WO1997049696A1

WO1997049696A1 - Pyridylaminopyrimidines as fungicides

Info

Publication number: WO1997049696A1
Application number: PCT/GB1997/001437
Authority: WO
Inventors: Patrick Jelf Crowley; William Guy Whittingham; James John Eshelby
Original assignee: Zeneca Limited
Priority date: 1996-06-21
Filing date: 1997-05-27
Publication date: 1997-12-31
Also published as: CO4790135A1; AU2911797A

Abstract

A fungicidal compound of formula (I): wherein R1 is C¿1-4?alkyl, halo(C1-4)alkyl, C3-6cycloalkyl, C1-4alkoxy, halo(C1-4)alkoxy, C2-4alkenyloxy or C2-4alkynyloxy, R?2¿ is H, C¿1-4?alkylcarbonyl or C1-4alkoxycarbonyl, R?3¿ is H or methyl, R4 is H, halo, methyl, methoxy or cyano, R5 is H, halo, methyl or methoxy, R6 is C¿1-4?alkyl or C1-4alkoxy and R?7¿ is H or halo, or an N-alkylated derivative thereof.

Description

PYRIDYLAMINOPYRIMIDINES AS FUNGICIDES

The present invention relates to novel pyridylaminopyrimidines, to processes for preparing them, to fungicidal compositions containing them and to methods of using them to combat fungi, especially fungal infections of plants.

It is well known that certain anilinopyrimidines possess fungicidal properties. Cyprodinil and pyrimethanil are examples of commercial products. It is also known that certain pyridylaminopyrimidines show fungicidal activity. Compounds of this type are described in, for example, BE-A-780547.

According to the present invention there is provided a compound of the general formula (I):

wherein R¹ is C_M alkyl, halo(Cι_-4)alkyl, C_3-6 cycloalkyl, C_M alkoxy or halo(C_M)alkoxy, C_2-4 alkenyloxy or C₂-₄ alkynyloxy, R² is H, C_M alkyl, C_M alkylcarbonyl or C_M alkoxycarbonyl, R³ is H or methyl, R⁴ is H, halo, methyl, methoxy or cyano, R⁵ is H, halo, methyl or methoxy, R⁶ is C_M alkyl or C_M alkoxy and R⁷ is H or halo, or an N-alkylated derivative thereof.

Throughout this description, unless otherwise stated, halo includes fluoro, chloro and bromo. Preferred values are fluoro and chloro. Alkyl and the alkyl moieties of alkoxy, alkylcarbonyl and alkoxycarbonyl contain from 1 to 4 carbon atoms and may be in the form of straight or branched chains. Examples are methyl, ethyl, wo-propyl and tert-butyl. A preferred value is methyl. Cycloalkyl contains from 3 to 6 carbon atoms. It is preferably cycloalkyl but also includes cyclobutyl, cyclopentyl and cyclohexyl. Halo(CM)alkyl is preferably halomethyl, for example, difluoromethyl, fluoromethyl, trichloromethyl and, especially, trifluoromethyl, but also includes other haloalkyl groups such as pentafluoroethyl. Halo(C_M)alkoxy is preferably halomethoxy and, especially, trifluoromethoxy. N-alkylated derivatives include compounds of Formula (I) which carry an alkyl grojp, for example a Q.₄ alkyl group as hereinbefore defined, on the nitrogen atom of the pyridinc ring. Quaternary compounds of this type will normally be ones where R³, R⁴, R⁵ and R⁷ in formula (I) are all hydrogen atoms.

In one aspect, the invention provides a compound of formula (I) wherein R¹ is methyl, cyclopropyl, methoxy or trifluoromethyl, R² is H, methyl or acetyl, R³ is H or methyl, R⁴ is H, fluoro, chloro, methyl, methoxy or cyano, R⁵ is H, fluoro, chloro, methyl or methoxy, R⁶ is methyl or methoxy and R⁷ is H, fluoro or chloro.

Generally it is preferred that the pyridine ring of (I) is unsubstituted or bears only one substituent, i.e. that all or all but one of R³ , R⁴ , R⁵ and R⁷ are hydrogen. It is also generally preferred that R³ and R⁵ are both hydrogen. Thus, in another aspect, the invention provides a compound of formula (I) wherein R¹ is methyl, cyclopropyl, methoxy or trifluoromethyl, R^~ is H, methyl or acetyl, R³ and R⁵ are both H, R⁶ is methyl or methoxy and either R⁴ is H, fluoro, chloro, methyl, methoxy or cyano and R⁷ is H or R⁴ is H and R⁷ is fluoro or chloro.

A further general preference is that R¹ is methyl or cyclopropyl and R⁶ is methyl. Thus, in yet another aspect, the invention provides a compound of the general formula (la) :

wherein R¹ is methyl or cyclopropyl, R² and R³ are independently H or methyl, R⁴ is H, fluoro, chloro or methoxy and R⁵ is H or, when R⁴ is methoxy, R⁵ is H or methoxy.

In yet another aspect, the invention provides a compound of formula (I) wherein R is cyclopropyl, R² and R³ are independently H or methyl, R⁴ is fluoro or chloro and R⁵ is H.

In yet another aspect, the invention provides a compound of formula (I) wherein R¹ is cyclopropyl, R² is H or methyl, R³ and R⁵ are both H and R⁴ is H, fluoro or chloro. A further general preference is that R² is hydrogen. Thus in still yet another aspect, the invention provides a compound of formula (I) wherein R¹ is cyclopropyl, R², R³ and R⁵ are all H, and R⁴ is H, fluoro or chloro.

The present invention is illustrated by the compounds of formula (I) listed in Table I below.

TABLE 1

QH5 is cyclopropyl + Compound 17 is the N-methylpyridine derivative of Compound 10.

TABLE 2 Table 2 shows selected proton ΝMR data for the compounds in Table 1 which were isolated as gums and for which no melting point is available. Chemical shifts are measured in ppm from tetramethylsilane and deuterochloroform was used as solvent. The following abbreviations are used: s = singlet t = triplet br = broad d = doublet m = multiplet ppm = parts per million

The compounds of formula (I) where R² is hydrogen can be prepared according to Scheme 1, in which R¹ and R³ to R⁷ have the meanings given before.

The compound (I) can be prepared by coupling a 2-methanesuIphonylpyrimidine (LI) with a 3-aminopyridine (HI) in a suitable solvent, for example, an ether such as tetrahydrofuran (THF), using a base such as lithium diwσpropylamide at low temperature, for example, about 10°C.

2-Methanesulphonylpyrimidine (LI), may be prepared by oxidising a 2- methylthiopyrimidine (IV), for example, with potassium permanganate. The 2- methylthiopyrimidines (IV) are readily available commercially or are well known in the literature. They may be prepared, for example, by reacting a 4-methyl- or 4-cyclopropyl-2, 4- butanedione (V) with 2-methyl-2-thiopseudourea in a suitable solvent such as N,N- dimethylformamide.

The butanedione (V) may be prepared by reacting dimethyl ketone or cyclopropyl methyl ketone (VI) with an ethyl alkanoate (X) in the presence of a base such as sodium ethoxide. Aminopyridines (III) are available commercially, or they can be made, for example, by reduction of the corresponding nitro compounds (VII). The reduction can be carried out, for example, using a metal such as iron or tin, in the presence of a mineral acid such as hydrochloric acid, in a suitable solvent such as aqueous ethanol, at a suitable temperature between room temperature and 100°C; or by hydrogenation over a catalyst such as palladium on carbon, in a suitable solvent such as methanol, at atmospheric pressure or raised pressure, for example between 2 and 20 bar, at a suitable temperature between room temperature and 100°C.

The nitro compounds (VII) can be made by nitration of pyridine derivatives (VIII), for example, by using concentrated nitric acid in concentrated sulphuric acid or oleum, at a suitable temperature, for example between room temperature and 100°C. Alternatively, certain derivatives, for example where R⁴ is cyano or fluoro, can be made by reaction of commercially available nitropyridines (DC), containing a group L in the 2- or 6-position of the pyridine, where L is a leaving group such as chlorine or bromine, with a metal fluoride such as potassium fluoride, or a metal cyanide such as cuprous cyanide, in a suitable solvent such as DMF or N-methylpyrrolidone, at a suitable temperature, for example between room temperature and 200°C. Where a metal fluoride is used, the reaction is usually carried out in the presence of a catalyst such as 18-crown-6.

Compounds of formula (I) where R² is methyl can be prepared by the N-methylation of compounds of formula (I) where R² is hydrogen using a methylating agent such as dimethyl sulphate using well known techniques.

Compounds of formula (I) where R² is acetyl can be made by reacting compounds of formula (I) where R² is hydrogen with an acetylating agent such as acetyl chloride in the presence of a base, for example triethylamine. N-alkylated derivatives of compounds of formula (I) can be made by reacting a compound of formula (I) with an alkylating agent such as an alkyl iodide, for example, methyl iodide, in a suitable solvent such as an ether. Scheme 1

Base

[O]

[H]

The compounds of formula (I) are active fungicides and may be used to control one or more of the following pathogens: Pyricularia oryzae on rice and wheat and other Pyricularia spp. on other hosts; Puccinia recondita, Puccinia striiformis and other rusts on wheat, Puccinia hordei, Puccinia striiformis and other rusts on barley, and rusts on other hosts e.g. turf, rye, coffee, pears, apples, peanuts, sugar beet, vegetables and ornamental plants; Erysiphe graminis (powdery mildew) on barley, wheat, rye and turf and other powdery mildews on various hosts such as Sphaerolheca maculaήs on hops, Sphaerotheca fidiginea on cucurbits (e.g. cucumber), Podosphaera leucotricha on apple and Uncinula necator on vines; Cochliobolus spp., Helminthosporium spp., Drechslera spp. (Pyrenophora spp.), Rhynchosporium spp., Septoria spp. (including Mycosphaerella graminicola and

Leptosphaeria nodorum), Pseudocercosporella herpotrichoides and Gaeumannomyces graminis on cereals (e.g. wheat, barley, rye), turf and other hosts; Cercospora arachidicola and Cercosporidium personatum on peanuts and other Cercospora species on other hosts, for example, sugar beet, bananas, soya beans and rice; Botrytis cinerea (grey mould) on tomatoes, strawberries, vegetables, vines and other hosts and other Botrytis spp. on other hosts; Alternaria spp. on vegetables (e.g. cucumber), oil-seed rape, apples, tomatoes, cereals (e.g. wheat) and other hosts; Venturia spp. (including Venturia inaequalis (scab)) on apples, pears, stone fruit, tree nuts and other hosts; Cladosporium spp. on a range of hosts including cereals (e.g. wheat); Monilinia spp. on stone fruit, tree nuts and other hosts; Didymella spp. on tomatoes, turf, wheat and other hosts; Phoma spp. on oil-seed rape, turf, rice, potatoes, wheat and other hosts; Aspergillus spp. and Aureobasidium spp. on wheat, lumber and other hosts; Ascochyta spp. on peas, wheat, barley and other hosts; Plasmopara viticola on vines; other downy mildews such as Bremia lactucae on lettuce, Peronospora spp. on soybeans, tobacco, onions and other hosts, Pseudoperonospora humuli on hops and Pseudoperonospora cubensis on cucurbits; Pythium spp. (including Pythium ultimum) on turf and other hosts; Phytophthora infestans on potatoes and tomatoes and other Phytophthora spp. on vegetables, strawberries, avocado, pepper, ornamentals, tobacco, cocoa and other hosts; Thanatephorus cucumeris on rice and turf and other Rhizoctonia species on various hosts such as wheat and barley, vegetables, cotton and turf; Sclerotinia spp. on turf, peanuts, oil-seed rape and other hosts; Sclerotium spp. on turf, peanuts and other hosts;

Colletotrichum spp. on a range of hosts including turf, coffee and vegetables; Laetisaria fuciformis on turf; Mycosphaerella spp. on banana, peanut, citrus, pecan, papaya and other hosts; Diaporthe spp. on citrus, soybean, melon, pear, lupin and other hosts; Elsinoe spp. on citrus, vines, olives, pecans, roses and other hosts; Pyrenopeziza spp. on oil-seed rape and other hosts; Oncobasidium theobromae on cocoa causing vascular streak dieback; Fusarium spp., Typhula spp., Microdochium nivale, Ustilago spp., Urocystis spp., Tilletia spp., and Claviceps purpurea on a variety of hosts but particularly wheat, barley, turf and maize;

Ramularia spp. on sugar beet and other hosts; post-harvest diseases particularly of fruit (e.g. Pencillium digitatum and P. italicum and Trichoderma viride on oranges, Colletotrichum musae and Gloeosporium musarum on bananas and Botrytis cinerea on grapes); other pathogens on vines, notably Eutypa lata, Guignardia bidwellii, Phellinus igniarus, Phomopsis viticola, Pseudopezicula tracheiphila and Stereum hirsutum; other pathogens on lumber, notably Cephaloascus fragrans, Ceratocystis spp., Ophiostoma piceae, Penicillium spp., Trichoderma pseudokoningii, Trichoderma viride, Trichoderma harzianum, Aspergillus niger, Leptographium lindbergi and Aureobasidium pullulans; and fungal vectors of viral diseases e.g. Polymyxa graminis on cereals as the vector of barley yellow mosaic virus (BYMV).

Further, some of the compounds may be useful as seed dressings against pathogens including Fusarium spp., Septoria spp., Tilletia spp., (e.g. bunt, a seed-borne disease of wheat), Ustilago spp. and Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Pyricularia oryzae on rice. The compounds may move acropetally/locally in plant tissue. Moreover, the compounds may be volatile enough to be active in the vapour phase against fungi on the plan:.

The invention therefore provides a method of combating fungi which comprises applying to a plant, to a seed of a plant or to the locus of the plant or seed a fungicidally effective amount of a compound as hereinbefore defined, or a composition containing the same.

The compounds may be used directly for agricultural purposes but are more conveniently formulated into compositions using a carrier or diluent. The invention thus provides fungicidal compositions comprising a compound as hereinbefore defined and an acceptable carrier or diluent therefor. It is preferred that all compositions, both solid and liquid formulations, comprise 0.0001 to 95%, more preferably 1 to 85%, for example 1 to 25% or 25 to 60%, of a compound as hereinbefore defined. When applied to the foliage of plants, the compounds of the invention are applied at rates of 0.1 g to 10kg, preferably lg to 8kg, more preferably lOg to 4kg, of active ingredient (invention compound) per hectare.

When used as seed dressings, the compounds of the invention are used at rates of 0.000 lg (for example 0.00 lg or 0.05g) to lOg, preferably 0.005g to 8g, more preferably 0.005g to 4g, of active ingredient (invention compound) per kilogram of seed.

The compounds can be applied in a number of ways. For example, they can be applied, formulated or unformulated, directly to the foliage of a plant, to seeds or to other medium in which plants are growing or are to be planted, or they can be sprayed on, dusted on or applied as a cream or paste formulation, or they can be applied as a vapour or as slow release granules.

Application can be to any part of the plant including the foliage, stems, branches or roots, or to soil surrounding the roots, or to the seed before it is planted, or to the soil generally, to paddy water or to hydroponic culture systems. The invention compounds may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.

The term "plant" as used herein includes seedlings, bushes and trees. Furthermore, the fungicidal method of the invention includes preventative, protectant, prophylactic, systemic, curative and eradicant treatments. The compounds are preferably used for agricultural and horticultural purposes in the form of a composition. The type of composition used in any instance will depend upon the particular purpose envisaged.

The compositions may be in the form of dustable powders or granules comprising the active ingredient (invention compound) and a solid diluent or carrier, for example, fillers such as kaolin, bentonite, kieselguhr, dolomite, calcium carbonate, talc, powdered magnesia, fuller's earth, gypsum, diatomaceous earth and china clay. Such granules can be preformed granules suitable for application to the soil without further treatment. These granules can be made either by impregnating pellets of filler with the active ingredient or by pelleting a mixture of the active ingredient and powdered filler. Compositions for dressing seed may include an agent (for example, a mineral oil) for assisting the adhesion of the composition to the seed; alternatively the active ingredient can be formulated for seed dressing purposes using an organic solvent (for example, N-methylpyrrolidone, propylene glycol or N.N-dimethylformarnide). The compositions may also be in the form of water dispersible powders or water dispersible granules comprising wetting or dispersing agents to facilitate the dispersion in liquids. The powders and granules may also contain fillers and suspending agents. The compositions may also be in the form of soluble powders or granules, or in the form of solutions in polar solvents.

Soluble powders may be prepared by mixing the active ingredient with a water-soluble salt such as sodium bicarbonate, sodium carbonate, magnesium sulphate or a polysaccharide, and a wetting or dispersing agent to improve water dispersibility/solubility. The mixture may then be ground to a fine powder. Similar compositions may also be granulated to form water-soluble granules. Solutions may be prepared by dissolving the active ingredient in polar solvents such as ketones, alcohols and glycol ethers. These solutions may contain surface active agents to improve water dilution and prevent crystallisation in a spray tank.

Emulsifiable concentrates or emulsions may be prepared by dissolving the active ingredient in an organic solvent optionally containing a wetting or emulsifying agent and then adding the mixture to water which may also contain a wetting or emulsifying agent. Suitable organic solvents are aromatic solvents such as alkylbenzenes and alkylnaphthalenes, ketones such as cyclohexanone and methylcyclohexanone, chlorinated hydrocarbons such as chlorobenzene and trichl ore thane, and alcohols such as benzyl alcohol, furfuryl alcohol, butanol and glycol ethers.

Aqueous suspension concentrates of largely insoluble solids may be prepared by ball or bead milling with a dispersing agent with a suspending agent included to stop the solid settling.

Compositions to be used as sprays may be in the form of aerosols wherein the formulation is held in a container under pressure of a suitable propellant.

The invention compounds can be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating in enclosed spaces a smoke containing the compounds.

Alternatively, the compounds may be used in micro-encapsulated form. They may also be formulated in biodegradable polymeric formulations to obtain a slow, controlled release of the active substance. By including suitable additives, for example additives for improving the uptake, distribution, adhesive power and resistance to rain on treated surfaces, the different compositions can be better adapted for various utilities. Other additives may be included to improve the biological efficacy of the various formulations. Such additives can be surface active materials to improve the wetting and retention on surfaces treated with the formulation and also the uptake and mobility of the active material, or additionally can include oil based spray additives, for example, certain mineral oil and natural plant oil (such as soya bean and rape seed oil) additives, or blends of them with other adjuvants.

The invention compounds can be used as mixtures with fertilisers (e.g. nitrogen-, potassium- or phosphorus-containing fertilisers). Compositions comprising only granules of fertiliser incorporating, for example coated with, a compound of formula (I) are preferred. Such granules suitably contain up to 25% by weight of the compound. The invention therefore also provides a fertiliser composition comprising a fertiliser and the compound of general formula (I) or a salt or metal complex thereof. Water dispersible powders, emulsifiable concentrates and suspension concentrates will normally contain surfactants, e.g. a wetting agent, dispersing agent, emulsifying agent or suspending agent. These agents can be cationic, anionic or non-ionic agents.

Suitable cationic agents are quaternary ammonium compounds, for example, cetyltrimethylammonium bromide. Suitable anionic agents are soaps, salts of aliphatic monoesters of sulphuric acid (for example, sodium lauryl sulphate), and salts of sulphonated aromatic compounds (for example, sodium dodecylbenzenesulphonate, sodium, calcium or ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of sodium dϋsopropyl- and triisopropylnaphthalene sulphonates).

Suitable non-ionic agents are the condensation products of ethylene oxide with fatty alcohols such as oleyl or cetyl alcohol, or with alkyl phenols such as octyl- or nonylphenol and octylcresol. Other non-ionic agents are the partial esters derived from long chain fatty acids and hexitol anhydrides, alkyl glucosides, polysaccharides and the lecithins and the condensation products of the said partial esters with ethylene oxide. Suitable suspending agents are hydrophilic colloids (for example, polyvinylpyrrolidone and sodium carboxymethylcellulose), and swelling clays such as bentonite or attapulgite.

Compositions for use as aqueous dispersions or emulsions are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being diluted with water before use. These concentrates should preferably be able to withstand storage for prolonged periods and after such storage be capable of dilution with water in order to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. The concentrates may conveniently contain up to 95%, suitably 1-85%, for example 1-25% or 25-60%, by weight of the active ingredient. After dilution to form aqueous preparations, such preparations may contain varying amounts of the active ingredient depending upon the intended purpose, but in aqueous preparation containing 0.0001 to 10%, for example 0.005 to 10%, by weight of active ingredient may be used. The compositions of this invention may contain other compounds having biological activity, e.g. compounds having similar or complementary fungicidal activity or which possess plant growth regulating, herbicidal or iπsecticidal activity.

By including another fungicide, the resulting composition can have a broader spectrum of activity or a greater level of intrinsic activity than the compound of general formula (I) alone. Further the other fungicide can have a synergistic effect on the fungicidal activity of the compound of general formula (I). Examples of fungicidal compounds which may be included in the composition of the invention are (E)-N-methyl-2-(2-phenoxyphenyl)-2- methoxyiminoacetamide, (E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyI]-2-methox}'- iminoacetamide, (Λ5)-l-aminopropylphosphonic acid, (/?->)-4-(4-chlorophenyl)- -2-phenyl-2-(lH-l,2,4-triazol-l-ylmethyl)butyronitrile, (Z)-N-but-2-enyloxymemyl- -2-chloro-2',6'-diethylacetanilide, l-(2-cyano-2-methoxyiminoacetyl)-3-ethyl urea, 4-(2,2-difluoro- 1 ,3-benzodioxol-4-yl)pyrrole-3-carbonitrile, 4-bromo-2-cyano-N,/V-dimethyl- -6-trifluoromethylbenzimidazole-l-sulphonamide, 5-ethyl-5,8-dihydro-8-oxo(l,3)-dioxol- (4,5-g)quinoline-7-carboxylic acid, α-[N-(3-chloro-2,6-xylyl)-2-methoxy- acetamido]-γ-butyrolactone, N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide, alanycarb, aldimorph, ampropylfos, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl, biloxazol, binapacryl, bitertanol, blasticidin S, bromuconazole, bupirimate, butenachlor, buthiobate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, CGA 245704, chinomethionate, chlorbenzthiazone, chloroneb, chlσrothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulphate, copper tallate, and Bordeaux mixture, cycloheximide, cymoxanil, cyproconazole, cyprodinyl, cyprofuram, debacarb, di-2-pyridyl disulphide l,l'-dioxide, dichlofluanid, dichlone, diclobutrazol, diclomezine, dicloran, didecyl dimethyl ammonium chloride, diethofencarb, difenoconazole, (9,c7-di-wσ-propyl-S-benzyl thiophosphate, dimefluazole, dimetconazole, dimethomoφh, dimethirimol, diniconazole, dinocap, dipyrithione, ditalimfos, dithianon, dodemorph, dodine, doguadine, edifenphos, epoxiconazole, etaconazole, ethirimol, ethoxyquin, ethyl (Z)-N-benzyl-7V-([methyl(methyl-thioethylideneaminooxycarbonyl)- amino]thio)-β-alaninate, etridiazole, famoxadone, fenaminosulph, fenapanil, fenarimol, fenbuconazole, fenfuram, fenpiclonil, fenpropidin, fenpropimoφh, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, fluoroimide, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fuberidazole, furalaxyl, furametpyr, furconazole-cis, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, imazalil, imibenconazole, ipconazole, iprobenfos, iprodione, isopropanyl butyl carbamate, isoprothiolane, kasugamycin, kresoxim-methyl, mancozeb, maneb, mepanipyrim, mepronil, metalaxyl, metconazole, methfuroxam, metiram, metiram-zinc, metsulfovax, myclobutanil, NTN0301, neoasozin, nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace, organomercury compounds, oxadixyl, oxolinic acid, oxycarboxin, pefurazoate, penconazole, pencycuron, phenazin oxide, phosetyl-Al, phosphorus acids, phthalide, polyoxin D, polyram, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, propionic acid, prothiocarb, pyracarbolid, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinconazole, quinomethionate, quintozene, rabenazole, sodium pentachlorophenate, streptomycin, sulphur, tebuconazole, techlofthalam, tecnazene, tetraconazole, thiabendazole, thicyofen, thifluzamide, 2-(thiocyanomethylthio)benzothiazole, thiophanatemethyl, thiram, timibenconazole, tolclofos-methyl, tolylfluanid, triacetate salt of l,r-iminodi(octamethylene)diguanidine, triadimefon, triadimenol, triazbutyl, triazoxide, tricyclazole, tridemoφh, triforine, triflumizole, triticonazole, validamycin A, vapam, vinclozolin, XRD-563, zineb and ziram. The compounds of general formula (I) can be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.

The following Examples illustrate the invention. Unless otherwise stated, chromatography was performed on a column of silica gel as the stationary phase. The following abbreviations are used throughout:

ppm = parts per million NMR = proton nuclear magnetic resonance mp = melting point s = singlet t = triplet d = doublet br = broad m = multiplet dd = doublet of doublets dddd = quartet of doublets

THF = tetrahydrofuran DMF = N,N-dimethylformamide Ether = dimethyl ether DMSO = dimethylsulphoxide

EXAMPLE 1

This Example illustrates the preparation of 2-(3-pyridylamino)-4-cyclopropyl-6- methylpyrimidine (compound 10 of Table 1).

4-CvclopropyI-2 ,4-butanedione

Sodium metal (5.52 g) was added to ethanol over 50 min with stirring until it had all dissolved. To this solution was added cyclopropyl metfryl ketone (16.8 ml) in ethyl acetate (200 ml), and the reaction refluxed under a Dean-Stark head and the distilled solvent removed and topped up with ethyl acetate as required. After 4.5 hour the reaction was cooled and stood overnight. 1M Hydrochloric acid was added to neutrality, and the mixture extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate and evaporated to give the crude product as a brown liquid. This was chromatographed on silica gel eluting with 5, 10 and then 20% ether/hexane to give the pure dione (12.47 g).

NMR (CDC1₃) δ 0.86-1.03 (2H,m), 1.07-1.17 (2H,m), 1.58-1.70 (lH,m), 2.03 (3H,s), 5.62 (lH,s), 15.62 (lH,s) ppm.

2-Methylthio-4-cyclopropyl-6-methylpyrimidine

To 4-cyclopropyI-2,4-butanedione (12 g) in DMF (25 ml) was added 2-methyl-2- thiopseudourea sulphate (70 g), and the mixture refluxed overnight. The reaction was poured into brine and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate and evaporated to give the crude product. This was chromatographed on silica gel eluting with 5, 10 and then 20% ether/hexane to give the desired product as a yellow liquid (12.04 g).

NMR (CDCI₃) δ 0.97-1.06 (2H,m), 1.10-1.20 (2H,m), 1.86 (lH,tt), 2.38 (3H,s), 2.50 (3H,s), 6.68 (lH,s) ppm.

2-Methanesulphonyl-4-cvclopropyl-6-methylpyrimidine

To 2-MethyIthio-4-cyclopropyl-6-methylpyrimidine (0.1 m) in acetic acid (100ml) and water (100ml) was added potassium permanganate (32 g in 500 ml water) and the mixture stirred for 2 hours and then quenched with sodium metabisulphite until colourless. It was then neutralised with potassium carbonate, diluted with water and extracted with ethyl actetate. The organic extract was washed with bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give the crude product. Trituration with etheπhexane gave the pure product as a white solid (11.725 g), mp 95-96 °C.

NMR (CDC1₃) δ 1.13-1.27 (4H,m), 2.06 (lH,tt), 2.58 (3H,s), 3.30 (7.21 (lH,s) ppm.

2- (3-Pyridylamino)-4-cvclopropyl-6-methylpyrimidine

n-Butyl lithium (1.25 ml of a 2.4 m solution in hexane) was added to diwopropylamine (0.42 ml) in dry THF (5 ml) at 0°C over 2 minutes, and then stirred for 5 minutes. 3- Aminopyridine (0.282 g) in dry THF (5 ml) was added over 2 minutes and the reaction mixture stirred for 5 minutes at 0°C, and then 2-methanesulphonyl-4-cyclopropyl-6- methylpyrimidine (0.530 g) in dry THF (5 ml) added over 2 minutes. The reaction was allowed to warm up to room temperature over 1.5 hour, and then quenched with saturated aqueous NH₄CI and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate and evaporated to give the crude material. This was chromatographed on silica gel eluting with 60% ether/hexane to give the desired product as an off-white solid (0.242 g), mp 108-110 °C. NMR (CDC1₃) δ 0.98-1.08 (2H,m), 1.10-1.29 (2H,m), 1.88 (2H,m), 2.38 (3H,s), 6.57 (lH,s), 7.03 (lH,br, NH), 7.23 (lH,dd), 8.26-8.15 (2H,m), 8.73 (IH,d) ppm.

EXAMPLE 2

This Example illustrates the preparation of 2-(3-pyridyl-(N-methyl)-amino)-4- cyclopropyl-6-methylpyrimidine (compound 11 of Table 1).

To 2-(3-pyridylamino)-4-cyclopropyl-6-methylpyrirnidine (0.12 g) in DMSO (10 ml) was added potassium hydroxide (0.112 g), and the mixture stirred for 10 minutes. Dimethyl sulphate (57 μl) was then added and the reaction mixture stirred for 40 minutes, and then quenched with saturated aqueous NH₄CI and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate and evaporated to give the crude material. This was chromatographed on silica gel eluting with 60% ether/hexane to give the desired product as a pale yellow gum (0.101 g); NMR data shown in Table 2.

EXAMPLE 3

This example illustrates the preparation of 2-(2-fluoro-5-ρyridylamino)-4- cyclopropyl-6-methylpyrimidine (compound 1 of Table 1).

2-Fluoro-5-nitropyridine

2-Chloro-5-nitropyridine (300 g), spray-dried potassium fluoride (118 g), and a spatula of 18- crown-6 were heated at 105-117 °C in DMF (400 ml) for 8 hours. The reaction mixture was filtered through Celite with ether added, and then water added. The mixture was filtered again, and extracted with ether. The organic extracts were washed with water, dried over magnesium sulphate, and evaporated to give the desired product as a dark red oil (236 g).

NMR (CDC1₃) δ 7.14 (lH,dd), 8.62 (lH,octet), 9.15 (lH,d) ppm.

2-Fluoro-5-aminopyridine 2-Fluoro-5-nitropyridine (4.26g) in ethanol (5 ml) was added to iron powder (8.39g) stirred in a mixture of concentrated hydrochloric acid (0.85 ml), ethanol (45 ml) and water (35 ml) at 75 °C. The reaction mixture was stirred at this temperature for 40 minutes and then filtered through Celite. The filtrate was diluted with 10% potassium hydroxide and extracted with ether. The organic fraction was washed with brine, dried over magnesium sulphate and then evaporated to give a brown solid, which was triturated with ether/pentane to give the desired product as grey crystals (3.15g).

NMR (CDC1₃) δ 3.62 (2H,brs), 6.75 ( lH,dd), 7.10 (lH,octet), 7.61 (lH.t) ppm.

2-(2-Fluoro-5-pyridylaιru^o)-4-cvclopropyl-6-methylpyrimidine

/i-Butyl lithium (3.0 ml of a 2.0 M solution in hexane) was added to diwσpropylarnine (0.84 ml) in dry THF (15 ml) at 0°C over 2 minutes, and then stirred for 5 minutes. 2-Fluoro-5- aminopyridine (0.674g) in dry THF (5 ml) was added over 5 minutes, and the reaction stirred for 15 minutes. 2-Methanesulphonyl-4-cyclopropyl-6-methylpyrimidine (1.06g) in dry THF (5 ml) was then added over 5 minutes, and the reaction mixture was stirred for 2 hours at 0°C. The reaction mixture was then quenched with aqueous NH₄CI, and extracted three times with diethyl ether. The ethereal solution was dried over magnesium sulphate, filtered and evaporated to give the crude material. This was chromatographed on silica gel, eluting with 40% ethyl acetate in hexane, to give the desired product as a solid (0.726g), mp 92-94 °C.

NMR (CDC1₃) δ 0.97-1.06 (2H,m), 1.06-1.14 (2H,m), 1.86 (lH,brm), 2.35 (3H,s), 6.57 (lH,s), 6.88 (lH,dd), 7.18 (lH,brs), 8.18 (lH.dddd), 8.36 (lH,t) ppm. EXAMPLE 4

This Example illustrates the preparation of N-acetyl-2-(2-fluoro-5-pyridylamino)-4- cyclopropyl-6-methylpyrimidine (compound 15 of Table 1)

Acetyl chloride (0.21 ml) was added to 2-(fluoro-5-pyridylamino)-4-cyclopropyl-6- methylpyrimidine (0.6 lOg; prepared as described in Example 3) and triethylamine (0.42 ml) in die hlorome thane (20 ml), and the reaction stirred at room temperature for 2 hours, and then left overnight. It was then quenched with aqueous ammonium chloride, and extracted with ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate and then evaporated to give crude product. This was chromatographed on silica gel eluting with 60-80% ethyl acetate/hexane, followed by neat ethyl acetate to give the desired product as a tan solid, (0.332g), mp 79-80 °C.

NMR (CDC1₃) δ 0.95-1.18 (4H,m), 1.90 (IH, septet), 2.40 (3H,s), 2.42(3H,s), 6.87(lH,s), 6.97 (lH.dd), 7.72 (IH, triplet of doublets), 8.05 (lH,s) ppm.

EXAMPLE 5 This Example illustrates the preparation of 2-(2-Fluoro-3-pyridylamino)-4-cvclopropyl-6- methylpyrimidine (compound 16 of Table 1)

2-Fluoro-3-nitropyridine

Potassium fluoride (6.4 g) and 18-crown-6 (catalytic amount) were added to 2-chloro-3- nitropyridine (16 g) which had been pre-dissolved in dry DMF (30ml). The reaction was stirred at 100°C for 11 hours and then further potassium fluoride (1.6 g) was added before stirring at 100°C for a further 24 hours. The reaction was quenched with water and extracted with ether. The organic fraction was dried with magnesium sulphate and evaporated to give a dark brown gum. Chromatography on silica gel with 60% terf-butylmethyl ether in hexane as eluent yielded the desired product as a yellow oil (13.8 g). NMR (CDC1₃) 7.57-7.46 (IH, m), 8.64-8.50 (2H, m) ppm

3 - Amino-2-fluoropyridine

5% Palladium on carbon (1 spatula) was added to 2-fluoro-3-nitropyridine (7.5 g) in methanol (20ml). The mixture was hydrogenated at room temperature and 2.5 bar with vigorous stirring for 1.5 hours. The reaction mixture was filtered through a pad of silica and washed with ethyl acetate. The filtrate was evaporated to give a brown gum, which was chromatographed on silica gel with 60% ethyl acetate in hexane as eluent to yield the desired product as a yellow oil (5.9 g).

NMR (CDC1₃) 3.89 (2H, brs), 7.02-6.92 (IH, m), ), 7.18-7.02 (IH, m), 7.60-7.48 (IH, m) ppm

2-(2-Fluoro-3-pyridylammo)-4-cvcloprσpyl-6-memylpyrimidine

3-Amino-2-fluoropyridine (0.56 g) in dry THF (10 ml) was added over 2 minutes to lithium diisopropylamide (5.2 mmol) in dry THF (10 ml) at 0°C and the reaction mixture stirred at this temperature for 30 minutes. 4-Cyclopropyl-6-methyl-2-methylsulphonyIpyrimidine ( 1.06 g) in dry THF ( 10 ml) was then added to the reaction mixture over 2 minutes. The dark brown reaction mixture was warmed to room temperature over 3 hours, quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic fraction was washed with brine, dried over magnesium sulphate and then evaporated to give a brown gum, which was chromatographed on silica gel with 20% ethyl acetate in hexane as eluent. Trituration with ether and hexane yielded the desired product as a pale pink solid (0.539 g), mp 84-85 °C

NMR (CDC1₃) 1.20-0.96 (4H, m), 1.97-1.78 (IH, m), 2.38 (3H, s), 6.60 (IH, s), 7.25-7.09 (2H, m + NH), 7.78-7.68 (IH, m), 8.99-8.86 (IH, m) ppm EXAMPLE 6

This Example illustrates the preparation of 3-(4-cyclopropyl-6-methyl-2-pyτimidinylamino)- N-methylpyridinium iodide (Compound 17 of Table 1)

Methyl iodide (0.12 ml) was added to 2-(3-pyridyIamko)-4-cyclopropyI-6-methyIpyrimidine (0.552 g; prepared as described in Example 1) in ether (10 ml). The reaction was stood for 24 hours and then cooled in a dry ice acetone bath to yield the desired product as a white solid which was filtered and washed with hexane (0.108 g), mp 254-255 °C (melts / decomposes).

NMR (DMSO) 1.12-0.93 (4H, m), 2.08-1.94 (IH, m), 2.33 (3H, s), 4.28 (3H, s), 6.87 (IH, s), 7.93 (IH, dd), 8.52-8.41 (2H, m), 9.36 (IH, brs) ppm.

EXAMPLE 7

The compounds were tested against a variety of foliar fungal diseases of plants. The technique employed was as follows.

The plants were grown in John Innes Potting Compost (No 1 or 2) in 4 cm diameter minipots. The test compounds were formulated either by bead milling with aqueous

Dispersol T or as a solution in acetone or acetone/ethanol which was diluted to the required concentration immediately before use. The formulations (100 ppm active ingredient) were sprayed on to the foliage of the plants to maximum retention. Tween 20 was added to give a final concentration of 0.1% by volume when the sprays were applied to cereals.

The compounds were applied to the foliage (by spraying) one day before the plant was inoculated with the disease. The exception was the test on Erysiphe graminis in which the plants were inoculated either 6 hours or 24 hours after chemical treatment. Foliar pathogens were applied as spore suspensions onto the leaves of test plants. After inoculation, the plants were put into an appropriate environment to allow infection to proceed and then incubated until the disease was ready for assessment. The period between inoculation and assessment varied from four to fourteen days according to the disease and environment. The disease level present (i.e. leaf area covered by actively sporulating disease) on each of the treated plants was recorded using the following assessment scale:

0 = 0% disease present 20 = 10.1-20% disease present

1 = 0.1-1% disease present 30 = 20.1-30% disease present 3 = 1.1-3% disease present 60 = 30.1-60% disease present 5 = 3.1-5% disease present 90 = 60.1-100% disease present 10 = 5.1-10% disease present

Each assessment was then expressed as a percentage of the level of disease present on the untreated control plants. This calculated value is referred to as a POCO (Percentage of Control) value. An example of a typical calculation is as follows:

Disease level on untreated control = 90

Disease level on treated plant = 30

POCO = disease level on treated plant x 100 = 30 x 100 = 33.3 disease level on untreated control 90 This calculated POCO value is then rounded to the nearest of the values in the 9-point assessment scale shown above. In this particular example, the POCO value would be rounded to 30. Lf the calculated POCO falls exactly mid-way between two of the points, it is rounded to the lower of the two values.

The results are shown in Table 3. TABLE 3

NT = Not tested - = No result

Unless otherwise indicated, data represent activity following application as a foliar spray at 100 ppm. Data for ERYSGT marked with ^»*^» indicates disease inoculation 6 hours after chemical treatment. For other ERYSGT data, plants were inoculated 24 hours after treatment.

Key to Disfta.ςps

ERYSGT Erysiphe graminis tritici

LEPTNO Septoria nodorum

PUCCRT Puccinia recondita

PLASVI Plasmopara viticola

PHYTLN Phytophthora infestans lycopersici BOTRCI Botrytis cinerea VENTIN Venturia inaequalis

Claims

CLAIMS 1. A fungicidal compound of formula (I):

wherein R¹ is CM alkyl, halo(CM)alkyl, C_3-6 cycloalkyl, Cι^ alkoxy, or halo(C_M) alkoxy, C₂-₄ alkenyloxy or C_2-4 alkynyloxy, R² is H, C_M alkyl, C_M alkylcarbonyl or C_1-4 alkoxycarbonyl, R³ is H or methyl, R⁴ is H, halo, methyl, methoxy or cyano, R⁵ is H, halo, methyl or methoxy, R⁶ is CM alkyl or C_M alkoxy and R⁷ is H or halo, or an /V-alkylated derivative thereof.

2. A compound according to claim 1 wherein R¹ is methyl, cyclopropyl, methoxy or trifluoromethyl, R² is H, methyl or acetyl, R³ is H or methyl, R⁴ is H, fluoro, chloro, methyl, methoxy or cyano, R⁵ is H, fluoro, chloro, methyl or methoxy, R⁶ is methyl or methoxy and R⁷ is H, fluoro or chloro.

A compound according to claim 1 wherein R¹ is methyl, cyclopropyl, methoxy or trifluoromethyl, R² is H, methyl or acetyl, R³ and R⁵ are both H, R⁶ is methyl or methoxy and either R⁴ is H, fluoro, chloro, methyl, methoxy or cyano and R⁷ is H or R⁴ is H and R⁷ is fluoro or chloro.

A compound according to claim 1 wherein R¹ is methyl or cyclopropyl and R⁶ is methyl.

A compound according to claim 1 having the general formula (La):

A compound according to claim 1 wherein R¹ is cyclopropyl, R² and R³ are independently H or methyl, R⁴ is fluoro or chloro and R⁵ is H.

7. A compound according to claim 1 wherein R¹ is cyclopropyl, R² is H or methyl, R³ and R⁵ are both H and R⁴ is H, fluoro or chloro and R⁵ is H.

8. A compound according to claim 1 wherein R is cyclopropyl, R , R and R are all H, and R⁴ is H, fluoro or chloro.

A process for preparing a compound according to claim 1 wherein R is H, which comprises reacting a 2-methanesulphonylpyrimidine of formula (LI):

with a 3-aminopyridine of formula (UJ):

in a solvent and in the presence of a base.

10. A fungicidal composition comprising a fungicidally effective amount of a compound according to claim 1 and a fungicidally acceptable carrier or diluent therefor.

11. A method of combating fungi which comprises applying to plants, to the seeds of plants or to the locus of the plants or seeds, a compound according to claim 1 or a composition according to claim 10.