EP1232149A2

EP1232149A2 - Fungicidal melithiazole derivatives

Info

Publication number: EP1232149A2
Application number: EP00988747A
Authority: EP
Inventors: Oliver Meyer; Werner Simon; Gerhard Hoefle; Udo Soeker
Original assignee: Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Current assignee: Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Priority date: 1999-11-24
Filing date: 2000-11-23
Publication date: 2002-08-21
Also published as: AU2508201A; WO2001038317A2; WO2001038317A3

Abstract

Compounds with contain essentially equimolar amounts of the enantiomer pair of formulae (IA and IB), wherein R1 represents a hydrogen atom or an optionally substituted alkyl, alkenyl, or aryl group; R?2, R3, R4 and R5¿ each independently represent an alkyl group; and R6 represents a group of formula -COOR7 or -CONR7R8, in which R?7 and R8¿ each independently represent a hydrogen atom or an alkyl group; L1 represents a hydrogen or halogen atom or an optionally substituted alkyl group; and wherein th ezigzag line indicates that the alkoximino group may have the (E)- or (Z)-configuration show excellent fungicidal activity and systemicity.

Description

FUNG1C1DAL MELITHIAZOLE DERIVATIVES

This invention relates to melithiazole derivatives, a novel process for their preparation, compositions containing such compounds, a method for combating a fungus at a locus comprising treating the locus with such compounds, and their use as fungicides.

Food production relies upon a variety of agricultural technologies to ensure the growing population's dietary needs remain affordable, nutritious and readily available on grocery store shelves. Crops and food are constantly threatened by a variety of fungal organisms, which, if left uncontrolled, can cause ruined crops and devastated harvests.

Fungicides are thus an important agricultural technology which can be used to protect crops and foods from fungus and fungal diseases. The preparation of melithiazole C by reductive cleavage of myxothiazol A with subsequent transformation of the resulting melithiazole C amide into the corresponding methyl ester has been described by a poster of B. Bόhlendorf et al. presented at the Dechema Naturstofftagung in Irsee, Germany in 1996. Melithiazole C disclosed on this poster shows weak in vitro activity against Bortrytis ciπerea.

International Patent Application WO 98/46583 discloses certain derivatives of Melithiazole C which show high activity against a broad range of phytopathogenic fungi. However, these derivatives are produced in very small amounts from natural Melithiazole C and are therefore enantiomeric pure compounds. Heretofore there has been no way to produce such derivatives on a commercial scale. The underlying problem of the present invention was to find similar derivatives having high in vivo activity against a broad range of phytopathogenic fungi, which are producible on an economic scale.

The present invention provides a fungicidal compound which contains essentially equimolar amounts of the enantiomer pair of formulae lA and IB:

wherein

R¹ represents a hydrogen atom or an optionally substituted alkyl, alkenyl, or aryl group;

R², R³, R⁴ and R⁵ each independently represent an alkyl group; and R⁶ represents a group of formula -COOR⁷ or -CONR⁷R⁸, in which R⁷ and R⁸ each independently represent a hydrogen atom or an alkyl group; L¹ represents a hydrogen or halogen atom or an optionally substituted alkyl group; and the zigzag line indicates that the alkoximino group may have the

(E)- or (Z)-confιguration.

The new compounds are easily produced and combine excellent fungicidal activities against a broad range of phytopathogenic fungi in various crops with comparably high systemicities.

Further, the present invention relates to a process for the preparation of the novel compound of formulae IA and IB, and to the novel intermediate compounds of formula II

in which R and L are as hereinbefore defined for formula I and L² represents a halogen atom,

It is thus an object of the invention to provide methods for controlling an undesired fungus by contacting said plants with a fungicidally effective amount of the new compounds.

It is another object of the invention to provide fungicidal compositions containing the new compounds as active ingredients.

These and other objects and features of the invention will be more apparent from the detailed description set forth hereinbelow, and from the appended claims.

It has surprisingly been found that a fungicidal compound which contains essentially equimolar amounts of the enantiomer pair of formulae lA and IB: wherein R¹, R², R³, R⁴, R⁵, R⁶ and L¹ are as hereinbefore defined possess excellent fungicidal activity against diseases caused by phytopathogenic fungi at low dose rates with high bioavailability due to their high systemicity. The skilled worker would not expect that this racemic mixture would have the almost the same fungicidal activity as the optically pure enantiomers disclosed by WO 98/46583.

Optionally substituted moieties in the compounds of formula I may be unsubstituted or have from one up to the maximal possible number of substituents. Typically, 0 to 2 substituents are present. Each optionally substituted group is independently substituted by one or more halogen atoms, or nitro, cyano, cycloalkyl, preferably C₃_s cycloalkyl, cycloalkenyl, preferably C₃.₆ cycloalkenyl, haloalkyl, preferably C-|_₆ haloalkyl, halocycloalkyl, preferably C₃_6 halocycloalkyl, alkoxy, preferably C^ alkoxy, haloalkoxy, preferably C-^ haloalkoxy, phenyl, mono- di- or trihalo-phenyl, pyridyl, furanyl or thienyl groups.

In general terms, unless otherwise stated, the term "halogen atom" as used herein denotes a bromine, iodine, chlorine or fluorine atom, and is preferably a bromine, chlorine or fluorine atom. In general terms, unless otherwise stated, the term "racemate IA/IB" as used herein denotes equimolar amounts of the enantiomer pair of formulae IA and IB.

In general terms, unless otherwise stated herein, the terms "alkyl", "alkenyl", "alkynyl" and "alkoxy" as used herein with respect to a radical or moiety refer to a straight or branched chain radical or moiety. As a rule, such radicals have up to 10, in particular up to 6, carbon atoms. Preferably, an alkyl or alkoxy moiety has from 1 to 6 carbon atoms, and most preferably, from 1 to 5 carbon atoms. A preferred alkyl moiety is the methyl, ethyl, n-propyl, isopropyl or n-butyl group.

An aryl group as substituent or part of other substituents is suitably an optionally substituted phenyl or naphthyl group. A heteroaryl group as substituent or part of other substituents is preferably an optionally substituted 5- or 6-membered heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, with at least one oxygen, one sulfur atom or 1 to 3 nitrogen atoms being preferred. Examples of such groups are thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidyl, py dazinyl, and triazinyl groups. 5- or 6-membered heterocycles may be fused with a benzene ring.

"Aryl" preferably represents a phenyl group substituted by one or more of the same or different substituents selected from halogen atoms, alkyl groups, alkoxy groups, cyano groups, haloalkyl groups, haloalkoxy groups, alkylthio groups and haloalkylthio groups. The invention particularly relates to compounds of racemate IA/IB in which any alkyl part of the groups R , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and 1_ , which may be straight chained or branched, contains 1 to 10 carbon atoms, preferably 1 to 9 carbon atoms, more preferably 1 to 6 carbon atoms, and, in which each optionally substituted group may be independently substituted by one or more halogen atoms or nitro, cyano, cycloalkyl, preferably C₃.₆ cycloalkyl, cycloalkenyl, preferably C₃.₆ cycloalkenyl, haloalkyl, preferably C-^ haloalkyl, halocycloalkyl, preferably C₃_5 halocycloalkyl, alkoxy, preferably C^ alkoxy, haloalkoxy, preferably C-|_5 haloalkoxy, phenyl, or pyridyl groups, in which the phenyl moiety is optionally substituted by one to three substituents selected from 5 halogen atoms, cyano, C-^ alkyl and C-|_s alkoxy groups. The invention especially relates to compounds of the general formula I in which R¹ represents a straight-chained or branched Cι_ ₀ alkyl, in particular, a straight-chained C₁.₆ alkyl group, in which the alkyl moiety may be unsubstituted or substituted by 1 to 3 substituents selected from the group 10 consisting of halogen atoms, aryl, alkoxy, haloalkyl and haloalkoxy groups, most preferably being a methyl, ethyl, propyl or benzyl group.

Particularly preferred are those racemates IA/IB in which R² represents a C^_Q alkyl group, preferably a C-^ alkyl, and most preferably a methyl group. Especially preferred compounds of the general 15 formula I are those in which R³ represents a Cι_₁₀ alkyl group, preferably a Cι_4 alkyl, in particular, a methyl group.

Also preferred are the racemates IA/IB wherein R⁴ represents a hydrogen atom or a C₁. _Q alkyl group, preferably a C-^ alkyl, in particular a methyl group. Most preferred are those racemates IA/IB in which both 20 R³ and R⁴ represents a C-^ alkyl, in particular, a methyl group.

Other preferred racemates IA/IB are those in which R⁵ represents a C-i-10 alkyl group, preferably a C-|^ alkyl, and most preferably, a methyl group.

Also preferred are racemates IA/IB in which R⁶ represents a group

2.3 of formula -COOR⁷, wherein R⁷ represents a C-|_₁₀ alkyl group, preferably a C-|_ alkyl, in particular, a methyl group.

The racemates IA/IB are oils, gums, or crystalline solid materials and possess valuable fungicidal properties when used as a fungicide for control of diseases in agronomic crops, additionally, the compound may be used as a biocide for the control of insect pests and nematodes, as a biocide of human/animal diseases/pests, and as a protectant or preservative for wood, leather or tissue. As a fungicide in agronomic crops, the compounds of the present invention can curatively and protectively be used against a broad spectrum of diseases in plant and fruit production such as grain producing crops (wheat, barley, rice, rye, triticale, oat, maize, sorghum and others), grape vine plants and fruits, solanaceous crops (potato, tomato, tobacco, pepper and others), top fruit, stone fruits, soft fruits and fruit crops (apples, pears, citrus, mango, bananas, coffee, cocoa and others), oil producing crops (soybeans, sunflowers, groundnuts, rape, olives, palms and others), vegetables (like beans, lettuce, cucumbers, pumpkins, brassicas and others), horticultural plants, hops, sugarbeets, ornamentals, flowers, forestry trees and crops and others. Protection for all parts of the plant including roots, stems, leaves, flowers and fruits can be provided by the racemates IA/IB. A broad spectrum of diseases belonging to the Oomycetes, Ascomycetes, Basidiomycetes, Hymenomycetes and Fungi Imperfecti are controlled. Examples (but not excluding others) of such diseases are powdery mildews, downy mildews and late blights, anthracnoses, septorioses, blasts and blights, scabs and spots, blotches, rots on fruits, stems, leaves and roots, rusts, alternarioses, cercosporoses, sclerotinioses, moulds, wilts, smuts and bunts and others.

The racemates IA IB possess a high degree of fungicidal activity over a wide concentration range. Moreover, the compounds according to the invention show enhanced curative and residual control of fungi and fungal diseases such as cereal, grape, apple and solanaceous crops diseases, and improved foliar systemicity compared with conventional fungicides.

Good results in terms of control of diseases caused by phythopathogenic fungi are obtained with the racemates IA/IB wherein R¹ represents a C-^ alkyl group, wherein L¹ represents a hydrogen atom or a C-i_4 alkyl group, R² represents a C _-6 alkyl or benzyl group, the phenyl moiety of which may be unsubstituted or substituted by one or two substituents selected from the group consisiting of halogen atoms, C-^ alkyl, C-|^ alkoxy, cyano and nitro groups, R³, R⁴ and R⁵ each represent a methyl group.

Especially good results in terms of control of phytopathogenic fungi are obtained by using compounds containing the enantiomer pair of formulae IA1 and IB1

The compounds of the present invention are prepared via a process which comprises the steps of

(a) treating a compound of formula II,

in which R and L¹ are as hereinbefore defined and L² represents a suitable leaving group, with the enantiomer pair of boronic acids or derivatives thereof of formulae IIIA and IIIB: in which R³, R⁴, R⁵ and R⁶ are as hereinbefore, and R⁹ and R¹⁰ each independently represent a hydrogen atom or an alkyl group, or R⁹ and R¹⁰ taken together represent an alkylenediyl, preferably an ethylene-1 ,2- diyl, a propylene-1 ,3-diyl or a 1 ,1 ,2,2-tetramethylethylene-1 ,2-diyl group, in the presence of a transition metal or a transition metal complex and optionally a base, and

(b) treating the resulting mixture of formulae IVA and IVB

,3

OR^"

in which R³, R⁴, R⁵ and R⁶ are as hereinbefore, with an O- alkylhydroxylamine of formula V

R²-O-NH₂ (V) The compounds of formula II, wherein L² represents a halogen atom are novel intermediates thus comprise a part of the present invention.

The intermediates may themselves be prepared according to established methods or routine adaptations thereof. Substituents which are not compatible with the selected reaction conditions may be introduced afterwards. They may be generated by known methods such as subsequent derivatization or substitution of a suitable group or by cleaving off a suitable protecting group.

The compounds of formula II, wherein L² represents halogen atom can be prepared by metal halogen exchange of known 2,4-dihalothiazoles (e.g., Reynaud er a/., Bull. Soc. Chim. France, 1962, 1735) with alkyllithium or lithium naphthaleπide to generate 4-halothiazol-2-yl-lithium, which is subsequently reacted with an alkyl alkanoate.

The intermediates of formulae IIIA/IIIB can be prepared according to the following reaction scheme 1 : Scheme 1

(A) (VIA) / (VIB)

(IIIA) / (IIIB) (VIIA) / (VllB) wherein R³, R⁴, R⁵ and R^s are as hereinbefore defined. The zigzag bonds in formulae VIA, VIB, VIIA, VllB, IIIA and IIIB indicate that each compound exists as a racemic mixture in which OR³ and R⁴ occupy the syn- positions. The reactions of Scheme 1 are preferably carried out analogously to the process described by Matteson et al., J. Am. Chem. Soc. 1977, 99, 3196, or Schummer et al, Tetrahedron, Vol. 51 , No 41 , pp. 11219-11222, 1995. The same applies to the preparation of compound (A).

The syn (2RS, 3Sf?)-diastereomers of formulae VIA / VIB can be prepared, for example, according to Martin et al., Tetrahedron Letters, Vol. 34, No. 32, 5151-5154, 1993.

The reactions mentioned hereinabove and hereinbelow are conveniently carried out in an organic solvent. Generally, any inert organic solvent is suitable, preferably aliphatic, cycloaliphatic or aromatic hydrocarbons, which may be halogenated such as hexane, ligroine, petrol ethers, cyclohexane, benzene, toluene, xylene, di-, tri- or tetrachloromethane, ethylenechloride, t chloroethylene and chlorobenzene; ethers such as diethylether, methylethylether, methyl-tert- butylether, diisopropylether, dibutylether, tetrahydrofuran and dioxane; ketones such as acetone and butan-2-one; nithles, such as acetonithle and propionitrile, carboxylic esters, such as ethyl acetate and amyl acetate; carboxylic amides, such as dimethyiformamide, dimethylacetamide and N-methylpyrrolidone; sulfoxides, such as dimethylsulfoxide; sulfones, such as sulfolane and water or mixtures of these solvents.

Suitable bases for use in the process of the present invention are inorganic and organic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium ethylate, sodium methylate, potassium tert-butylate, triethylamine, dimethylaminopy dine, pyhdine, sodium hydride, sodium amide, butyllithium and lithium diisopropylamide.

Suitable transition metals for the use in the process of the present invention are palladium and nickel, in particular palladium which is complexed by phosphine ligands such as triphenylphosphine, tricyclohexylphosphine or t -isopropylphosphine, most preferred is tetrakis-(triphenylphosphine)-palladium or a mixture of palladium acetate and triphenylphosphine.

The prepared racemates IA IB may be isolated and purified using conventional methods and techniques.

The starting compounds for the preparation of compounds of this invention are either known or can be prepared according to known methods.

The molar ratio between the compounds of formula II and formulae IIIA/IIIB in step (a) is as a rule in the range of 0.3 to 1.9, preferably 0.8 to 1.2, and in particular, 0.9 to 1.1. Most preferably, the compounds of formulae II and IIIA/IIIB are used in about equimolar ratios. The reaction is preferably carried out at a temperature from 0 to 150 °C, and preferably from 25 to 120 °C. The molar ratio between the compounds of formula V and formulae

IVA/IVB in step (b) is as a rule in the range of 0.8 to 2.5, preferably 1 to 2.0, and, in particular, 1.1 to 1.8. The reaction is preferably carried out at a temperature from 0 to 150 °C, and, preferably, at ambient temperature. Due to their biological activity, the racemates IA IB may be used in cultivation of all plants where infection by phytopathogenic fungi is not desired, e.g. cereals, solanaceous crops, vegetables, legumes, apples, and vines.

The racemates IA/IB have been found to have fungicidal activity. Accordingly, the invention further provides a fungicidal composition which. comprises an active ingredient, which is at least one racemate IA/IB as defined above, and one or more carriers. A method of making such a composition is also provided which comprises bringing a compound of formula I as defined above into association with the carrier(s). Such a composition may contain a single active ingredient or a mixture of several active ingredients of the present invention. It is also envisaged that different isomers or mixtures of isomers may have different levels or spectra of activity and thus compositions may comprise individual isomers or mixtures of isomers.

A composition according to the invention preferably contains from 0.5% to 95% by weight (w/w) of active ingredient with a suitable carrier. A carrier in a composition according to the present invention is any material with which the active ingredient is formulated to facilitate application to the locus to be treated, which may be, for example, a plant, seed, soil, or water in which a plant grows, or to facilitate storage, transport or handling. A carrier may be a solid or a liquid, including material which is normally a gas but which has been compressed to form a liquid.

The compositions of the present invention may be manufactured into suitable agricultural formulations, e.g., emulsion concentrates, solutions, oil in water emulsions, wettable powders, soluble powders, suspension concentrates, dusts, granules, water dispersible granules, micro-capsules, gels, tablets and other formulation types by well-established procedures. These procedures include intensive mixing and/or milling of the active ingredients with other substances, such as fillers, solvents, solid carriers, surface active compounds (surfactants), and optionally solid and/or liquid auxiliaries and/or adjuvants. The form of application such as spraying, atomizing, dispersing or pouring may be chosen, like the compositions, according to the desired objectives and the given circumstances.

Typical solvents are those such as aromatic hydrocarbons, e.g., Solvesso^® 200, substituted naphthalenes, phthalic acid esters, such as dibutyl or dioctyl phthalate, aliphatic hydrocarbons, e.g., cyclohexane or paraffins, alcohols and glycols as well as their ethers and esters, e.g., ethanol, ethyleneglycol mono- and dimethyl ether, ketoπes such as cyclohexaπone, strongly polar solvents such as N-methyl-2-pyrrolidone, or γ-butyrolactone, higher alkyl pyrrolidones, e.g., n-octylpyrrolidone or cyclohexylpyrrolidone, epoxidized plant oil esters, e.g., methylated coconut or soybean oil ester and water. Mixtures of different liquids are often suitable.

Solid carriers, which may be used for dusts, wettable powders, water dispersible granules, or granules, may be mineral fillers, such as calcite, talc, kaolin, montmorillonite or attapulgite. The physical properties may be improved by addition, of highly dispersed silica gel or polymers. Carriers for granules may be porous material, e.g., pumice, kaolin, sepiolite, beπtonite; non-sorptive carriers may be calcite or sand. Additionally, a multitude of pre- granulated inorganic or organic materials may be used, such as dolomite or crushed plant residues.

Pesticidal compositions are often formulated and transported in a concentrated form which is subsequently diluted by the user before application. The presence of small amounts of a carrier which is a surfactant facilitates this process of dilution. Thus, preferably at least one carrier in a composition according to the invention is a surfactant. For example, the composition may contain at two or more carriers, at least one of which is a surfactant.

Surfactants may be nonionic, anionic, cationic or zwitterionic substances with good dispersing, emulsifying and wetting properties depending on the nature of racemates IA/IB to be formulated. Surfactants may also mean mixtures of individual surfactants.

The compositions of the invention may, for example, be formulated in a variety of forms such as wettable powders, water dispersible granules, dusts, granules, tablets, solutions, emulsifiable concentrates, emulsions, suspension concentrates and aerosols. Wettable powders usually contain 5 to 90% w/w of active ingredient and usually contain in addition to solid inert carrier, 3 to10% w/w of dispersing and wetting agents and, where necessary, 0 to 10% w/w of stabilizer(s) and/or other additives such as penetrants or stickers. Dusts are usually formulated as a dust concentrate having a similar composition to that of a wettable powder but without a dispersant, and may be diluted in the field with further solid carrier to give a composition usually containing 0.5 to 10% w/w of active ingredient. Water dispersible granules and granules are usually prepared to have a size between 0.15 mm and 2.0 mm and may be manufactured by a variety of techniques. Generally, these types of granules will contain 0.5 to 90% w/w active ingredient and 0 to 20% w w of additives such as stabilizer, surfactants, slow release modifiers and binding agents. The so-called "dry flowables" consist of relatively small granules having a relatively high concentration of active ingredient. Emulsifiable concentrates usually contain, in addition to a solvent or a mixture of solvents, 1 to 80% w/v active ingredient, 2 to 20% w/v emulsifiers and 0 to 20% w/v of other additives such as stabilizers, penetrants and corrosion inhibitors. Suspension concentrates are usually milled so as to obtain a stable, non-sedimenting flowable product and usually contain 5 to 75% w/v active ingredient, 0.5 to 15% w/v of dispersing agents, 0.1 to 10% w/v of suspending agents such as protective colloids and thixotropic agents, 0 to 10% w/v of other additives such as defoamers, corrosion inhibitors, stabilizers, penetrants and stickers, and water or an organic liquid in which the active ingredient is substantially insoluble; certain organic solids or inorganic salts may be present dissolved in the formulation to assist in preventing sedimentation and crystalization or as antifreeze agents for water.

Of particular interest in enhancing the duration of the protective activity of the compounds of this invention is the use of a carrier which will provide slow release of the pesticidal compounds into the environment of a plant which is to be protected. The biological activity of the active ingredient can also be increased by including an adjuvant in the spray dilution. An adjuvant is defined here as a substance which can increase the biological activity of an active ingredient but is not itself significantly biologically active. The adjuvant can either be included in the formulation as a coformulant or carrier, or can be added to the spray tank together with the formulation containing the active ingredient. As a commodity the compositions may preferably be in a concentrated form whereas the end user generally employs diluted compositions. The compositions may be diluted to a concentration down to 0.001% of active ingredient to provide doses usually in the range of from 0.01 to 10 kg a.i./ha. Compositions obtained by diluting the formulated product according to the invention with water, such as aqueous dispersions and emulsions also lie within the scope of the invention.

Examples of formulations according to the invention are: Emulsion Concentrate (EC) Active Ingredient Racemate IA1/IB1 30 % (w/v)

Emulsifier(s) Atlox^® 4856 B / Atlox^® 4858 B ¹⁾ 5 % (w/v)

(mixture containing calcium alkyl aryl sulfonate, fatty alcohol ethoxylates and light aromatics / mixture containing calcium alkyl aryl sulfonate, fatty alcohol ethoxylates and light aromatics) Solvent Shellsol^® A ²⁾ to 1000 ml

(mixture of C₉ - C₁₀ aromatic hydrocarbons) Suspension Concentrate (SO

Active Ingredient Racemate IA1/IB1 50 % (w/v)

Dispersing agent Soprophor^® FL ³⁾ % (w/v)

(polyoxyethylene polyaryl phenyl ether phosphate amine salt) Antifoaming agent Rhodorsil^® 422 ³⁾ 0-2 % (w/v)

(nonionic aqueous emulsion of polydimethylsiloxanes) Structure agent Kelzan^® S ⁴⁾ 0.2 % (w/v)

(Xaπthan gum) Antifreeziπg agent Propylene glycol 5 % (w/v) Biocidal agent Proxel^{® S)} 0.1 % (w/v)

(aqueous dipropylene glycol solution containing 20% 1 ,2-beπisothiazolin-3-one)

Water to 1000 ml

Wettable Powder (WP)

Active Ingredient Racemate IA1/IB1 60 % (w/w)

Wetting agent Atlox^® 4995 ¹⁾ 2 % (w/w)

(polyoxyethylene alkyl ether) Dispersing agent Witcosperse^® D-60 ⁶⁾ 3 % (w/w) (mixture of sodium salts of condensed naphthalene sulfoπic acid and alkylarylpolyoxy acetates

Carrier / Filler Kaolin 35 % (w/w)

Water Dispersible Granules (WG)

Active Ingredient Racemate IA1/IB1 50 % (w/w)

Dispersing / Witcosperse^® D-450 ⁶⁾ 8 % (w/w) Binding agent (mixture of sodium salts of condensed naphthalene sulfoπic acid and alkyl sulfonates)

Wetting agent Morwet^® EFW ⁶⁾ 2 % (w/w)

(formaldehyde condensation product) Antifoaming agent Rhodorsil^® EP 6703 ⁾ 1 % (w/w)

(encapsulated silicone) Disintegrant Agrimer^® ATF ⁷⁾ 2 % (w/w)

(cross-linked homopolymer of N-viπyl-2- pyrrolidone) Carrier / Filler Kaolin 35 % (w/w)

1 ) commercially available from ICI Surfactants 2) commercially available from Deutsche Shell AG 3) tommercially available from Rhόne-Poulenc commercially available from Kelco Co. ⁵¹ commercially available from Zeneca

⁶⁾ commercially available from Witco

⁷⁾ commercially available from International Speciality Products

The compositions of this invention can also comprise other compounds having biological activity, e.g., compounds having similar or complementary pesticidal activity or compounds having plant growth regulating, fungicidal or insecticidal activity. These mixtures of pesticides can have a broader spectrum of activity than the compound of general formula I alone. Furthermore, the other pesticides can have a synergistic effect on the pesticidal activity of the racemate IA IB.

The other fungicidal compounds can be, for example, one which is also capable of combating diseases of cereals (e.g., wheat) such as those caused by Erysiphe, Puccinia, Septoπa, Gibberella and Helminthosporium spp., seed and soil borne diseases and downy and powdery mildews on vines, early and late blight on solanaceous crops, and powdery mildew and scab on apples etc. Examples of such fungicidal compounds are:

AC 382042, alanycarb, aldimorph, ampropyifos, andoprim, anilazine, azaconazole, azafenidin, azoxystrobin, benalaxyl, benodanil, benomyl, benzamacril, bialaphos, biloxazol, binapacryl, biphenyl, bitertanol, blasticidin S, Bordeaux mixture, bromuconazole, bupirimate, butenachlor, buthiobate, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chinomethionate, chlorbenzthiazon, chlorfenazol, chloroneb, chloropicrin, chlorothalonil, chlozolinate, clozylacon, copper-containing compounds such as copper oxychloride, and copper sulfate, cufraneb, cycloheximide, cymoxanil, cypofuram, cyproconazole, cyprodinil, cyprofuram, debacarb, dichlofluanid, dichlone, dichloran, dichlorophen, diclobutrazol, diclocymet, diclomezine, dicloran, diethofencarb, difenoconazole, difenzoquat, diflumetorim, dimefluazole, dimethirimol, dimethomorph, diniconazole, dinocap, diphenylamin, dipyrithione, ditalimfos, dithianon, dodemorph, dodine, drazoxolon, edifenphos, epoxiconazole, etaconazole, ethirimol, ethoxyquiπ, etridiazole, famoxadone, fenapanil, feπamidone, fenaminosulph, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenitropan, fenpiclonil, fenpropidin, feπpropimorph, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, fluoromid, fluquinconazole, flurprimidol, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, furcarbonil, furconazole-cis, furmecyclox, guazatine, hexachlorobenzol, hexaconazole, hydroxyisoxazole, hymexazole, IKF-916, imazalil, imibenconazole, iminoctadine, iodocarb, ipconazole, iprobeπfos, iprodione, iprovalicarb, isoprothiolane, isovaiedione, kasugamycin, RH-7281 , kitazin P, kresoxim-methyl, mancozeb, maneb, mefenoxam, meferimzone, mepanipyrim, mepronil, metalaxyl, metconazofe, methasulfocarb, methfuroxam, metiram, metomeclam, metominostrobon, metsulfovax, MON 65500, myclobutanil, myclozolin, neoasozin, nickel dimethyldithiocarbamate, nitrothalisopropyl, nuarimol, ofurace, organo mercury compounds, oxadixyl, oxamocarb, oxasulfuron, oxpoconazole, oxycarboxin, paclobutrazol, pefurazoate, penconazole, pencycuron, phenazineoxide, phosdiphen, phthalide, pimaricin, piperaliπ, polyoxin D, polyram, probenazole, prochloraz, procymidione, propamocarb, propiconazole, propineb, prothiocarb, pyracarbolid, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, quinconazole, quinomethionate, quinoxyfen, quintozene, rabenazole, spiroxamiπe, SSF-126, SSF-129, streptomycin, sulfur, tebuconazole, tecloftalame, tecnazene, tetcyclacis, tetraconazole, thiabendazole, thicyofen, thifluzamide, thiophanate-methyl, thiram, tioxymid, tolclofosmethyl, tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, trichlamid, tricyclazole, tridemorph, trifloxystrobiπ, triflumizole, triforine, triticonazoie, uniconazol, validamycin A, vapam, vinclozoliπ, XRD-563, zarilamid, zineb, and ziram.

In addition, the compositions according to the invention may contain at least one compound of formula I and any of the following classes of biological control agents such as viruses, bacteria, nematodes, fungi, and other microorganisms which are effective in the control of insects, weeds or plant diseases, or to induce host resistance in the plants. Examples of such biological control agents are: Bacillus thuπngiensis, Verticillium lecanii, Autographica califomica NPV, Beauvaπa bassiana, Ampelomyces quisqualis, Bacilis subtilis, Pseudomonas cholororaphis, Pseudomonas fluorescens, Steptomyces gπseoviπdis and Trichoderma harzianum.

Moreover, the co-formulations according to the invention may contain at least one racemate IA/IB and a chemical agent that induces the systemic acquired resistance in plants such as, for example, isonicotinic acid or derivatives thereof, 2,2-dichloro-3,3-dimethylcyclopropylcarboxylic acid or BION.

The racemate IA/IB can be mixed with soil, peat or other rooting media for the protection of the plants against seed-borne, soil-borne or foliar fungal diseases. The invention still further provides the use as a fungicide of a racemate IA/IB as defined above or a composition as defined above, and a method for combating fungus at a locus, which comprises treating the locus, which may be, for example, plants subject to or subjected to fungal attack, seeds of such plants or the medium in which such plants are growing or are to be grown, with such a compound or composition.

The present invention is of wide applicability in the protection of crop and ornamental plants against fungal attack. Typical crops which may be protected include vines, grain crops such as wheat and barley, rice, sugar beet, top fruit, peanuts, potatoes, vegetables and tomatoes. The duration of the protection is normally dependent on the individual compound selected, and also a variety of external factors, such as climate, whose impact is normally mitigated by the use of a suitable formulation.

The compounds according to the invention have curative, protective and residual activity and are systemic in plants. The compounds control diseases after foliar, soil, into water or seed application. They can be applied in different formulations. The compounds have better curative and systemic properties than the presently commercialised strobilurine derivatives.

Biological Investigation Test Procedure

Test Plants: Test plants were grown up in the greenhouse. Either seed, pregerminated seed or rooted vegetative plant material was planted in pots containing a fertilized soil/peat mixture. Test plants were used for treating them with the various fungicides when they were in the primary leaf stage (cereals) or in the 3-4 leaf stage (tomatoes). The number of leaves of vegetatively propagated plant material was cut back to 3-4 leaves per plant.

Application: Test plants were treated with the test compound either 1 day before (protective treatments = 1 d res) or 2 days after (curative treatments = 2 d cur) the inoculation with a pathogen. The test compounds were applied to the test plants using a had held airbrush at a pressure of 0.5 bar. 2-4 plants were used per treatment.

Compounds: Technical material of the compound according to the invention was dissolved in acetone with 0.5% Triton X155 at a concentration of 0.5%. For application to the test plants, the dissolved materials were further diluted with demineralized water to obtain final concentrations of 100, 20, 4 and 0.8 ppm ingredient. The test plants were sprayed and wetted 'just before run-off with the spray wash containing the desired compound concentration.

Inoculations and culture conditions: For the protective tests, treated plants were kept 1 day in the greenhouse and then inoculated with a pathogen. For inoculation an aqueous spore suspension was sprayed or spores were dusted onto the plants. Then the plants were kept in specific chambers for incubation if required, and then were moved to a greenhouse for disease development. For curative tests, plants were inoculated and, if required, incubated 2 day before the application of the compound, and then moved to a greenhouse after application of the compounds. The temperature in the greenhouse was between 18 and 25 degree C. The relative humidity was about 50-80% in the greenhouses and up to 100% in the incubation chambers. The plants were watered as required for good plant growth. In the greenhouse additional light was supplied to maintain a 14 hours day and 10 hours night cycle.

Assessment of diseases: The percentage of leaf area infected was assessed by visual estimation when untreated control plants were just completely diseased. Each plant was individually evaluated and then the mean infection rating was calculated for each treatment. The fungicidal activity was calculated using the following formula: infection in treated leaves

% activity = 100 x 100 % infection in untreated leaves The diseases, dose rate and % activity is given in Tables I to III, in which the following abbreviations have been used:

Abbreviatic )n Disease Fungus

AS Apple scap Venturia inaequalis

BB Botrytis blights of bean Botrytis cinerea

BNB barley net blotch Pyrenophora teres

BPM barley powdery mildew Blumeπa graminis f. sp. hordei

GDM grape downy mildew Plasmopara viticola

TLB tomato late blight Phytophthora infestans

WLR wheat leaf rust Puccinia recondita

WPM wheat powdery mildew Blumeπa graminis f. sp. tritici Table I: Curative (2 d cur) and protective (2 d res) activities on cereals

Table II: Protective (1 d res) activities on beans and apples

Table III: Curative (2 d cur) and protective (1 d res) activities compared with the compound of Example 8 of WO 98/46583

The following examples further illustrate the present invention. It should be understood, however, that the invention is not limited solely to the particular examples given below.

Example 1

Preparation of syn (ΛRS, 5SR)-[Methyl 7-[2-(1-(E/Z)-methoxyimino)- ethyl]thiazol-4-yl]-3,5-dimethoxy-4-methylheptan-2,6-dienoate (IA1/IB1)

IA 2-Acetyl-4-bromothiazole

A flask was charged with 2.6 g (10.7 mmol) 2,4-dibromothiazole (obtained according to: Reynaud et al., Bull. Soc. Chim. France 1962, 1735) and 25 ml diethyl ether and was cooled to -78°C. Then, n-BuLi (12.8 mmol) as added and the resulting reaction mixture stirred for 30 minutes at -78°C. Then, 2.64 g (30 mmol) ethyl acetate was added. After 10 minutes, the reaction mixture was poured into saturated NaHCO₃ and extracted with ethyl acetate. The volatile components were removed at the rotary evaporator, and the residue was purified by column chromatography; 1.34 g (61 %), off-white crystals.

1 B syn (3RS, 4SR)-(3,5-dimethoxy-6-methoxycarbonyl-4-methylhexa-

1 ,5-dien-1-yl)-boronic acid To a solution of 2.83 g (20 mmol) tetramethylpiperidine in THF (tetrahydrofuran) (50 ml) at 0°C was added n-BuLi (20 mmol) and 2.32 g (20 mmol) TMEDA. The mixture was stirred for 15 min at 0°C and cooled to -78°C. Then, 3.44 g (19 mmol) bis(trimethylenedioxyboryi)methane (obtained according to Matteson er a/., J. Am. Chem. Soc. 1977, 99, 3196), dissolved in THF (25 ml), was slowly added, stirred for 30 minutes at -78°C and 1 h at 0°C, resulting in a white precipitate. The slurry was cooled to -78°C and the crude syn methyl 3,5-dimethoxy-5-formyl-4- methylpent-2-enoate (2 g, < 9.2 mmol, obtained according to Martin et al., Tetrahedron Letters, Vol. 34, No. 32, pp. 5151-5154, 1993), dissolved in THF (10 ml), was slowly added. The mixture was allowed to warm to room temperature over night. Saturated NH₄CI was added, and the organic phase extracted with ethyl acetate, giving 1.69 g of a brown oil that was used without purification in the next reaction step.

1C syn (4RS, 5SR)-Methyl 7-(2-acetylthiazol-4-yl)-3,5-dimethoxy-4- methylheptan-2,6-dienoate 2.47 g (12 mmol) IA, 0.27 g (1.2 mmol) Pd(OAc)₂ and 1.26 g (4.8 mmol) PPh₃ were stirred in DME (100 ml) for 10 minutes at ambient temperature. Then, 1.69 g crude I B, 1.68 g (20 mmol) NaHCO₃ and H₂O (3 ml) were added. The mixture was heated to 90°C for 4 hours. After standard work- up and column chromatography, 1_C was isolated as slightly yellow solid, 0.72 g (2 mmol), 23 % yield referring to the aldehyde I B.

I D syn (4RS, 5SR)-[Methyl 7-[2-(1-(E/Z)-methoxyimino)-ethyl]thiazol-4- yl]-3,5-dimethoxy-4-methylheptan-2,6-dienoate (IA1/IB1) Pyridine (0.36 g) was added to a mixture of 1C (0.72 g, 2.1 mmol), O- methylhydroxylamine hydrochloride (3.6 mmol) and 100 ml of methanol. The reaction mixture was stirred for 15 hours at room temperature. The solvent was distilled off in vacuo and the residue acidified with 0.1 M hydrochloric acid and extracted with ether. The combined organic phases are washed with water and dried with sodium sulfate. The solvent is distilled off in vacuo. 0.76 g of D were obtained as a yellow oil. Examples 2-9

Using essentially the same procedures described hereinabove for Example 1 and the appropriate starting materials, and employing standard derivatization techniques where appropriate, the following compounds containing equimolar amounts of enantiomers are prepared as shown in Table IV:

Claims

1. A fungicidal compound which contains essentially equimolar amounts of the enantiomer pair of formulae IA and IB:

wherein

R², R³, R⁴ and R⁵ each independently represent an alkyl group; and

R⁶ represents a group of formula -COOR⁷ or -CONR⁷R⁸, in which R⁷ and

R^a each independently represent a hydrogen atom or an alkyl group;

L¹ represents a hydrogen or halogen atom or an optionally substituted alkyl group; and

wherein the zigzag line indicates that the alkoximino group may have the (E)- or (Z)-configuration.

2. A compound according to Claim 1 containing the enantiomer pair of formulae IA and IB wherein R¹ represents a C,.₆ alkyl or benzyl group, the phenyl moiety of which may be unsubstituted or substituted by one or two substituents selected from the group consisiting of halogen atoms, C^ alkyl, C^ alkoxy, cyano and nitro groups, R² represents a C^ alkyl group, R³ and R⁴ represent a methyl group, and L represents a hydrogen atom or a C^ alkyl group.

3. A compound according to Claim 1 , containing the enantiomer pair of formulae IA and IB, wherein R^s represents a group of formula -COOCH₃.

4. A compound according to Claim 1 containing the enantiomer pair of formulae IA1 and IB1 :

5. A process for the preparation of a compound containing essentially equimolar amounts of the enantiomer pair of formulae IA and IB which comprises the steps of (a) treating a compound of formula II

in which R¹ represents hydrogen atom or an optionally substituted alkyl, alkenyl, or aryl group, L¹ represents a hydrogen or halogen atom or an optionally substituted alkyl group; and L² represents a suitable leaving group, with the enantiomer pair of a boronic acid derivative of formulae IIIA and

IIIB:

in which R³ , R⁴ and R⁵ each independently represent an alkyl group R⁶ represents a group of formula -COOR⁷ or -CONR⁷R⁸, in which R⁷, and R⁸ each independently represent a hydrogen atom or an alkyl group; R⁹ and R¹⁰ each independently represent a hydrogen atom or an alkyl group; or R⁹ and R¹⁰ together represent an alkylenediyl group; in the presence of a transition metal or a transition metal complex; and (b) treating the resulting mixture of formulae IVA and IVB

OR

in which R³ , R⁴, R⁵, R⁶ and L¹ are as hereinbefore defined with an O-alkylhydroxylamine of formula V

R²-0-NH₂ (V)

in which R² represents an alkyl group.

6. A compound of formula II

in which R¹ represents a hydrogen atom or an optionally substituted alkyl, alkenyl, or aryl group; L¹ represents a hydrogen or halogen atom or an optionally substituted alkyl group, and L² represents a halogen atom.

7. A fungicidal composition which comprises a carrier, and as active agent, a fungicidally effective amount of at least one compound, which contains essentially equimolar amounts of the enantiomer pair of formulae IA and IB of Claim 1.

8. A method of combating fungi or fungal plant diseases at a locus comprising a plant or plant parts which comprises treating the locus with a fungicidally effective amount of at least one compound, which contains essentially equimolar amounts of the enantiomer pair of formulae IA and IB of Claim 1.

9. The method according to Claim 8 wherein the disease is caused by a phytopathogenic fungus selected from the group consi- sting of Oomycetes, Ascomycetes, Basidiomycetes and Fungi im- perfecti.

10. A method of combating fungi or fungal plant diseases at a locus comprising a plant or plant parts which comprises trea- ting the locus with a fungicidally effective composition as defined in Claim 7.

11. The method according to Claim 10 wherein the disease is caused by a phytopathogenic fungus selected from the group con- sisting of Oomycetes, Ascomycetes, Basidiomycetes and Fungi imperfecti .