CA1293973C - Fungicidal pyridyl cyclopropane carboxamides - Google Patents

Abstract

FUNGICIDAL PYRIDYL CYCLOPROPANE CARBOXAMIDES
Abstract of the Disclosure Novel fungicidal pyridyl cyclopropane carboxamides having the general structural formula

Description

FUNGICI~AL PYRIDYL C~CIOPROPANE C'ARBOXAMIDFS

Background of the Invention Fungal infection of crops such as barley, rice, tomatoes, ~heat, beans, roses, grapes and other agriculturally important crops can cause heavy losses in both quantity and quality of agricultural products. It is therefore extremely desirable to have means of preventing, controlling or eliminatiny fungal growth. Much preventive spraying with commercial fungicides is conducted to attempt to prevent the establishment and growth of fungi on agriculturally important crops. It would also be desirable to have a cura~ive fungicide which, on detection of fungal infestation, could destroy the fungi and eliminate the deleterious effects by use of a postinfestation curative spray.

Summary~of the Invention ~ ovel fungicidal pyridyl cyclopropane carboxamides having the formula R ~ ~h wherein R is selected from the group consisting of halogen such as chlorine, fluorine and bromine, preferably chlorine, C1-C3 alkoxy such as propoxy~
ethoxy and methoxy, preferably methoxy, and C1-C3 haloalkoxy; R1 is selected from the group consisting of hydrogen and cyano; R2 is selected from the group consisting of methyl and hydrogen; X is either oxygen or sulfur; and fungicidally acceptable organic and inorganic salts thereof which are highly effective fungicides for use both as preventive and curative fungicides are disclosed herein.

m e term "fungicide" is used to mean a compound ~hich controls fungal growth. "Controls" includes prevention, destruction and inhibition of fungal growth. The tenm "curative" is meant to refer to a post-infec-tion application of a fungicide which establishes control of fungal infec-tion and prevents development of deleterious effects of the fungi on thehost crop.

'7~

The novel fungicidal compounds of this invention are pyridyl cyclopropane carboxyamides having the general formula:

R--\ ~J ~- C ~ ~

wherein R is selected from the group consisting of halogen such as chlorine, fluorine and bromine, preferably chlorine, Cl-C3 alkoxy such as propoxy~
S ethoxy and methoxy, preferably methoxy, and C1~C3 haloalkoxy~ R1 is selected from the group consisting of hydrogen and cyano; and R2 is selected from the group consisting of methyl and hydrogen; X is either oxygen or sulfur; and fungicidally acceptable organic and inorganic salts thereof.

By the term "halogen" is meant bromine, fluorine and chloride.

By the term "C1-C3 alkoxy" is meant methoxy~ethoxy, propoxy and isopropoxy.
;
By the term "C1-C3 haloalkoxy" is meant halogen substituted methoxy, ethoxy, propoxy and isopropoxy.

Ihe compounds of this invention can be generally prepared by reacting a properly substituted 5-aminopyridine with a properly substi-tuted cyclopropane carboxylic acid chloride in a polar solvent such as dichloromethane in a suitable reactor. It is desirable to maintain an acid scavenger such as pyridine in the reaction vessel. The reaction generally will proceed at room tempqrature but will operate at a tempera-ture range from -30 to 60C, depending on the substitutions on the amino pyridine and the cyclopropane carboxylic acid chloride. The reaction should yo to completion within 1 to 3 hours. m e resulting product is recovered in a conventional manner by washing with an aLkali solution such as ~aOH and water, drying over conventional drying agents such as magnesium sulfate, and crystallizing in hexane. m e thiono carboxamides of this invention are also active. ~hese compounds are prepared in general by reaction of the corresponding amide with phosphorous pentasulfide in a neutral solvent such as benzene, toluene, chloroform, methylenechloride or pyridine. m e product is soluble in strong aIkali and may be isolated from the reaction muxture in that manner by readjustment of the pH of the extract to neutrality~

~2~ 73 Salts of the various pyridyl cycloproFa~le carboxamides can be convention-ally prepared by reacting at least a molar amount of a Lewis acid with the carboxamide. Preferably the reaction is run in a solvent for the carbox-amide with heating if necessary. The prepared salt is recovered frQm the reaction mixture by conventional techniques.

Pyridyl carboxamides of the invention are basic. The unproton-ated nitrogen atom of the pyridyl ring can be protonated by an acid, either organic or inorganic. Representative inorganic acids are hydro-chloric, nitric, hydrobromic, sulfuric, sulfamlc and phosphoric. Repre-sentative organic acids are acetic, trifluoroacetic, benzoic, benzenesul-fonic, p-toluenesulfonic, naphthalenesulfonic, phenylphosphonic and organophosphonic. The salts so formed are also fungicidal.

-Pre~aration.of ~ ~cyclopropan_ _arboxamide 5-Amino-2-methoxy pyridine (12.4 grams, 0.10 mole) and 10 milli-liters (ml) of pyridine were mixed together in 200 ml dichloromethane in a reaction flask. 9.1 ml (0.10 mole) of cyclopropane carboxylic acid chlo-ride was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and temperature rose to 34C. The reaction was allowed to stand for one hour at room temperature, after which the reac-tion mixture was washed with 200 ml of 5% sodium hydroxide and 100 ml of water. The resulting organic phase was separated and dried over anhydrous magnesium sulfate. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated ln vacuo to give a ~olid that was triturated with hexane to yield 16.7 grams, after drying.
The product was i~entified by rR and NMR as the title compound, having a melting point of 130-131~C. This compound will be referred to as Compound 1.

EXA~PLE 2 Preparation of N-(2-Methoxy-5-~y--id~y---cyclopro~ane carboxamude dodecanoic acid salt `
qhree grams (0.016 mole) of the compound of Example 1 was dissolved in 100 ml of acetone in a 300 mlr one-neck, round-bottom flask by swirling. 3.2 g (0.016 mole) dodecanoic acid wa~s added which went into solution The resulting solution was evaporated on a rotary evaporator, 35~3 yielding 6.2 g, of a white solid having a melting point of 9~-96~C, which was identified by nuclear magnetic resonance spectroscopy as the title compound. mis compou~d will be known as Compound 7.

Pre~aration of N-(2-methoxy~5-pyri ~ -cyclopropanethiocarboxamide A solution of 5.0 g of N-(2-methoxy-5-pyridyl)-cyclopropanecar-boxamude (Ø02~ moles) in methylene chloride (10oml~ was refluxed with stirriny with 6.1 9 of phosphorous pentasulfide (0.03 moles). The reac-tion mixture wa~ cooled to room temperature and diluted with chlorofonm (100 ml) and washed with a saturated sodium bicarbonate solution (200 ml).
The organic phase was extracted with 5% sodium hydroxide solution (2 X 100 ml). This extract was acidified with concentrated hydrochloric acid to pH
7 and extracted with chloroform (3 X 100 ml). This chloroform extract was dried over magnesium sulfate and evaporated in vacuo to yield O.Ç g of the desired product having a melting point of 79 - 83C.

Representative compounds of this invention and their physical properties are shown in Table I.

TABI E

~N--~ ~

ampd. nD30 or No. R R1 R2 X ~LJ~ nt C
1 ~OCH3 -H H 0130.0 - 131.0 2 -Cl -H -H 0167.0 - 169.Q

3 -OCH3 -C~N -H 084.0 - 92.0 4 -OCH3 -H 1-C~3 070.0 - 74.0 -OCH3 -H 2-CH3 066.0 - 70.0 6 hydrochloric acid salt of Cmpd. 1 144.0 - 146.0 7 dcdecanoic acid salt of Cmpd. 1 92.0 - 96.0 8 2-naphthalene-sulfonic acid salt 90.0 - 96.0 of Cmpd. 1 9 acetic acid salt of Cmpd. 1 112.0 - 120.0 benzoic acid salt of Cmpd. 1 78.0 - 8S.0 11 chlororethyl-phosphonic acid salt 110.0 - 118.0 of Cmpd. 1 12 hydrochloric acid salt of Cmpd. 2 134.0 - 136.0 13 -Br -H -H 0172.0 - 175.0 14 phenyl phosphonic acid salt of Cmpd. 1 108.0 - 115.0 sulfa~ic acid salt of Cmpd. 1 131.0 - 136.0 16 trifluoroacetic acid salt of Cmpd. 1 89.0 - 93.0 17 nitric acid salt of Cmpd. 1 144.0 - 145.0 18 -OCH3 -H -H S 79.0 - 83.0 19 -F -H -~ O 116.0 - 117.0 EX~MPLE 3 Mole Equivalent Preventative Spray Evaluation Procedure~
Barley Powdery Mildew (PM) Northrup King Sunbar 401 barley seed is planted (12 seeds/2"
pot) in a sandy-loam soil seven days prior to tésting. The test compound is diluted in a 50/50 acetone/water solution to produce concentrations decreasing fro~ 0.004 molar. The test solution is then sprayed onto the S barley plants with atomizmg sprayers.

Twenty-four hours later, test plants are placed in an inocula-tion box equipped with a circulating fan. ~arley plants with heavily sporulating ~ ~ lesions are placed in front of the fan to di~lodge and distribute the spores. After two munutes the fan is shut off S and the cham~er is left closed five minutes for the spores to settle.
Inoculated plants are then placed on an automatic sub-irrigation green-house bench.

Results are recorded seven days following inoculation as percent disease control based on the percent reduction in lesion area as compared to the untreated control plants. Compound concentrations which provide 90% disease control (CO 90) are determined from dosage/dilution curves.

Leaf Rust (LR) Seven seeds of Anza wheat are planted in 2" pots in a sandy-loam soil 12 days prior to testing. The compound to be tested is diluted with a 50/50 acetone/water solution to produce con oe ntrations decreasing from 0.004 lar. Twelve ml of test solution are sprayed onto the ~heat plants with an atomizirlg sprayer.

A suspension of Puccinia _econdita urediospores is prepared by vacuuoung spores from wheat leaves with ureida pustules and suspending 105 spores/ml in deionized water plus 0.5% Tween~ 20 (polyoxyethylene sorbitan monolaurate). Plants are inoculated 24 hours after treatment by spraying with the spore suspension to runoff, allowing it to dry on the leaves, respraying to runoff, and then placing the plants into a dark mist cham-ber. Following 48 hours in the mist, plants are rnoved to a ~ubirrigation greenhouse bench.

Results are recorded ten days following inoculation as percent disease control based on the percent reduction in lesion area as compared to the untreAted control plants. Compound concentrations which provide 90% disease control (EC 90) are datermined from dosage/dilution curves.

~otrytis Bud Bli ht (~B) ~ --Two w ~lte~rose petals are placed in a petri dish lined with wet filter paper. The compound to be tested is diluted with a 50/50 acatone/
water solution to produce concentrations decreasing from 0.004 molar. On half ml of test solution is atomized onto the petals, and allowed to dry Inoculum is prepared by adding a 5 mm plug from a two-week old Botry~ cineria culture grown on Elliot's V-8 agar, to 10 ml sterile ___ distilled wa~er plus 0.5~ grape juice. ~ 20 ul drop of this inoculum suspension is placed on each petal. Petri dishes with inoculated pe~als are stored in sealed plastic boxes to maintain saturated humidity.

Results are read four day~ following inoculation as a percent reduction in necrotic area compared to the acetone/water controls. Ccm-pound con~entrations which provide 90% disease control (EC 90) are deter-mined from dosage/dilution curves.

The molar equivalent o~ 0.004 used as the initial dilution in these evaluation procedures is equivalent to 750 parts per mullion (ppm) of the amides. All salts tested were adjusted in a solution to 0.004 molar which is equivalent to the 750 ppm of the amide from which the salt was made.

me results are presented in Table II as an approximate EC 90 in partC per million. The entry (750) indicates partial control at 750 p~n.
I~BLE II
d. No. PM LR BB

3 (750) 500 25 4 >750 >750 750 (750) 200 200 13 (750) (750) (750) 18 (750) t750) 20 19 (750) 250 80 ~3~'73 EX~MRLE 4 Post-In n~icide Screenin~ Procedures ApFle scab (AS?
Apple seedlings are inoculated by spraying the foliage with Venturia ~ using standard procedures 24 hours. Following inocu-lation the test compound is applied in solution as a foliage spray at the rate of 160 mg/l. Results are determined after sympton development from the reduction in lesion area as compared to the untreated control plants~

Rice Blast (RB) Six days before inoculation, seedling rice plants are drenched with a solution containg 50 mg test compound/liter of soil. Inoculation with Piricularia oryzae is performed using standard procedures. Results are determined after symptom development from the reduction in lesion area as ccmpared to the untreated control plants.

Wheat Blume Blotch (GB) Two aays before inoculation, the test compound is applied in solution to whe~t seedlings as a foliage spray at the rate of 500 ~g/l.
Inoculation with Septo a nodorum is performed using standard procedures.
Results are determined after sympton development from the reduction in lesion area as compared to the untreated control plants.

Wheat Foot Rot (FR) Wheat seed infested with Fusarium culmorum is trea~ed with 500 mg/kg of test compound using standard methods. Results are determined after symptom development from the reduction in disease as compared to the untreated control plants.

Astivity is reported on the following basis: 0 - nil; X = light;
XX ~ moderate and XXX ~ high.

TABLE III
.. . .
Disease . . _ .
Ch~. No. AS RB GB FR
~X X X~ X

:~2~73 CURATrVE SPRAY EV~LUATION PROCEDURF9 Leaf Rust (IR) Seven seeds of Anza wheat are planted in 2" pots in a sandy loam soil 12 days prior to testing. A suspension of Puc inia recondika uredi-ospores is prepared by vacuumlng spores from wheat leaves with uredia pustules and suspending 105 spores/ml in deionized water plus 0O5%
Tween~ 20 (polyoxyethylene sorbitan monolaurate). Plants are inocula~ed by spraying with the spore suspension to runoff, allowing it to dry on the leaves, respraying to runoff, and then placing the plants into a mist chamber. Following 48 hou~s in the mist, plants are moved to a subirrigation greenhouse bench.

~he compound to be tested is diluted in a 50/50 acetone/wa~er solution to produ~e concentrations decreasing from 0.075%. Fifty hours following inoculation, the plants are placed on a rotating turntable and sprayed with the test solution to near runoff with atcmizing nozzles.
(Time of inoculation is defined as when plants are placed into the mist chamber.) Results are recorded ten days following inoculation as percent disease control based on the percent reduction in lesion area as ccmpared to the untreated control plants.

TABLE III
CmQd. No. LR

~3~3 ~ he compounds of this invention are particularly effective against ~ Bud Blight and are particularly effective as preventative foliar sprays and curative foliar sprays when compared to sta~dard commer-cial compounds used as Bot~ytls preventative and curative sprays~ Fungi on which the compounds of the present invention are particularly effective are as follows: tr~tis cinerea; Venturia ~ ; Septoria nodorum;
Ery~i~he graminis; Fusarium culmorum; Piricularia ~ ; and Puccinia __ graminis.

lhe compounds of the present invention are useful as fungicides, especially as preventative or curative fungicides, and can be applied in a variety of ways at various concentrations. In general, these co~pounds and formulations of these co~pounds can be applied directly to the crop foliage, the soil in which ~he crop is growing, or in the irrigation water for the crop or soil. In practice, the compounds herein defined are formulated into fungicidal compositions, by admixture, in fungicidally effective amounts, with the adjuvants and carriers normally employed for facilitating the dispersion of active ingredients for agricultural appli-cations, recognizing the fact that the formulation and mode o application of a toxicant may æfect the activity of the materials in a given applica-tion. Thus, these active fungicidal cornpounds may be fonmulated aswettable powders, as emulsifiable concentrates, as powdery dusts, as solutions or as any of several other known types of formulations, depend-ing upon the desired mode of application. Preferred fonmulations for preventative or curative fungicidal applications are wettable powders and em~lsifiable concentrates. ~hese fonnulations may contain as little as about 0.1% to as much as about 9S~ or more by weight of active ingredient.
A fungicidally effective amount depends upon the nature of the seeds or plants to be treated and the rate of application varies from about 0.05 to approximately 25 pounds per acre, preferably fram about O.l to about lO
pounds per acre.

Wettable powders are in the form of finely divided particles which disperse readily in water or other dispersants. The wettable powder is ultimately applied to the soil or plant either as a dry dust or as a dispersion in wa~er or other liquid. Typical carriers or wettable pow-ders include fuiler's earth, kaolin clays, silicas and other readily wet organic or inorganic diluents. Wettable powders normally are prepared tocontain about 5% to about 95% of the active ingredient and usually also contain a small amount of wetting, dispersing, or emulsifying agent to facilitate wetting and dispersion.

Dry flowables or water dispersible granules are ag~lomerated wettable powders made by either pan granulation or by fluidized bed. The dry flo~able is ultimately applied to the soil or plant as a dispersion in water or other liquid. These ~ranules are dust-free and free flcwing when dry and yet upon dilution in water, form homogeneous disperslons. Typical carriers for dry flowables include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic diluents. The dry flowables normally are prepared to contain from about 5% to about 95% of the active ingredient and usually contain a small amount of wetting, dispersing or emulsifying agent to facilitate wetting and dispersion.

Bmulsifiable conce~trates are homogeneous liquid compositions which are dispersible in water or other dispersant, and may consist entirely of the active co~pound with a liquid or solid emulsifying agent, or may also contain a li~uid carrier, such a~ xylene, heavy aromatic naphtha, isophorone and other non-volatile organic solvents. For fungicidal application, these concentrates are dispersed in water or other liguid carrier and normally applied as a spray to the area to be treated.
me percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises about 0.1% to 95% of active ingredient by weight of the fungicidal composition.

Typical wet~ing, dispersing or emulsifying agents used in agri-cultural formulations include, for example, the aIkyl and alkylaryl sul-fonates and sulfates and their sodium salts; polyhydroxy alcohols; and other types of surface-active agents, many of which are available in com-merce. Ihe surface-active agent, when used, normally comprises from 0~1 to 15% by weight of the fungicidal composition.

Dusts, which are free-flowing admixtures of the active ingredi-ent with finel~ divided solids such as talc, clays, flours and other ~3~73 organic and inorganic solids which act as dispersants and carriers for the toxicant, are useful formulations for many applications.

Pastes, which are homogeneous suspensions of a finely divided solid toxicant in a liquid carrier such as water or oil, are employed for specific purposes. m ese formulations normally contain about 5% to ahout 95% of active ingredient by weight, and may also contain amall amounts of a wetting, dispersing or emulsifying agent to facilitate dispersion. For application, the pastes are normally diluted and applied as a spray to the area to be afected.

EXAMPLES OF TYPICAL EO~MULATIONS

Oil Ingredient Wei~ht %
Ccmpound 1 Oil solvent-heavy aromatic naphtha 99 Total 100 Emulsifiable Concentrate Ccmpound 2 50 Rerosene 45 ~mulsifying agent (mixture of long chain ethoxylated polyethers with long chain sulfonate) 5 Ibtal -m~s Emulsifiable Concentrate Ccnpound 3 90 Rerosene 5 Emulsifying agen~ (mixture of long chain ethoxylated polyethers with long chain sulfonate) 5 Total Dusts and/or Powder8 .
Compound 4 0.5 50.0 90.0 Attapulgite Clay Powder 93.5 44.0 4.0 Sodium lignin ~ulfonate 5.0 5.0 S.0 Sodium dioctyl sulfosuccinate 1.0 1 0 1 0 Total100.~ 100 0 ~ 7~3 Other useful formulations for fungicidal applications include simple solutions of the active ingredient in a dispersant in which it is cRmpletely soluble at the desired conce~tration, such as acetone, alky-lated naphthalenes~ xylene an~ other organic solvents. Pressurized sprays, typically aerosols, wherein the active ingredient is dispersed in finely divided fonm as a result of vaporization of a low ~oiling dispers-ant solvent carrier, such as the Freons, may also be used.

The fungicidal compositions of this invention are applied to the plants in the conventional manner. Thus, the dust and liquid compositions can be applied to the plant by the use of pcwer-dusters, boom and hand sprayers and spray dusters. The compositions can also be applied from airplanes as a dust or a spray because they are effective in low dosages.

Claims (10)

1. A compound having the structural formula in which R is selected from the group of halogen, C1-C3 alkoxy and C1-C3 haloalkoxy, R1 is selected from the group of -H and -C?N; and R2 is selected from the group of -H, 1-CH3 and 2-CH3; X is O or S; and fungicidally acceptable organic and inorganic salts thereof.

2. The compound of Claim 1 wherein R is -OCH3, R1 is -H and R2 is -H.

3. The compound of Claim 1 wherein R is -Cl, R1 is -H and R2 is -H.

4. The compound of Claim 1 wherein R is OCH3, R1 is -H, R2 is -H
and X is -S.

5. The compound of Claim 1 wherein R is -OCH3, R1 is -C?N
and R2 is -H.

6. A fungicidal composition comprising a fungicidally effective amount of a compound having the structural formula in which R is selected from the group halogen C1-C3 alkoxy and C1-C3 haloalkoxy, R1 is selected from the group of -H and -C?N; and R2 is selected from the group of -H, 1-CH3 and 2-CH3; X is O or S; and fungicidally acceptable organic and inorganic salts thereof, and an inert diluent carrier therefor.

7. The method of controlling fungi comprising applying to the area where control is desired, a fungicidally effective amount of a compound having the formula in which R is selected from the group halogen C1-C3 alkoxy and C1-C3 haloalkoxy, R1 is selected from the group of -H and -C?N; and R2 is selected from the group of -H, 1-CH3 and 2-CH3; X is O or S; and fungicidally acceptable organic and inorganic salts thereof.

8. The method of Claim 7 wherein R1 is -H and R2 is -H.

9. The method of Claim 7 wherein R is -Cl.

10. The method of Claim 7 wherein R is -OCH3, R1 is -C?N
and R2 is -H.