Microbiocidal quinoline (thio)carboxamide derivatives
11185074 · 2021-11-30
Assignee
Inventors
Cpc classification
International classification
Abstract
Compounds of the formula (I) wherein the substituents are as defined in claim 1. Furthermore, the present invention relates to agrochemical compositions which comprise compounds of formula (I), to preparation of these compositions, and to the use of the compounds or compositions in agriculture or horticulture for combating, preventing or controlling infestation of plants, harvested food crops, seeds or non-living materials by phytopathogenic microorganisms, in particular fungi. ##STR00001##
Claims
1. A compound of formula (I) ##STR00093## wherein X is O or S; R.sub.1 is hydrogen, halogen, methyl or cyano; R.sub.2 is hydrogen, methyl or halogen; R.sub.3 and R.sub.4 are each independently selected from hydrogen, halogen and methyl; R.sub.5 is C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.3-C.sub.5 cycloalkyl(C.sub.1-C.sub.2)alkyl or C.sub.3-C.sub.6 cycloalkyl, wherein the alkyl, alkenyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkylthio; R.sub.6 is hydrogen, cyano or C.sub.1-C.sub.4 alkyl, wherein the alkyl may be optionally substituted with 1 to 3 substituents independently selected from halogen and C.sub.1-C.sub.3 alkoxy; A is a direct bond or CR.sub.8R.sub.9; R.sub.7 is CF.sub.3, C.sub.2-C.sub.5 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.5 alkenyl, C.sub.4-C.sub.7 cycloalkenyl, wherein the alkyl, cycloalkyl, alkenyl and cycloalkenyl may be optionally substituted with one or more substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, C.sub.1-C.sub.3 haloalkoxy, C.sub.1-C.sub.3 haloalkylthio, C.sub.3-C.sub.7 cycloalkyl and phenyl (which itself may be optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 alkylthio, C.sub.1-C.sub.3 haloalkoxy, C.sub.1-C.sub.3 haloalkylthio and C.sub.3-C.sub.5 cycloalkyl); and R.sub.8 and R.sub.9 are each independently selected from hydrogen, fluoro and methyl; or a salt, enantiomer or N-oxide thereof.
2. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.1 is hydrogen, fluoro, chloro, methyl or cyano.
3. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.2 is hydrogen, methyl, chloro or fluoro.
4. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.3 and R.sub.4 are each independently selected from hydrogen and methyl.
5. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.5 is C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.5 cycloalkyl-CH.sub.2- or C.sub.3-C.sub.5 cycloalkyl, wherein the alkyl, alkenyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro and C.sub.1-C.sub.3 alkyl.
6. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.6 is hydrogen, or C.sub.1-C.sub.3 alkyl, wherein the alkyl may be optionally substituted with a methoxy group.
7. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein R.sub.7 is CF.sub.3, C.sub.2-C.sub.5 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.5 alkenyl, C.sub.4-C.sub.7 cycloalkenyl, wherein the alkyl, cycloalkyl, alkenyl and cycloalkenyl may be optionally substituted with one or more substituents independently selected from fluoro, chloro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.3-C.sub.4 cycloalkyl and phenyl (which itself may be optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, methyl and trifluoromethyl).
8. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein A is a direct bond or CH.sub.2.
9. The compound according to claim 1 wherein X is O or S; R.sub.1 is hydrogen, fluoro, chloro or methyl; R.sub.2 is hydrogen, chloro or fluoro; R.sub.3 is methyl and R.sub.4 is hydrogen; or R.sub.3 is hydrogen and R.sub.4 is methyl; or R.sub.3 is hydrogen and R.sub.4 is hydrogen; R.sub.5 is C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.3-C.sub.4 cycloalkyl-CH.sub.2- or C.sub.3-C.sub.5 cycloalkyl, wherein the alkyl, alkenyl and cycloalkyl groups may be optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro and methyl; R.sub.6 is hydrogen or methyl, wherein the methyl may be optionally substituted with a methoxy group; A is a direct bond or CH.sub.2; R.sub.7 is CF.sub.3, C.sub.2-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.4-C.sub.6 cycloalkenyl, wherein the alkyl, cycloalkyl, alkenyl and cycloalkenyl may be optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, methyl, trifluoromethyl and cyclopropyl and/or one phenyl; or a salt, enantiomer or N-oxide thereof.
10. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein A is CH.sub.2.
11. The compound according to claim 1 wherein X is O or S; R.sub.1 is fluoro, chloro or methyl; R.sub.2 is hydrogen or fluoro; R.sub.3 and R.sub.4 are both hydrogen; R.sub.5 is trifluoroethyl, ethyl, isopropyl, iso-butyl, tert-butyl, neo-pentyl, C.sub.2-C.sub.4 alkenyl or cyclopropyl-CH.sub.2-, wherein the ethyl, isopropyl, iso-butyl, alkenyl and cyclopropyl groups may be optionally substituted with 1 to 3 substituents independently selected from fluoro and chloro and/or one methyl group; R.sub.6 is methyl; A is CH.sub.2; R.sub.7 is CF.sub.3, ethyl, isopropyl, tert-butyl, C.sub.2-alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl, wherein the ethyl, isopropyl, alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl may be optionally substituted with 1 to 3 substituents independently selected from fluoro and chloro and/or one or two methyl groups; or a salt, enantiomer or N-oxide thereof.
12. The compound, or a salt, enantiomer or N-oxide thereof, according to claim 1 wherein X is O.
13. A composition comprising a fungicidally effective amount of a compound of formula (I) as defined claim 1.
14. The composition according to claim 13, wherein the composition further comprises at least one additional active ingredient and/or a diluent.
15. A method of combating, preventing or controlling phytopathogenic fungi which comprises applying to phytopathogenic fungi, to the locus of phytopathogenic fungi, or to a plant susceptible to attack by phytopathogenic fungi, or to propagation material thereof, a fungicidally effective amount of a compound of formula (I) as defined in claim 1.
16. A compound selected from the group consisting of: ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105##
17. The compound of claim 16, wherein the compound is selected from the group consisting of: ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112##
18. The compound of claim 16, wherein the compound is selected from the group consisting of: ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117##
19. A compound selected from the group consisting of: ##STR00118##
20. The compound of claim 19, wherein the compound is selected from the group consisting of: ##STR00119##
21. The compound of claim 19, wherein the compound is selected from the group consisting of: ##STR00120##
Description
EXAMPLES
(1) The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.
(2) Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus and the methods are:
(3) Method G:
(4) Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min) 0.85
(5) Method H:
(6) Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 2.7 min; Flow (ml/min) 0.85
(7) Method I:
(8) Spectra were recorded on a Mass Spectrometer (ACQUITY UPLC) from Waters (SQD, SQDII or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary (kV) 3.5, Cone (V) 30.00, Extractor (V) 3.00, Source Temperature (° C.) 150, Desolvation Temperature (° C.) 400, Cone Gas Flow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700, Mass range: 140 to 800 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters ACQUITY UPLC HSS T3; Column length: 30 mm; Internal diameter of column: 2.1 mm; Particle Size: 1.8 micron; Temperature: 60° C., DAD Wavelength range (nm): 210 to 400. Solvent Gradient A: Water/Methanol 9:1, 0.1% formic acid and Solvent B: Acetonitrile, 0.1% formic acid
(9) TABLE-US-00002 Time A B Flow rate (minutes) (%) (%) (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.8 0 100 0.75 3.0 100 0 0.75
Formulation Examples
(10) TABLE-US-00003 Wettable powders a) b) c) active ingredient [compound of formula (I)] 25% 50% 75% sodium lignosulfonate 5% 5% — sodium lauryl sulfate 3% — 5% sodium diisobutylnaphthalenesulfonate — 6% 10% phenol polyethylene glycol ether — 2% — (7-8 mol of ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27% —
(11) The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
(12) TABLE-US-00004 Powders for dry seed treatment a) b) c) active ingredient [compound of formula (I)] 25% 50% 75% light mineral oil 5% 5% 5% highly dispersed silicic acid 5% 5% — Kaolin 65% 40% — Talcum — 20%
(13) The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
(14) TABLE-US-00005 Emulsifiable concentrate active ingredient [compound of formula (I)] 10% octylphenol polyethylene glycol ether 3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (35 mol of ethylene oxide) 4% Cyclohexanone 30% xylene mixture 50%
(15) Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
(16) TABLE-US-00006 Dusts a) b) c) Active ingredient [compound of formula (I)] 5% 6% 4% talcum 95% — — Kaolin — 94% — mineral filler — — 96%
(17) Ready-for-use dusts are obtained by mixing the active ingredient with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.
(18) TABLE-US-00007 Extruder granules Active ingredient [compound of formula (I)] 15% sodium lignosulfonate 2% carboxymethylcellulose 1% Kaolin 82%
(19) The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
(20) TABLE-US-00008 Coated granules Active ingredient [compound of formula (I)] 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
(21) The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
(22) TABLE-US-00009 Suspension concentrate active ingredient [compound of formula (I)] 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6% Sodium lignosulfonate 10% carboxymethylcellulose 1% silicone oil (in the form of a 75% emulsion in water) 1% Water 32%
(23) The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
(24) TABLE-US-00010 Flowable concentrate for seed treatment active ingredient [compound of formula (I)] 40% propylene glycol 5% copolymer butanol PO/EO 2% tristyrenephenole with 10-20 moles EO 2% 1,2-benzisothiazolin-3-one (in the form of a 20% solution in 0.5%.sup. water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% emulsion in water) 0.2%.sup. Water 45.3%
(25) The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
(26) Slow Release Capsule Suspension
(27) 28 parts of a combination of the compound of formula (I) are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed.
(28) The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns.
(29) The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
Preparation Examples
Example 1: Preparation of N-[1,3-dimethyl-1-(2-methylallyl)but-3-enyl]-8-fluoro-quinoline-3-carboxamide
Step 1: Preparation of 2,4,6-trimethylhepta-1,6-dien-4-amine
(30) To a solution of acetonitrile (0.191 mL, 3.65 mmol) in diethyl ether (0.3 M, 11 mL) at room temperature was added dropwise a solution of 2-methylallylmagnesium chloride (0.5 M in THF, 3 equiv., 22 mL, 11 mmol). The yellow solution was stirred at rt for 30 min. Titanium (IV) isopropoxide (1.1 mL, 1.0 equiv., 3.65 mmol) was then added and the orange solution was stirred at rt for 16 h. The reaction mixture was quenched with aqueous NaOH (2 M), diluted with 100 mL of dichloromethane and vigorously stirred. The resulting suspension was filtered over a pad of Celite. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 2,4,6-trimethylhepta-1,6-dien-4-amine (0.52 g, 93% yield) as a yellow liquid:
(31) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 (s, 3H) 1.78 (s, 6H) 2.09 (s, 4H) 4.67 (s, 2H) 4.87 (s, 2H).
Step 2: Preparation of N-[1,3-dimethyl-1-(2-methylallyl)but-3-enyl]-8-fluoro-quinoline-3-carboxamide
(32) ##STR00023##
(33) To a solution of 2,4,6-trimethylhepta-1,6-dien-4-amine (0.14 g, 0.91 mmol) in dichloromethane (7.3 mL, 0.12 M) and triethylamine (0.32 mL, 2.5 equiv., 2.28 mmol) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.20 g, 1.1 equiv., 1.0 mmol) followed by O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.39 g, 1.1 equiv., 1.0 mmol) and 8-fluoroquinoline-3-carboxylic acid (0.19 g. 1.1 equiv., 1.0 mmol). The solution was stirred at rt for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO.sub.3 and extracted twice with dichloromethane. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4 anhydrous, filtered and concentrated. Purification by flash chromatography gave N-[1,3-dimethyl-1-(2-methylallyl)but-3-enyl]-8-fluoro-quinoline-3-carboxamide (0.20 g, 69% yield) as a white solid, mp=116-118° C., LC-MS (Method G), Rt=1.11 min, MS: (M+1)=327;
(34) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60 (s, 3H) 1.85 (s, 6H) 2.52 (d, 24H) 2.90 (d, 2H) 4.83 (s, 2H) 5.01 (s, 2H) 6.30 (s, 1H, NH) 7.48-7.61 (m, 2H) 7.73 (d, 2H) 8.58 (s, 1H) 9.22 (s, 1H).
Example 2: 4,4,4-trifluoro-N-(8-fluoro-3-quinolyl)-2-methyl-2-[(1-methylcyclopropyl)methyl]butanamide
Step 1: Ethyl 2,4-dimethyl-2-(2,2,2-trifluoroethyl)pent-4-enoate
(35) To a cooled (−70° C.) solution of lithium diisopropylamide (2 M, 30.6 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl 4-methyl-2-(2,2,2-trifluoroethyl)pent-4-enoate (20.4 mmol, 6.09 g) in tetrahydrofuran (60 mL) dropwise, and the mixture was stirred at −70° C. for 30 min. Then, iodomethane (26.5 mmol, 3.80 g) was added dropwise at −70° C., and the mixture was stirred at −70° C. for an additional 1 h. The reaction mixture was carefully poured into 100 ml of saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (cyclohexane/ethyl acetate gradient) to give ethyl 2,4-dimethyl-2-(2,2,2-trifluoroethyl)pent-4-enoate as a yellow oil:
(36) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (t, J=6.97 Hz, 3H) 1.33 (d, J=1.10 Hz, 3H) 1.71 (s, 3H) 2.16-2.33 (m, 2H) 2.46-2.53 (m, 1H) 2.69-2.85 (m, 1H) 4.08-4.26 (m, 2H) 4.69-4.76 (m, 1H) 4.89-4.96 (m, 1H)
Step 2: Ethyl 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanoate
(37) To a cooled (0° C.) solution of diethylzinc (79.5 mmol, 79.5 mL) in dichloromethane (63.6 mL) was added 2,2,2-trifluoroacetic acid (47.7 mmol, 3.71 mL) dropwise, and the mixture was stirred at 0° C. for 30 min (white suspension). Then, diiodomethane (47.7 mmol, 3.88 mL) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 30 min. To finish, ethyl 2,4-dimethyl-2-(2,2,2-trifluoroethyl)pent-4-enoate (2.06 mmol, 0.49 g) in dichloromethane (1 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for additional 5 h. The reaction mixture was carefully poured into 50 ml of saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanoate as a yellow oil:
(38) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.17-0.40 (m, 4H) 1.00 (s, 3H) 1.31 (m, 4H) 1.41 (d, J=1.10 Hz, 3H) 1.93-2.02 (m, 1H) 2.14-2.30 (m, 1H) 2.67-2.84 (m, 1H) 4.10-4.24 (m, 2H)
Step 3: 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanoic Acid
(39) A suspension of ethyl 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanoate (1.70 mmol, 430 mg), Sodium hydroxide (6.8 mmol, 0.27 g), ethanol (6.9 mL) and 1,4-dioxane (6.9 mL) was stirred at 80° C. for 4 h. The reaction mixture was poured into 20 ml of water. The aqueous phase was washed with dichloromethane, acidified with aqueous hydrochloric acid 2 M (pH 1-2) before being extracted with dichloromethane. The combined organics extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanoic acid as a dark orange oil:
(40) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.14-0.46 (m, 4H) 1.07 (s, 3H) 1.37-1.48 (m, 4H) 1.88-2.02 (m, 1H) 2.19-2.38 (m, 1H) 2.68-2.90 (m, 1H)
Step 4: 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanamide
(41) To a solution of 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanoic acid (1.44 mmol, 322 mg), N,N-dimethylformamide (1 drop) in dichloromethane (5.74 mL) at room temperature was added oxalyl chloride (2.87 mmol, 0.25 mL) dropwise and the mixture was stirred for 30 min (gas evolution). The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (5.74 mL). To the previous solution, was added at room temperature a solution of ammonia in methanol (7 M, 4.31 mmol, 0.615 mL) dropwise, and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 20 ml of saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted with dichloromethane and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanamide as an orange oil:
(42) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.17-0.48 (m, 4H) 1.10 (s, 3H) 1.13-1.22 (m, 1H) 1.49 (d, J=1.10 Hz, 3H) 2.06-2.24 (m, 2H) 2.73-2.91 (m, 1H) 5.39-6.04 (m, 2H)
Step 5: 4,4,4-trifluoro-2-methyl-1-(1-methylcyclopropyl)butan-2-amine
(43) A solution of 4,4,4-trifluoro-2-methyl-2-[(1-methylcyclopropyl)methyl]butanamide (1.16 mmol, 259 mg), [hydroxy(phenyl)-1-iodanyl] 4-methylbenzenesulfonate (1.39 mmol, 0.56 g) and acetonitrile (4.64 mL) was stirred at 65° C. for 2 h. The reaction mixture was poured into 20 ml of water. The mixture was acidified with hydrochloric acid 2 M until pH 1-2 before being washed with dichloromethane. The aqueous phase was basified with aqueous sodium hydroxide 2 M until pH 10. The mixture was extracted with dichloromethane and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4,4,4-trifluoro-2-methyl-1-(1-methylcyclopropyl)butan-2-amine as a yellow oil:
(44) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.25-0.45 (m, 4H) 1.20 (s, 3H) 1.40 (s, 3H) 1.50-1.62 (d, 2H) 2.34-2.49 (m, 2H)
Step 6: 8-fluoro-N-[3,3,3-trifluoro-1-methyl-1-[(1-methylcyclopropyl)methyl]propyl]quinoline-3-carboxamide
(45) A solution of 4,4,4-trifluoro-2-methyl-1-(1-methylcyclopropyl)butan-2-amine (0.91 mmol, 177 mg), 8-fluoroquinoline-3-carboxylic acid (0.95 mmol, 0.18198 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.00 mmol, 0.19312 g), triethylamine (2.27 mmol, 0.319 mL), HATU (1.00 mmol, 0.39095 g) and dichloromethane (3.62 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into 10 ml of saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (cyclohexane/ethyl acetate gradient) to give 8-fluoro-N-[3,3,3-trifluoro-1-methyl-1-[(1-methylcyclopropyl)methyl]propyl]quinoline-3-carboxamide as a white solid mp=126-128° C., LC-MS (Method G) UV Detection: 220 nm, Rt=1.07 min; MS: (M+1)=369;
(46) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.28-0.59 (m, 4H) 1.22 (s, 3H) 1.53-1.59 (d, 1H) 1.75 (s, 3H) 2.41-2.45 (d, 1H) 2.64-2.82 (m, 1H) 3.08-3.30 (m, 1H) 6.26-6.51 (m, 1H) 7.50-7.55 (m, 1H) 7.57-7.62 (m, 1H) 7.73-7.75 (d, 1H) 8.57-8.58 (t, 1H) 9.25-9.26 (d, 1H)
(47) TABLE-US-00011 TABLE E Physical data of compounds of formula (I) RT [M + H] MP Entry STRUCTURE (min) (measured) Method ° C. E-1
(48) TABLE-US-00012 TABLE F Physical data of compounds of formula (I) as individual enantiomers RT [M + H] MP No IUPAC name STRUCTURE (min) measured ° C. method F-1 8-fluoro-N-[(1R)- 3,3,3-trifluoro-1- methyl-1-[(1- methylcyclo- propyl)meth- yl]propyl] quinoline-3- carboxamide
Biological Examples
(49) Botryotinia fuckeliana (Botrytis cinerea)/Liquid Culture (Gray Mould)
(50) Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(51) The following compounds gave at least 80% control of Botryotinia fuckeliana at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(52) E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-22, E-23, E-24, E-25, E-26, E-27, E-28, E-29, E-31, E-33, E-34, E-36, E-37, E-38, E-39, E-40, E-41, E-42, E-43, E-44, E-45, E-46, E-47, E-48, E-49, E-50, E-51, E-52, E-53, E-54, E-55, E-56, E-57, E-58, E-59, E-60, E-61, E-62, E-63, E-64, F-1, F-2, F-3, F-4, F-5
Glomerella lagenarium (Colletotrichum lagenarium)/Liquid Culture (Anthracnose)
(53) Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is measured photometrically 3-4 days after application.
(54) The following compounds gave at least 80% control of Glomerella lagenarium at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(55) E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-22, E-23, E-24, E-25, E-26, E-27, E-29, E-30, E-33, E-36, E-37, E-38, E-39, E-40, E-41, E-42, E-43, E-44, E-45, E-46, E-47, E-48, E-49, E-50, E-51, E-52, E-53, E-54, E-55, E-56, E-57, E-58, E-59, E-60, E-61, E-62, E-63, E-64, F-1, F-2, F-3, F-4, F-5
Fusarium culmorum/Liquid Culture (Head Blight)
(56) Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(57) The following compounds gave at least 80% control of Fusarium culmorum at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(58) E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-22, E-23, E-24, E-25, E-26, E-27, E-28, E-29, E-30, E-33, E-34, E-35, E-36, E-37, E-38, E-39, E-40, E-41, E-42, E-43, E-44, E-45, E-46, E-47, E-48, E-49, E-50, E-51, E-52, E-53, E-54, E-55, E-56, E-57, E-58, E-59, E-60, E-61, E-62, E-63, E-64, F-1, F-2, F-3, F-4, F-5
Fusarium culmorum/Wheat/Spikelet Preventative (Head Blight)
(59) Wheat spikelets cv. Monsun are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The spikelets are inoculated with a spore suspension of the fungus 1 day after application. The inoculated spikelets are incubated at 20° C. and 60% rh under a light regime of 72 h semi darkness followed by 12 h light/12 h darkness in a climate chamber and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check spikelets (6-8 days after application).
(60) The following compounds gave at least 80% control of Fusarium culmorum at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(61) E-2, E-5, E-6, E-9, E-12, E-14, E-16, E-17, E-18, E-19, E-20, E-21, E-23, E-26, E-37, E-43, E-46, E-47, E-48, E-50, E-52, E-54, E-55, E-59, E-60, E-63, E-64, F-1, F-2, F-5
(62) Gaeumannomyces graminis/Liquid Culture (Take-All of Cereals)
(63) Mycelial fragments of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores iss added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.
(64) The following compounds gave at least 80% control of Gaeumannomyces graminis at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(65) E-4, E-9, E-14, E-21, E-22, E-23, E-24, E-25
(66) Gibberella zeae (Fusarium graminearum)/Wheat/Spikelet Preventative (Head Blight)
(67) Wheat spikelets cv. Monsun are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. One day after application, the spikelets are inoculated with a spore suspension of the fungus. The inoculated test leaf disks are incubated at 20° C. and 60% rh under a light regime of 72 h semi darkness followed by 12 h light/12 h darkness in a climate chamber, the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears on untreated check spikelets (6-8 days after application).
(68) The following compounds gave at least 80% control of Gibberella zeae at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(69) E-2, E-5, E-6, E-9, E-14, E-18, E-21, E-23, E-45, E-46, E-59, F-1, F-2
(70) Monographella nivalis (Microdochium nivale)/Liquid Culture (Foot Rot Cereals)
(71) Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.
(72) The following compounds gave at least 80% control of Monographella nivalis at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(73) E-2, E-3, E-5, E-6, E-7, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-20, E-21, E-22, E-23, E-25, E-26, E-27, E-31, E-33, E-34, E-37, E-38, E-40, E-42, E-44, E-45, E-47, E-48, E-50, E-51, E-52, E-53, E-54, E-55, E-56, E-57, E-58, E-59, E-60, E-61, E-62, E-63, E-64, F-1, F-2, F-3, F-4
Puccinia recondita f. sp. tritici/Wheat/Leaf Disc Curative (Brown Rust)
(74) Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format). The leaf segments are inoculated with a spore suspension of the fungus. Plates are stored in darkness at 19° C. and 75% rh. The formulated test compound diluted in water is applied 1 day after inoculation. The leaf segments are incubated at 19° C. and 75% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (6-8 days after application).
(75) The following compounds gave at least 80% control of Puccinia recondita f. sp. tritici at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(76) E-8
(77) Puccinia recondite f. sp. tritici/Wheat/Leaf Disc Preventative (Brown Rust)
(78) Wheat leaf segments cv. Kanzler are placed on agar in multiwell plates (24-well format) and sprayed with the formulated test compound diluted in water. The leaf disks are inoculated with a spore suspension of the fungus 1 day after application. The inoculated leaf segments are incubated at 19° C. and 75% rh under a light regime of 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (7-9 days after application).
(79) The following compounds gave at least 80% control of Puccinia recondita f. sp. tritici at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(80) E-8, E-31
(81) Magnaporthe grisea (Pyricularia oryzae)/Liquid Culture (Rice Blast)
(82) Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(83) The following compounds gave at least 80% control of Magnaporthe grisea at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(84) E-2, E-3, E-4, E-5, E-6, E-8, E-9, E-10, E-11, E-12, E-13, E-14, E-15, E-17, E-18, E-19, E-20, E-21, E-22, E-24, E-25, E-37, E-43, E-44, E-45, E-47, E-48, E-52, E-53, E-54, E-55, E-56, E-57, E-58, E-59, E-60, E-61, E-62, E-63, E-64, F-1, F-2, F-3, F-4, F-5
(85) Magnaporthe grisea (Pyricularia oryzae)/Rice/Leaf Disc Preventative (Rice Blast)
(86) Rice leaf segments cv. Ballila are placed on agar in a multiwell plate (24-well format) and sprayed with the formulated test compound diluted in water. The leaf segments are inoculated with a spore suspension of the fungus 2 days after application. The inoculated leaf segments are incubated at 22° C. and 80% rh under a light regime of 24 h darkness followed by 12 h light/12 h darkness in a climate cabinet and the activity of a compound is assessed as percent disease control compared to untreated when an appropriate level of disease damage appears in untreated check leaf segments (5-7 days after application).
(87) The following compounds gave at least 80% control of Magnaporthe grisea at 200 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(88) E-27, E-37, E-42, E-47, E-56, E-57, E-58, E-59, E-61, E-62, F-2, F-3, F-4
(89) Sclerotinia sclerotiorum/Liquid Culture (Cottony Rot)
(90) Mycelia fragments of a newly grown liquid culture of the fungus are directly mixed into nutrient broth (Vogels broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format) the nutrient broth containing the fungal material is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 3-4 days after application.
(91) The following compounds gave at least 80% control of Sclerotinia sclerotiorum at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(92) E-4, E-8, E-37, E-48, E-53, E-54, E-56, E-57, E-58, E-59, E-61, E-62, E-63, E-64, F-3, F-4, F-5
(93) Mycosphaerella graminicola (Septoria tritici)/Liquid Culture (Septoria Blotch)
(94) Conidia of the fungus from cryogenic storage are directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of test compound into a microtiter plate (96-well format), the nutrient broth containing the fungal spores is added. The test plates are incubated at 24° C. and the inhibition of growth is determined photometrically 4-5 days after application.
(95) The following compounds gave at least 80% control of Mycosphaerella graminicola at 20 ppm when compared to untreated control under the same conditions, which showed extensive disease development:
(96) E-57