Method for treating coffee rust, citrus black spot, citrus scab and banana black sigatoka diseases

Abstract

The invention relates to the use of a compound of formula (I) or salts thereof for controlling coffee rust, citrus black spot, citrus scab or banana black sigatoka disease, and to corresponding methods. ##STR00001##

Claims

1. A method for treating plants in need of control of citrus black spot, comprising applying to said plants or parts of said plants, to the seeds from which they grow or to the locus in which they grow, an effective amount for controlling the disease, of N-(5-chloro-2-isopropylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, or an agrochemically acceptable salt thereof, wherein the citrus black spot is caused by Guignardia citricarpa.

2. The method according to claim 1, wherein N-(5-chloro-2-isopropylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide or an agrochemically acceptable salt thereof, is applied to said plants, to the seeds from which they grow or the locus in which they grow at an application rate of from about 0.001 kg/ha to about 1 kg/ha of N-(5-chloro-2-isopropylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide.

3. The method according to claim 1, wherein N-(5-chloro-2-isopropylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, or an agrochemically acceptable salt thereof, is applied by spray application to plants and plant parts in combination with one or more active ingredients selected from the group consisting of insecticides, attractants, acaricides, fungicides, nematicides, herbicides, growth regulators, fertilizers, safeners, substances which influence plant maturity and bactericides.

4. The method according to claim 1, wherein N-(5-chloro-2-isopropylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide, or an agrochemically acceptable salt thereof, is applied to genetically modified cultivars, the seed thereof, or to cultivated areas on which these cultivars grow.

Description

(1) The following examples illustrate in a non limiting manner the preparation of the compounds of formula (I) according to the invention.

Preparation of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide (Compound A1)

Step A: Preparation of N-(2-isopropylbenzyl)cyclopropanamine

(2) To a solution of 55.5 g (971 mmol) of cyclopropanamine in 900 mL of methanol, are successively added 20 g of 3 molecular sieves and 73 g (1.21 mol) of acetic acid. 72 g (486 mmol) of 2-isopropyl-benzaldehyde are then added dropwise and the reaction mixture is further heated at reflux for 4 hours.

(3) The reaction mixture is then cooled to 0 C. and 45.8 g (729 mmol) of sodium cyanoborohydride are added by portion in 10 min and the reaction mixture is stirred again for 3 hours at reflux. The cooled reaction mixture is filtered over a cake of diatomaceous earth. The cake is washed abundantly by methanol and the methanolic extracts are concentrated under vacuum. Water is then added to the residue and the pH is adjusted to 12 with 400 mL of a 1 N aqueous solution of sodium hydroxide. The watery layer is extracted with ethyl acetate, washed by water (2300 mL) and dried over magnesium sulfate to yield 81.6 g (88%) of N-(2-isopropylbenzyl)cyclopropanamine as a yellow oil used as such in the next step.

(4) The hydrochloride salt can be prepared by dissolving N-(2-isopropylbenzyl)cyclopropanamine in diethyl-ether (1.4 mL/g) at 0 C. followed by addition of a 2 M solution of hydrochloric acid in diethylether (1.05 eq.). After a 2 hours stirring, N-(2-isopropylbenzyl)cyclopropanamine hydrochloride (1:1) is filtered off, washed by diethylether and dried under vacuum at 40 C. for 48 hours. Mp (melting point)=149 C.

Step B: preparation of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide

(5) To 40.8 g (192 mmol) of N-(2-isopropylbenzyl)cyclopropanamine in 1 L of dry tetrahydrofurane are added at room temperature, 51 mL (366 mmol) of triethylamine. A solution of 39.4 g (174 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride in 800 mL of dry tetrahydrofurane is then added dropwise while maintaining the temperature below 34 C. The reaction mixture is heated at reflux for 2 hours then left overnight at room temperature. Salts are filtered off and the filtrate is concentrated under vacuum to yield 78.7 g of a brown oil. Column chromatography on silica gel (750 ggradient n-heptane/ethyl acetate) yields 53 g (71% yield) of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide as a yellow oil that slowly crystallizes. Mp=76-79 C.

(6) In the same way, compounds A2 to A19 can be prepared according to the preparation described for compound A1.

Preparation of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carbothioamide (Compound A20)

(7) A solution of 14.6 g (65 mmol) of phosphorus pentasulfide and 48 g (131 mmol) of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carboxamide in 500 ml of dioxane are heated at 100 C. for 2 hours. 50 ml of water are then added and the reaction mixture is further heated at 100 C. for another hour. The cooled reaction mixture is filtered over a basic alumina cartridge. The cartridge is washed by dichloromethane and the combined organic extracts are dried over magnesium sulfate and concentrated under vacuum to yield 55.3 g of an orange oil. The residue is tritured with a few mL of diethyl-ether until crystallisation occurs. Crystals are filtered off and dried under vacuum at 40 C. for 15 hours to yield 46.8 g (88% yield) of N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-1-methyl-1H-pyrazole-4-carbothioamide. Mp=64-70 C.

(8) Table 1 provides the log P and NMR data (.sup.1H) of compounds A1 to A20.

(9) In table 1, the log P values were determined in accordance with EEC Directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on a reversed-phase column (C 18), using the method described below:

(10) Temperature: 40 C.; Mobile phases: 0.1% aqueous formic acid and acetonitrile; linear gradient from 10% acetonitrile to 90% acetonitrile.

(11) Calibration was carried out using unbranched alkan-2-ones (comprising 3 to 16 carbon atoms) with known log P values (determination of the log P values by the retention times using linear interpolation between two successive alkanones). lambda-max-values were determined using UV-spectra from 200 nm to 400 nm and the peak values of the chromatographic signals.

(12) TABLE-US-00001 Cmpd logP NMR A1 3.35 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.64 (bs, 4H), 1.21 (d, J = 6.60 Hz, 6H), 2.44-2.80 (m, 1H), 3.01-3.29 (m, 1H), 3.78 (s, 3H), 4.76 (bs, 2H), 6.89 (t, J = 54.70 Hz, 1H), 7.12-7.33 (m, 4H). A2 3.44 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.47-0.77 (m, 6H), 0.80-1.04 (m, 2H), 1.92 (bs, 1H), 2.66 (bs, 1H), 3.80 (s, 3H), 4.92 (bs, 2H), 6.90 (t, J = 54.50 Hz, 1H), 7.01-7.25 (m, 4H). A3 4.06 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.61 (bs, 4H), 1.46 (s, 9H), 2.77-2.98 (m, 1H), 3.89 (s, 3H), 5.05 (bs, 2 H), 6.91 (t, J = 54.70 Hz, 1H), 7.20 (bs, 3H), 7.35-7.48 (m, 1H). A4 3.76 .sup.1H NMR (300 MHz, CHCl.sub.3-d): ppm 0.65-0.69 (m, 4H), 1.21 (t, 3H), 2.62-2.64 (m, 3H), 3.81 (s, 3H), 4.70 (s, 2H), 6.85 (t, J = 54.6 Hz, 1H), 7.04-7.22 (m, 3H). A5 4.09 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.63-0.73 (m, 4H), 1.22 (d, J = 6.92 Hz, 6H), 2.59-2.87 (m, 1H), 2.98-3.30 (m, 1H), 3.82 (s, 3H), 4.74 (bs, 2H), 6.88 (t, J = 54.40 Hz, 1H), 7.20-7.27 (m, 3H). A6 3.41 .sup.1H NMR (300 MHz, CHCl.sub.3-d): ppm 0.65-0.66 (m, 4H), 1.21 (t, 3H), 2.62 (q, 2H), 2.64 (bs, 1H), 3.81 (s, 3H), 4.71 (s, 2H), 6.86 (t, J = 54.6 Hz, 1H), 6.89-6.95 (m, 2H), 7.13-7.18 (m, 1H). A7 3.70 .sup.1H NMR (300 MHz, CHCl.sub.3-d): ppm 0.65-0.69 (m, 4H), 1.22 (d, 6H), 2.69 (bs, 1H), 3.10-3.14 (m, 1H), 3.81 (s, 3H), 4.75 (s, 2H), 6.86 (t, J = 54.6 Hz, 1H), 6.88-6.93 (m, 2H), 7.23-7.28 (m, 1H). A8 3.46 .sup.1H NMR (300 MHz, CHCl.sub.3-d): ppm 0.60-0.66 (m, 6H), 0.89-0.95 (m, 2H), 1.82-1.84 (m, 1H), 2.73 (bs, 1H), 3.81 (s, 3H), 4.89 (s, 2H), 6.68-6.99 (m, 4H). A9 4.21 .sup.1H NMR (300 MHz, CHCl.sub.3-d): ppm 0.64-0.68 (m, 4H), 1.56-1.62 (m, 2H), 1.62-1.70 (m, 2H), 1.76-1.83 (m, 2H), 1.96-2.05 (m, 2H), 2.71 (bs, 1H), 3.13-3.19 (m, 1H), 3.81 (s, 3H), 4.76 (s, 2H), 6.86 (t, J = 54.0 Hz, 1H), 6.87-6.97 (m, 2H), 7.23-7.28 (m, 1H). A10 3.65 .sup.1H NMR (400 MHz, CHCl.sub.3-d): ppm 0.65 (bs, 4H), 1.21 (d, J = 6.75 Hz, 5H), 2.29-2.59 (m, 1H), 3.00-3.36 (m, 1H), 3.79 (s, 3H), 4.83 (s, 2H), 6.68-7.06 (m, 2H), 7.13 (d, J = 7.78 Hz, 1H), 7.27-7.33 (m, 1H). A11 3.70 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.65 (bs, 4H), 2.31 (s, 3H), 2.64 (m, 1H), 3.81 (s, 3H), 4.73 (bs, 2H), 6.89 (t, J = 54.6 Hz, 1H), 7.01-7.14 (m, 3H). A12 3.99 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.66 (bs, 4H), 1.22 (d, J = 6.97 Hz, 6H), 2.31 (s, 3H), 2.54-2.75 (m, 1H), 2.99-3.25 (m, 1H), 3.81 (s, 3H), 4.75 (bs, 2H), 6.89 (t, J = 53.90 Hz, 1H), 7.01-7.23 (m, 3H). A13 3.76 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.61-0.68 (m, 6H), 0.80-1.00 (m, 2H), 1.74-2.00 (m, 1H), 2.31 (s, 3H), 2.53-2.82 (m, 1H), 3.81 (s, 3H), 4.89 (bs, 2H), 6.83 (t, J = 54.80 Hz, 1H), 6.91-7.06 (m, 3H). A14 4.36 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.62 (m, 4H), 1.44 (s, 9H), 2.28 (s, 3H), 2.74-3.02 (m, 1H), 3.83 (bs, 3H), 5.02 (bs, 2H), 6.85 (t, J = 54.40 Hz, 1 H), 7.01 (bs, 1H), 7.21-7.29 (m, 2 H). A15 3.80 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.50-0.67 (m, 4H), 2.81 (bs, 1H), 3.78 (s, 3H), 4.85 (bs, 2H), 6.78 (t, J = 55.00 Hz, 1H), 7.20-7.29 (m, 2H), 7.54 (d, J = 8.17 Hz, 1H). A16 3.78 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.55-0.70 (m, 4H), 2.37 (s, 3H), 2.72-3.04 (m, 1H), 3.83 (bs, 3H), 4.91 (bs, 2H), 6.86 (t, J = 54.50 Hz, 1H), 7.10-7.20 (m, 2H), 7.54 (d, J = 7.89 Hz, 1H). A17 3.46 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.47-0.64 (m, 4H), 2.29-2.55 (m, 1H), 3.80 (s, 3H), 5.05 (s, 2H), 6.95 (t, J = 54.40 Hz, 1H), 7.40 (t, J = 7.86 Hz, 1H), 7.60-7.70 (dd, 2H). A18 3.62 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.50-0.74 (m, 4H), 2.45-2.71 (m, 1H), 3.81 (s, 3H), 4.99 (s, 2H), 6.91 (t, J = 54.40 Hz, 1H), 7.45-7.57 (m, 2H). A19 4.04 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.65 (bs, 4H), 1.20 (t, J = 7.43 Hz, 3H), 2.22 (s, 3H), 2.24 (s, 3H), 2.58-2.64 (m, 2H), 3.80 (s, 3H), 4.70 (bs, 2H), 6.89 (t, J = 54.70 Hz, 3H), 6.98 (bs, 2H). A20 4.36 .sup.1H NMR (500 MHz, CHCl.sub.3-d): ppm 0.55-0.84 (m, 4H), 1.27 (d, J = 6.97 Hz, 6H), 2.73-2.85 (m, 1H), 3.04-3.23 (m, 1H), 3.80 (s, 3H), 4.60-5.06 (m, 1H), 6.99-7.38 (m, 5H).

BIOLOGICAL EXAMPLES

(13) 1. Control of Rust (Hemileia vastatrix) on Coffee Crop (Field Trials).

(14) Four field trials were implemented in Brazil in 2013 and 2014 to evaluate the performance of compounds against Hemileia vastatrix on Coffee.

(15) The trials were carried out according to standard experimental practice to protect the canopy from the rust, responsible to defoliation and then yield losses. A typical fungicide formulation containing 100 g of compound per liter was applied in consecutive foliar sprays at 3 occasions every 30 to 50 days in most of the trials. Spray volumes vary from 400 L to 500 L/Ha.

(16) Assessments were realized on leavesData are expressed in % efficacy against rust on leaves compared to untreated plants.

(17) TABLE-US-00002 Trial(s) 400-300 L/Ha rates active A B C D Compound ingredient % Efficacy % Efficacy % Efficacy % Efficacy (concentration) g a.i./ha (Abbott) (Abbott) (Abbott) (Abbott) N-(5-chloro-2- 50 84 61 95 73 isopropylbenzyl)-N- cyclopropyl-3- (difluoromethyl)-5-fluoro- 1-methyl-1H-pyrazole-4- carboxamide (compound A5) (100 g/L) Opera 50 + 133 79 (Epoxyconazole + Pyraclostrobin.)

(18) The assessments realized in the four trials reported in the table show the high level of efficacy of compound A5 used in solo at 50 g ai/ha, against coffee rust. The level of efficiency is in the same range than the one obtained with the standard Opera, used at the recommended dose. Nevertheless, compound A5 is able to obtain said high efficiency when it is used in solo, and at the very low dose of 50 g ai/ha, while Opera is a mix of two active ingredient, and used at the high concentration of 183 g a.i./ha (50+133).

(19) Conclusion

(20) The example above demonstrates that compound A5 represents a new alternative tool to control Coffee rust with low active rates of 50 g ai/ha. The efficacy at these low rates competes with already sold ready mix compounds based on mixtures of epoxyconazole and pyraclostrobin (Opera), while said latest mixtures is used at the concentration of 183 g a.i./ha.

(21) Compound A5 has a high and unexpected better efficiency (comparable control at much less rate) than Opera and can participate to the reduction of chemical loading in plantations.

(22) 2. Control of Black Spot (Guignardia citricarpa) and Scab (Elsinoe Spp) on Citrus Crop (Field Trials).

(23) Five field trials were implemented in South Africa, Brazil and Japan in 2013 and 2014 to evaluate the performance of compounds against two main diseases having high effect on marketable yield: Elsinoe fawcettii and Guignardia citricarpa are hosted by many citrus species. Both are able to infest fruits and both are quarantine pathogens limiting the exportation outside of the growing countries. The protection against these two pathogens gives a clear advantage for farmers to be present on the export market.

(24) The trials were carried out according to standard experimental practice to protect the canopy including fruits in each country. A typical fungicide formulation containing 100 g of compound per liter was applied in consecutive foliar sprays at 5 to 6 occasions every month to control black spot and at 1 to 3 occasions every 14 days to control Scab infections. Spray volumes vary from 2000 L to 3000 L/Ha.

(25) Results from the Trials Guignardia citricarpa (Black Spot)

(26) TABLE-US-00003 Trial(s) 2000 to 3000 L/Ha rates A B C active % % % Compound ingredient Efficacy Efficacy Efficacy (concentration) g a.i./100 L (Abbott) (Abbott) (Abbott) N-(5-chloro-2- 10 73 72 91.3 isopropylbenzyl)-N- 15 70 83 93.9 cyclopropyl-3- (difluoromethyl)- 5-fluoro-1-methyl-1H- pyrazole-4- carboxamide (compound A5) (100 g/L) Sancozeb (Mancozeb) 160 40 35

(27) The assessments show that compound A5 used at very low rates (from 10 g to 15 g a.i./100 L) gives superior efficacy than Mancozeb currently used to control Black Spot, despite Mancozeb is used as a very higher rate (160 g a.i./100 L). Commercial standard Mancozeb needs significantly higher a.i. concentration (around 15 times higher) to obtain comparable or even lower efficiency.

(28) Results from the Trials Elsinoe fawcettii (Scab)

(29) TABLE-US-00004 Trial(s) 3000 L/Ha rates active A B Compound ingredient % Efficacy % Efficacy (concentration) g a.i./100 L (Abbott) (Abbott) N-(5-chloro-2- 2.5 96 92 isopropylbenzyl)- 5 95 70 N-cyclopropyl-3- (difluoromethyl)-5-fluoro-1- methyl-1H-pyrazole-4- carboxamide (compound A5) (100 g/L) Stroby DF (Kresoxim methyl) 23.5 86 82 Delan FL (Dithianon) 400 65 48

(30) The assessments show that compound A5 used at very low rates (from 2.5 g to 5 g ai/100 L) gives superior efficacy than commercial standards Kresoxim methyl and Dithianon currently used to control Black Spot, although said commercial standards are used at very higher rate (around 10 times higher for Stroby DF and around 160 times higher for Dithianon).

(31) Conclusion

(32) The examples above demonstrate that compound A5 brings high level of activity at very low rates (below 15 g ai/ha) to protect significantly citrus plantations against quarantine diseases like Black spot and Scab.

(33) The efficacy at these low rates is superior to commercial compounds, although said commercial compounds are used currently at very higher rates: at least 10 times higher (Kresoxim methyl), 15 times higher (Mancozeb) or even 160 times higher (Dithianon). Compound A5 can participate to the reduction of chemical loading in plantations.

(34) 3. Control of Black Sigatoka on Banana Crop (Field Trials).

(35) Two field trials were implemented in 2013 in Costa Rica and Philippines to evaluate the performance of compounds against Mycosphaerella fijiensis infection on Banana.

(36) A typical fungicide formulation containing 100 g of compound per liter was applied every 7 to 12 days in consecutive foliar sprays. The trials were carried out according to standard experimental practice with spay adjuvant and mineral oil used in tank mix as it is usual on banana plantation in each country.

(37) Data are expressed in Number of healthy leaves present at the end of the trial on each Banana plant (more leaves present mean better quantity and quality of harvest).

(38) Results from the Trials Black SigatokaNumber of Healthy Leaves Per Plant.

(39) TABLE-US-00005 Trial(s) A B rates Number Number active healthy healthy Composition ingredient Leaves Leaves (concentration) g a.i./ha 2DAT7 25DAT13 UNTREATED 8.5 8.7 N-(5-chloro-2-isopropylbenzyl)-N- 6.25 11.5 13.4 cyclopropyl-3-(difluoromethyl)- 12.5 12.2 14.4 5-fluoro-1-methyl-1H-pyrazole-4- 25 12 16.2 carboxamide (compound A5) (100 g/L) Boscalid 500 g/L 150 13.1

(40) The assessments show that compound A5 used at very low rates (6.25 g ai/ha) is able to control Black Sigatoka in plantation areas. The average of about +3 leaves per plant gives a significant advantage for further fruit production levels. Registered compound Boscalid needs higher rate (150 g a.i./ha) for equivalent or even lower efficacy measured in the trial.

CONCLUSION

(41) The example above demonstrates that compound A5 represents a new standard for Banana protection with a high level of activity at very low rates, below 25 g ai/ha, to protect significantly plants against Black Sigatoka. The efficacy at these low rates is at least equivalent to already registered compound Boscalid which is used at rates at least 6 to 24 times higher, and can participate to the reduction of chemical loading in plantations.