PL228473B1 - Proton ionic liquid of propiconazole and method for producing them - Google Patents

Description

(12) PATENT DESCRIPTION ₍ i ₉₎ PL ₍ n) 228473 (13) B1 (51) Int.CI.

(21) Filing number: 406946 C07D 405/06 (2006.01)

C07C 59/68 (2006.01) C07C 59/70 (2006.01) (22) Date of notification: 27.01.2014 ^{A01N 43/653} (2006.01)

A01P 3/00 (2006.01) A01P 13/00 (2006.01) (54) Propiconazole proton ionic liquids and the method of their preparation (73) The right holder of the patent:

INSTITUTE OF PLANT PROTECTION - PAŃSTWOWY INSTYTUT BADAWCZY, Poznań, PL (43) Application was announced:

03.08.2015 BUP 16/15 (45) The following was announced about the grant of the patent:

30/04/2018 WUP 04/18 (72) Inventor (s):

JULIUSZ PERNAK, Poznań, PL BARTOSZ MARKIEWICZ, Poznań, PL TADEUSZ PRACZYK, Luboń, PL KATARZYNA MARCINKOWSKA, Mosina, PL ROMUALD GWIAZDOWSKI, Poznań, PL KRZYSZTOF KUBIAK, Poznań, PL (74) Plenipotentiary:

thing, pat. Barbara Urbańska-Łuczak co r'St co

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PL 228 473 B1

Description of the invention

The subject of the invention is the protic ionic liquids of propiconazole and the method of their preparation, useful as fungicidal compounds and herbicides.

The increase in the number of people at the turn of the last few centuries has resulted in a greater demand for natural resources and food. To do this, you need to use the planet effectively to protect yourself from past mistakes. In 1845, when the potato blight caused dramatic effects in Western Europe, it was considered the greatest scourge known to man in the history of the earth. Over a million people died of starvation over the course of a few years. Such large losses of food and population resulted in intensive research into means of protection against fungi - fungicides.

From the 1930s, the period of synthesis of new, organic fungicides began, which include: derivatives of phenols, quinone, dithiocarbamate, captan, chloronitrobenzene, triazine and quinolinol. Since the 1960s, scientists have focused on obtaining compounds with a nitrogen atom in the ring in their structure. This group of compounds includes: morpholines, piperazines, imidazoles and triazoles, with triazoles dominating the fungicide market since the nineties. This is due not only to their very high efficiency, but also to their low environmental toxicity and lower accumulation in the soil.

Propiconazole was obtained in 1979. It is synthesized first by ketonization of 2-bromo-1- (2,4-dichlorophenyl) ethanone with pentadium-1,2-ol, and then by nucleophilic substitution with 1,2,4-triazole in the presence of a base, at 433K in DMF (US Patent 4911750A). Propiconazole has two chiral centers, therefore there are four stereoisomers, consisting of two pairs of diastereoisomers. S-isomers exhibit a higher biological activity than the R-isomers.

Propiconazole has proven to be one of the most effective triazole fungicides used to protect rice, nuts, maize, stone fruit and cereals against disease. In Poland, it is available in the preparation Bumper 250 EC. Apart from its fungicidal activity, its ability to complex metals is also used. The 1,2,4-triazole ring present in propiconazole is protonated to give the cation.

The essence of the invention are ionic liquids of the general formula 1, in which the cation is protonated propiconazole, and A is an organic anion of the general formula 2-2-methyl-4-chlorophenoxyacetate, in which R ¹ = H, R ² = CH3, R ³ = H ; or 2-methyl-4-chlorophenoxypropionate where R ¹ = H, R ² = CH 3, R ³ = CH 3; or 2,4-dichlorophenoxyacetate, where R ¹ = Cl, R ² = H, R ³ = H.

The method of their preparation consists in reacting propiconazole of the general formula 3 with an organic acid of the general formula 4-2-methyl-4-chlorophenoxyacetic acid in which R ¹ = H, R ² = CH 3, R ³ = H; or 2-methyl-4-chlorophenoxypropionic acid where R ¹ = H, R ² = CH 3, R ³ = CH 3; or 2,4-dichlorophenoxyacetic acid, where R ¹ = Cl, R ² = H, R ³ = H; at the molar ratio of propiconazole to organic acid equal to 1: 0.8-1.5 in an alcoholic medium, at a temperature from 273 to 363K, preferably at 298K, for 1-48 h, preferably 8 h, then the solvent, the residue is evaporated off washed with hexane to remove excess unreacted acid, and the residue was dried in vacuo at 303 to 343K for 4-12 hours, preferably 323K for 10 hours.

It is preferred that the alcohol is methanol or isopropanol.

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

- a new group of compounds belonging to the proton salts of the triazole was obtained,

- the synthesized proton salts contain an organic anion derived from a phenoxy acid,

- protic salts with an organic anion show low melting points, they are new representatives of protic ionic liquids,

- the synthesized proton salts of propiconazole are soluble in alcohols, slightly in chloroform, partially in acetone, toluene, ethyl acetate and are insoluble in hexane,

- the obtained new forms of propiconazole show strong fungicidal effects,

- synthesized forms of propiconazole with an anion derived from phenoxyacid destroy fungi and act on weeds. They are effective herbicides and fungicides at the same time.

The invention relates to protic salts of propiconazole of the general formula I and the preparation thereof is illustrated by the following examples:

PL 228 473 B1

P r z k ł a d I

Propiconazole 2-methyl-4-chlorophenoxyacetate (propiconazole-MCPA)

To a flask of 100 ^cm3 equipped with a magnetic stir bar was added 0.007 mol of propiconazole dissolved in 25 cm ³ of methanol and 0.008 mol of the sodium salt of 2-methyl-4-chlorophenoxyacetate dissolved in 25 cm ³ of methanol. The reaction mixture was vigorously stirred for 4 hours at room temperature. The resulting inorganic salt was filtered off and the solvent was removed under reduced pressure. Then the mixture was dried for 24 hours under reduced pressure at the temperature of 323K. ^{15 cm 3 of} anhydrous acetone were added to the dried reaction mixture, the inorganic salt was NaCl, the mixture was separated by filtration, and the solvent of the filtrate was evaporated. At the final stage, the product was dried for 24 hours at the temperature of 313K under reduced pressure.

Propiconazole 2-methyl-4-chlorophenoxyacetate was obtained with a yield of 97%.

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

¹ H NMR (DMSO-d6) δ (ppm) = 0.86 (m, 3H); 1.2-1.39 (m, 4H); 2.18 (s, 3H); 3.23 (s. 1H); 3.34 (t, J = 15.9 Hz, 1H) 3.91 (m, 2H); 4.72 (m, 2H); 6.85 (d. 1H); 7.14 (m, 1H); 7.22 (m, 1H); 7.4-7.48 (m, 2H); 7.66 (m, 1H); 7.86 (d, J = 10.2 Hz, 1H); 8.41 (s. 1H); 13.07 (s. 1H).

¹³ C NMR (DMSO-d6) δ (ppm) = 13.82; 15.73; 18.45; 34.36; 53.48; 64.92; 69.48; 76.23; 77.27; 124.23; 126.25; 128.40; 130.44; 132.45; 135.51; 145.65; 150.72; 154.71; 170.05.

Elemental analysis for C24H26Cl3N3O5 (M = 542.84 g / mol): calculated values (%): C = 53.10; H = 4.83; N = 7.74; measured values: C = 53.21; H = 4.78; N = 7.68.

P r z x l a d II

Propiconazole 2-methyl-4-chlorophenoxypropionate (propiconazole-MCPP)

0.015 mol of propiconazole dissolved in 10 cm ^{3 of} methanol was introduced into the round bottom flask. Then, with continuous stirring, is added 0.016 mol of 2-ethyl-4-chlorophenoxypropionate dissolved in 25 cm ³ of methanol. The reaction was carried out for 14 hours at the temperature of 300K. Methanol was evaporated from the reaction mixture on a rotary evaporator, and then 15 cm ^{3 of} hexane was added to remove the remaining unreacted phenoxy acid. The product was dried for 24 hours at the temperature of 313K under reduced pressure.

Propiconazole 2-ethyl-4-chlorophenoxypropionate was obtained with a yield of 99%.

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

¹ H NMR (DMSO-d6) δ (ppm) = 0.85 (m, 3H); 1.2-1.39 (m, 4H); 1.52 (d, 3H); 2.17 (s, 3H); 3.23 (s. 1H); 3.34 (t, J = 15.9 Hz, 1H) 3.91 (m, 2H); 4.73 (m, 2H); 4.83 (t, 2H); 6.78 (d. 1H); 7.12 (m, 1H); 7.30 (m, 1H); 7.4-7.48 (m, 2H); 7.63 (m, 1H); 7.87 (d, J = 10.2 Hz, 1H); 8.41 (s. 1H); 13.11 (s. 1H).

¹³ C NMR (DMSO-d6) δ (ppm) = 13.82; 15.75; 18.41; 34.33; 53.48; 64.95; 69.46; 76.24; 77.25; 106.49; 124.24; 126.22; 128.41; 130.43; 132.44; 135.56; 145.65; 150.78; 154.74; 170.01.

Elemental analysis for C24H28Cl3N3O5 (M = 556.87 g / mol): calculated values (%): C = 53.92; H = 5.07; N = 7.55; measured values: C = 53.81; H = 5.18; N = 7.68.

P r x l a d III

Propiconazole 2,4-dichlorophenoxyacetate (propiconazole 2,4 D)

In a reactor equipped with a magnetic stirrer was dissolved 0.006 mol of propiconazole in isopropanol, then with constant stirring is added 0.006 mol of 2,4-dichlorophenoxyacetic acid dissolved in 25 cm ^{3 of} isopropanol. The reaction was carried out for 2 hours at the temperature of 303K. After the end of the process, the solvent was evaporated and the product was dried at the temperature of 323K for 48 hours under reduced pressure. Propiconazole 2,4-dichlorophenoxyacetate was obtained with a yield of 99%.

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

¹ H NMR (DMSO-d6) δ (ppm) = 0.86 (m, 3H); 1.27-1.36 (m, 4H); 3.24 (s. 1H); 3.36 (t, J = 16.1 Hz, 1H); 3.71 (s. 1H); 3.91 (m, 2H); 4.74 (m, 2H); 4.85 (t, 2H); 7.09 (m, 1H); 7.33 (m, 1H); 7.4-7.48 (m, 2H); 7.57 (d. 1H); 7.65 (m, 1H); 7.88 (s. 1H); 8.42 (s. 1H); 13.11 (s. 1H).

¹³ C NMR (DMSO-d6) δ (ppm) = 13.81; 18.42; 34.31; 53.44; 65.17; 69.49; 76.21; 77.28; 114.88; 124.2; 127.3; 129.4; 130.51; 132.39; 135.52; 145.35; 150.78; 152.35; 169.55.

PL 228 473 B1

Elemental analysis for C23H23Cl4N3O5 (M = 563.26 g / mol): calculated values (%): C = 49.04; H = 4.12; N = 7.46; measured values: C = 49.15; H = 4.18; N = 7.58.

Application examples:

P r z k ł a d 1

Determination of biological activity against pathogenic fungi

The obtained protic ionic liquids of propiconazole were tested against the fungal species: Botrytis cinerea, Fusarium culmorum ATCC 44417, Sclerotinia sclerotiorum and Microdochium Nivale (from the IOR-PIB collection).

The new triazole forms were dissolved in 4 cm ^{3 of} pure methanol and then added to a sterile medium / medium (PDA - Potato Dextrose Agar, Difco ™) heated to 323K. The concentration of triazoles in the medium was adjusted to 10, 100 and 1000 ppm. The liquid medium with the compounds 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 broth with the addition of water and on the broth with the addition of pure methanol. The tested preparations were compared to the Tebu 250 EW fungicide containing tebuconazole as the active substance. The plates were incubated at room temperature 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. Four 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.

Growth inhibition of the mycelium of Botrytis cinerea, Fusarium culmorum, Sclerotinia sclerotiorum and Microdochium Nivale is summarized in Table 1.

P r z k ł a d 2

Determination of biological activity against plants (herbicidal effect)

The tests were performed in greenhouse conditions. The test plants were white mustard (Sinapis album L.) and white quinoa (Chenopodium album L).

The seeds were sown in pots filled with soil to an equal depth of 1 cm and placed in a greenhouse to provide optimal conditions for plant growth. After producing the cotyledons, a break was made, leaving 4 plants in each pot. After the fourth leaf was produced, the plants were sprayed with the liquid containing the test compounds using a sprayer equipped with a Tee Jet 1102 sprayer, moving over the plants at a constant speed of 3.1 m / s. The distance of the sprayer from the tops of the plants was 40 cm, the liquid pressure in the sprayer was 0.2 MPa, and the liquid output per 1 ha was 200 liters.

The test compounds were dissolved in a solution of water + ethanol (1: 1) in an amount corresponding to 170 g of MCPA, 2,4-D or MCPP per 1 ha. The herbicides registered in Poland containing MCPA (Chwastox Extra 300 SL) or 2,4-D (Aminopielik Standard 600 SL) were used as comparative agents.

After spraying, the pots with plants were placed back in the greenhouse at 293K (± 2K) and 60% air humidity. The lighting time was 16 hours. per day.

After 2 weeks, the plants were cut just above the soil and their weight was determined with an accuracy of 0.01 g, separately for each pot. The study was performed in 4 repetitions in a completely randomized design. On the basis of the obtained measurements, the reduction of the fresh weight of the plants was calculated as compared to the control (plants not sprayed with the test compounds). The obtained results are presented as percentages of the agent's effectiveness in Table 2.

PL 228 473 Β1

Table 1

Inhibition of mycelium growth

Object name Increase P. culmorum [cm] Increase M. π ί ναιe [cm] Increase 5. cinerec [cm] Increase 5. sclerotiorum [cm] 10 ppm 100 ppm 1000 ppm 10 ppm 100 ppm 1000 ppm 10 ppm 100 ppm 1000 ppm 10 ppm 100 ppm 1000 ppm Control 4.6 a 4.6 a 4.6 a 4.6 a 4.6 a 4.6 a 4.6 a 4.6 a 4.6 a 4.6 a 4.6 A. 4.6 a propiconosol MCPA 0.4 c 0.0 c 0.0 c 0.1 c 0.0 c 0.0 c 0.0 d 0.0 c 0.0 c 1.3 c 0.0 C 0.0 c propiconazole- MCPP 0.3 c 0.0 c 0.0 c 0.1 c 0.0 c 0.0 c 0.0 d 0.0 c 0.0 c 0.9 c 0.0 C 0.0 c propiconazole- 2,4-D 0.4 c 0.0 c 0.0 o 0.0 c 0.0 c 0.0 c 0.1 d 0.0 c 0.0 c 1.3 c 0.0 C 0.0 c Bumper 250 EC 0.4 o 0.0 o 0.0 c 0.1 c 0.0 c 0.0 o 0.8 c 0.1 c 0.0 c 0.8 c 0.0 C 0.0 c NIR (P = 0.05) 0.39 0.29 0.05 0.53 0.15 0.03 0.18 0.50 - 0.85 0.05 -

Mean values followed by the same letter do not differ significantly (P = 0.05, Student-Newman-Keuls)

Table 2

The effectiveness of the protic ionic liquids of propiconazole

The name of the measure Operation efficiency in% White mustard White quinoa propiconazole-MCPA 41 31 propiconazole-MCPP 13 24 propiconose P-2,4-D 34 16 Weeds Extra 300 SL 25 16 AminDpielik Standard 600 SL 40 0

Patent claims

Claims (3)

1. Ionic liquids of the general formula 1, in which the cation is the protonated propiconazole, A and organic anion of the formula 2-2-methyl-4-chlorofenoksyoctanowym, wherein R ¹ = H, R ² = CH 3, R ³ = H; or 2-methyl-4-chlorophenoxypropionate where R ¹ = H, R ² = CH 3, R ³ = CH 3; or 2,4-dichlorophenoxyacetate, where R ¹ = Cl, R ² = H, R ³ = H. Process for the preparation of the protic ionic liquids of propiconazole according to claim 1, characterized in that propiconazole of the general formula 3 is reacted with an organic acid of the general formula 4-2-methyl-4-chlorophenoxyacetic acid, in which R ¹ = H, R ² = CH 3, R ³ = H; or 2-methyl-4-chlorophenoxypropionic acid where R ¹ = H, R ² = CH 3, R ³ = CH 3; or 2,4-dichlorophenoxyacetic acid, where R ¹ = Cl, R ² = H, R ³ = H; at the molar ratio of propiconazole to organic acid equal to 1: 0.8-1.5 in an alcoholic medium, at a temperature from 273 to 363K, preferably at 298K, for 1-48 h, preferably 8 h, then the solvent, the residue is evaporated off washed with hexane to remove excess unreacted acid, and the residue was dried in vacuo at 303 to 343K for 4-12 hours, preferably 323K for 10 hours. 3. The method of producing protic salts of propiconazole according to claim 1, The process of claim 2, wherein the alcohol is methanol or isopropanol.