PL235469B1 - Protonic salts of cyproconazole, containing inorganic anion, method for obtaining them and application as fungicides - Google Patents

Abstract

The subject of the application are proton salts of cyproconazole, of the general formula 1, in which A- is an anion derived from inorganic sulfuric (VI) or nitric (V) or phosphoric (V) or tetrafluoroboric acid or hydrochloric acid. The application also includes a method for their preparation, which consists in dissolving cyproconazole of the formula 2 in an aliphatic alcohol with a carbon chain length of one to four carbon atoms or a mixture thereof, preferably in methanol, then reacting with an inorganic acid (sulfuric VI), nitric (V), phosphoric (V), tetrafluoroboric or salt) in a molar ratio from 1: 1 to 1: 1.1 at 20°C for at least 20 minutes, then the resulting mixture is evaporated or the solvent is filtered off, after which the obtained product is dried under reduced pressure. The application also includes the use of cyproconazole protic salts as fungicides.

Description

Description of the invention

The present invention relates to a process for the preparation of cyproconazole protic salts containing an inorganic anion.

Proton ammonium salts are compounds with a positively charged nitrogen atom in their structure. This atom is linked through four covalent bonds to other moieties, including at least one hydrogen atom. The nitrogen atom can form bonds in two ways - it can have four σ bonds or one π bond and three σ bond. Ammonium salts can be divided according to the type of nitrogen atom hybridization: aliphatic (sp ³ hybridization) or heterocyclic, which in turn can be aromatic (sp ² hybridization) or non-aromatic (sp ³ hybridization).

Azoles are aromatic compounds that have at least one azomethine nitrogen heteroatom (pyridine type) in the five-membered ring. More heteroatoms may be present in the ring structure; the second heteroatom can be a pyrrole nitrogen atom or another heteroatom (most often an oxygen or sulfur atom) that contributes two electrons to the π-electron sextet in the ring.

Triazoles (Htrz) are five-membered compounds whose ring consists of two carbon atoms and three nitrogen atoms. The five-membered rings of triazoles exist in the form of the structural isomers 1,2,3-triazole or 1,2,4-triazole.

One of the main uses of compounds belonging to the triazole group or having a triazole substituent is as fungus control agents. There are various mechanisms of fungicide action, among which we can distinguish: limiting respiration processes, reducing the biosynthesis of nucleic acids and proteins, causing disturbances in the exchange of chemical substances between fungal cells and the environment, and in the case of plant protection products, activating the immune processes in plants. Fungicidal plant protection products can be divided into: fungicides with surface action (so-called contact), which remain on the plant surface and prevent the germination of fungal spores (e.g. copper compounds, sulfur and its organic compounds) and systemic fungicides (so-called systemic) , penetrating plant tissues and preventing them from the process of infection or the development of the disease.

An example of a fungicide from the triazole group is cyproconazole, which is a component of preparations used mainly in horticulture as a fungicide. It has been proven that it fights apple and pear scab and powdery mildew. Cyproconazole adversely affects the metabolism of pathogenic fungi, inhibiting the biosynthesis of sterols. It disrupts the process of building ergosterol in cell membranes, which causes their incorrect biosynthesis. Ergosterol is a component of the fungal cell membrane, additionally it has important hormonal functions in the process of fungal growth, and is structurally similar to cholesterol.

The essence of the invention is the preparation of proton salts of cyproconazole of the general formula I, in which A - is an anion derived from inorganic sulfuric (VI) or nitric (V) or phosphoric (V) acid, or tetrafluoroboric acid, which consists in the fact that cyproconazole with The formula 2 is dissolved in an aliphatic alcohol with a carbon chain length of one to four carbon atoms, or a mixture of them, preferably methanol, then reacted with an inorganic acid - (sulfuric (VI), or nitric (V), or phosphoric (V ), or tetrafluoroboric) in a molar ratio of 1: 1 to 1: 1.1 at 20 ° C for 20 minutes to 1 hour, then the solvent of the mixture obtained is evaporated or filtered off, and the obtained product is dried in under reduced pressure.

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

• a new group of compounds was obtained - protic salts of cyproconazole with an inorganic anion, • synthesized compounds can be easily isolated from the reaction mixture, • the method of obtaining compounds enables synthesis under mild temperature conditions (20 ° C), • synthesis of proton salts of cyproconazole is highly efficient, • the obtained compounds are non-flammable and non-toxic, • the vapor pressure of the obtained compounds under normal pressure is immeasurable, due to the fact that they have an ionic structure,

• all obtained salts are very soluble in methanol and dimethylsulfoxide, • the obtained compounds show fungicidal properties, they are fungicides.

The preparation of protic salts of cyproconazole with an inorganic anion is shown in the following examples:

P r z k ł a d I:

Process for the production of cyproconazole bisulfate:

0.01 mol (2.92 g) of cyproconazole dissolved in 10 cm ^{3 of} methanol was introduced into the flask equipped with a magnetic stirrer, then 0.01 mol (0.98 g) of concentrated sulfuric acid (VI) dissolved in 10 cm ^{3 of} methanol was added. . The reaction was carried out for 40 minutes at 20 ° C with vigorous stirring. After evaporating off the solvent, the resulting product was dried under reduced pressure for 24 hours. The cyproconazole bisulfate (VI) was obtained with a yield of 99%.

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

¹ H NMR (DMSO-d₆) δ [ppm] = 0.05 (m, 2 H); 0.34 (m, 1H); 0.55 (m, 2H); 0.80 (dd, J = 82.24; 6.90 Hz, 3H); 1.35 (m, 1H); 4.88 (m, 1H); 5.07 (m, 1H); 5.46 (br. S, 1H); 7.32 (m, 2H); 7.43 (m, 2H); 8.07 (br. S, 1H); 8.48 (s, 1H); 8.53 (s, 1H); 9.27 (d, J = 1.55 Hz, 1H).

¹³ C NMR (DMSO- de) δ [ppm] = 2.9; 6.4; 12.7; 14.7; 46.1; 58.3; 77.6; 127.3; 127.6; 127.9; 128.8; 131.3; 140.9; 142.9; 144.7.

P r z x l a d II:

The method of obtaining cyproconazole nitrate (V):

In a reactor equipped with a stirrer, 0.02 mol (5.84 g) of cyproconazole dissolved in 20 cm ^{3 of} isopropanol and 0.02 mol (1.26 g) of nitric acid dissolved in 10 cm ^{3 of} isopropanol were introduced. The reaction mixture was vigorously stirred using a magnetic stirrer for 50 minutes at 20 ° C. A precipitate formed in the reaction mixture, which was filtered off and dried under reduced pressure for 24 hours. The cyproconazole nitrate (V) was obtained with a yield of 97%.

The structure of the compound was confirmed by proton and carbon nuclear magnetic resonance spectra: 1H NMR (DMSO-de) δ [ppm] = 0.03 (m, 2H); 0.34 (m, 1H); 0.54 (m, 2H); 0.80 (dd, J = 85.66; 6.75 Hz, 3H); 1.33 (m, 1H); 4.86 (m, 1H); 5.05 (m, 1H); 5.39 (br. S, 1H); 7.32 (m, 2H); 7.43 (m, 2H); 8.10 (br. S, 1H); 8.45 (d, J = 16.06 Hz, 1H); 9.15 (d, J = 3.74Hz, 1H).

¹³ C NMR (DMSO-d6) δ [ppm] = 2.8; 6.3; 12.7; 14.6; 46.0; 58.2; 77.6; 127.2; 127.6; 127.8; 128.7; 131.3; 140.4; 141.9; 145.0.

P r z x l a d III:

The method of obtaining cyproconazole dihydrogen phosphate (V):

0.005 mol (1.46 g) of cyproconazole was placed in a flask equipped with a magnetic stirrer. Then 10 cm ^{3 of} ethanol was added. After dissolving the compound, 0.006 mol (0.59 g) of phosphoric acid dissolved in 10 cm ^{3 of} ethanol was added and stirring was started. The reaction was carried out for 55 minutes at 20 ° C. The solvent was evaporated under reduced pressure and the obtained solid was dried under reduced pressure for 24 hours to obtain the finished product with a yield of 99%.

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

¹ H NMR (DMSO-d₆) δ [ppm] = 0.04 (m, 2 H); 0.31 (m, 1H); 0.51 (m, 2H); 0.81 (dd, J = 88.39; 6.78 Hz, 3H); 1.28 (m, 1H); 4.70 (m, 1H); 4.92 (m, 1H); 5.36 (br. S, 1H); 7.28 (m, 2H); 7.38 (m, 2H); 7.74 (s, 1H); 7.78 (s, 1H); 8.07 (br. S, 1H); 8.12 (s, 1H); 8.24 (s, 1H).

¹³ C NMR (DMSO-d6) δ [ppm] = 2.8; 6.3; 12.8; 14.6; 46.0; 56.7; 77.8; 127.1; 127.4; 127.8; 128.7; 131.0; 141.1; 142.6; 150.1.

p NMR (DMSO-d6) δ [ppm] = 0.31.

P r z x l a d IV:

Method to obtain cyproconazole tetrafluoroborate:

0.01 mol (2.92 g) of cyproconazole dissolved in 10 cm ^{3 of} 1-butanol was successively charged to the reactor, followed by the addition of 0.011 mol (0.97 g) of tetrafluoroboric acid dissolved in 10 cm ^{3 of} 1-butanol. The reaction was carried out for 1 hour with vigorous stirring with a stirrer

PL 235 469 Β1 magnetic at 20 ° C. After evaporating off the solvent, the obtained solid was dried under reduced pressure for 24 hours. Cyproconazole tetrafluoroborate was obtained with a yield of 94%.

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

¹ H NMR (DMSO-cfe) δ [ppm] = 0.03 (m, 2 H); 0.27 (m, 1H); 0.49 (m, 2H); 0.75 (sd, J = 85.34;

6.90 Hz, 3H); 1.27 (m, 1H); 4.80 (m, 1H); 4.98 (m, 1H); 5.42 (br. S, 1H); 7.12 (br. S, 1H); 7.26 (m, 2H); 7.36 (m, 2H); 8.44 (d, J = 16.53 Hz, 1H); 9.14 (d, J = 3.14 Hz, 1H).

¹³ C NMR (DMSO-cfe) δ [ppm] = 2.8; 6.3; 12.7; 14.7; 46.0; 58.3; 77.6; 127.3; 127.6; 127.8; 128.8;

131.4; 140.4; 142.8; 144.7.

¹⁹ B NMR (DMSO-cfe) δ [ppm] = -147.64.

Table 1 provides a summary of the synthesized cyproconazole salts, and Table 2 is a summary of the solubilities of the synthesized cyproconazole salts.

Table 1

Relationship Anion A. Performance [%] Melting point [° C] Elemental analysis Computed value Measured value [%] C. H. N C. H. N 1 HSO4 99 141.2-145.9 46.21 5.17 10.78 46.42 5.09 10.87 2 NO3 97 162.0 -166.2 50.70 5.40 15.79 50.44 5.15 16.02 3 H2PO4 99 125.9-128.5 46.22 5.43 10.78 45.87 5.28 11.06 4 bf ₄ 94 83.6 - 87.2 47.46 5.05 11.07 47.32 5.21 10.88

Table 2

Relationship water acetone toluene hexane DMSO CHCl3 iPrOH MeOH EtOH ACN 1 - - - - + - - + + - 2 - - - - + - - + + - 3 - + +/- - + - + + + - 4 - + - - + +/- + + 4- +

Application example:

Use of cyproconazole proton salts containing an inorganic anion as fungicides.

Determination of biological activity against pathogenic fungi

PL 235 469 Β1

The obtained salts: cyproconazole bisulfate (VI), cyproconazole nitrate (V), cyproconazole dihydrogenphosphate (V), cyproconazole tetrafluoroborate, cyproconazole hydrochloride were tested against four species of fungi: Sclerotinia sclerotiorum, Falerytis micrium-nerea. Test compounds were dissolved in 4 ml of 96% 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 effect and the active substance contained in the comparison agent Tebu 250 EW). The liquid medium containing cyproconazole derivatives was poured into petri dishes (0 50 mm). Discs of the test mushroom with a diameter of 4 mm were placed in the center of the plate. On the control plates, the fungi were grown on the nutrient medium supplemented with ethyl alcohol. The tested preparations were compared to the Tebu 250 EW fungicide containing tebuconazole as the active substance. The plates were incubated at room temperature (approximately 21 ° C) until the mycelium in the control reached the edge of the plate. The diameter of the mycelium was then measured by subtracting the initial diameter of the mushroom disc (4 mm) from the measurement. 3 repetitions were made 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.

Table 3 shows the results of inhibition of growth of Sclerotinia sclerotiorum and Botrytis cinerea by salts containing cyproconazole, and Table 4 shows the results of inhibition of growth of Fusarium culmorum and Microdochium nivale by salts containing cyproconazole.

Table 3

No Object name Increase 5. sclerotiorum [cm] Height a cinerea [cm] 10 ppm 100 ppm 1000 ppm 10 ppm 100 ppm 1000 ppm 1 Control + ethanol 4.6 4.6 4.6 4.6 4.6 4.6 2 CYP ^ NOf 4.1 0.0 0.0 0.6 0.0 0.0 3 CYP ^ł HS04 0.0 0.0 0.0 0.0 0.0 0.0 4 CYP ⁺ BF4 ' 0.0 0.0 0.0 0.0 0.0 0.0 5 CYP ^ HiPOż 0.0 0.0 0.0 0.0 0.0 0.0 6 CYP ⁺ CL 4.5 0.0 0.0 4.1 0.0 0.0 7 Tebu 250 EW 0.1 0.0 0.0 1.0 0.0 0.0 NIR (P = 0.05) 0.259 - - 0.156 -

PL 235 469 Β1

Table 4

No Object name Increase F. culmorum [cm] Increase M.nivole [cm] 10 ppm 100 ppm 1000 ppm 10 ppm 100 ppm 1000 ppm 1 Control + ethanol 4.6 4.6 4.6 4.6 4.6 4.6 2 cyp'no ₃ 3.8 0.0 0.0 4.6 0.2 0.0 3 Cyp ^L HSO4 0.4 0.0 0.0 1.7 0.1 0.0 4 CYP'BF. ’ 0.8 0.0 0.0 2.4 0.1 0.0 5 CYP * HiPO <T. 0.7 0.0 0.0 2.1 0.1 0.0 6 CYP'CL- 4.5 0.0 0.0 4.6 0.1 0.0 7 Tebu 250 EW 0.0 0.0 0.0 0.7 0.0 oh oh NIR (P = 0.05; 0.153 0.028 0.163 0.052 -

Description of the results:

Tables 3 and 4 summarize the results showing the effect of the tested cyproconazole salts on the growth of pathogenic fungi: Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium culmorum and Microdochium nivale. All test compounds used at a concentration of 100 and 1000 ppm completely inhibited the growth of S. sclerotiorum, B. cinerea and F. culmorum, and almost completely the growth of M. nivale. At a concentration of 10 ppm, the strongest fungistatic effect was demonstrated by: hydrogen sulphate (VI), tetrafluoroborate and cyproconazole dihydrogen phosphate (V).

Claims (1)

A method for the preparation of proton salts of cyproconazole of the general formula I, wherein A is an anion derived from inorganic sulfuric (VI) or nitric (V) or phosphoric (V) acid, or tetrafluoroboric acid, characterized in that cyproconazole of formula 2 is dissolved in an aliphatic alcohol with a carbon chain length of one to four carbon atoms, or a mixture thereof, preferably in methanol, then reacted with an inorganic acid - (sulfuric (VI), or nitric (V), or phosphoric (V), or tetrafluoroboric acid in a molar ratio from 1: 1 to 1: 1.1 at 20 ° C for 20 minutes to 1 hour, the solvent of the mixture obtained was further evaporated or filtered off, and the obtained product was dried under reduced pressure.