V), sulfuric (VI) or tetrafluoroboric acid dissolved in propanol at a concentration of at least 1%, in a molar ratio of diphenoconazole hydroxide to salt from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably 20 ° C, for at least 40 minutes, then the product is isolated then the solvent is removed. Method for the preparation of the quaternary salts of diphenoconazole with an inorganic anion of the general formula 1 as defined in claims A process as claimed in claim 1, characterized in that the quaternary diphenoconazole chloride or bromide of general formula 2 is dissolved in butanol, mixed with sulfuric (VI), hydrochloric, nitric (V) or tetrafluoroboric acid dissolved in butanol at a concentration of at least 1% , in a molar ratio of diphenoconazole bromide to acid from 1: 1 to 1: 1.05, preferably 1: 1, at a temperature below 100 ° C, preferably 20 ° C, for at least 40 minutes, then separating the reaction product and then the solvent is removed. 6. Use of the novel quaternary salts of diphenoconazole with an inorganic anion as defined in claim 1 1 as fungicides. Use of the quaternary salts of diphenoconazole with an inorganic anion according to claim 1; 6. A method according to claim 6, characterized in that the salts are used in pure form. 8. Use of the quaternary salts of diphenoconazole with an inorganic anion according to claim 1; 6. A method according to claim 6, characterized in that the salts are used in the form of hydroalcoholic solutions. Use of the quaternary salts of diphenoconazole with an inorganic anion according to claim 1; 6. A method according to claims 6 and 8, characterized in that the salts are used in hydroalcoholic solutions with a concentration of at least 0.1%.