BE898070A - NOVEL ETHANOL DERIVATIVES, THEIR PREPARATION AND THEIR USE AS FUNGICIDES. - Google Patents

Abstract

The subject of the invention is new alpha-aryl-alpha-R1-1H-azole-ethanols in which R1 is a halogenated cyclopropyl group bonded directly, or via an alkyl group to the alpha carbon atom, and their preparation. These compounds can be used as fungicides for plants and to treat fungal infections in humans and animals.

Description

       

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    "New ethanol derivatives, their preparation and their use as fungicides." Invention of: Fritz SCHAUB Claiming priority of the patent application filed in SWITZERLAND on October 28, 1982 under no. 6300 / 82-6 in the name of SANDOZ S. A.

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   The present invention relates to new ethanol derivatives, their preparation and their use as fungicides to combat phytopathogenic fungi and for the treatment of fungal infections in humans and animals.



   The invention relates in particular to the a-aryl-a-Rl-1H-1,2,4-triazole-1-ethanols and the a-aryl-Rl-1H-imidazole-1-ethanols in which Ri represents a group halogenated cyclopropyl linked to the carbon atom a either directly or via an alkyl group, as well as their ethers and esters. These compounds will be designated in the present description, the compounds of the invention.



     The expression “carbon atom a” in the present description designates the carbon atom of the ethanol residue to which the R 1, aryl and hydroxy groups are linked.



   The a-aryl group of the compounds of the invention is advantageously an aromatic hydrocarbon group, preferably a phenyl group, unsubstituted or substituted, or a heteroaromatic ring linked by one of its cyclic carbon atoms, for example a ring with 5 or 6 links having 1 or 2 heteroatoms chosen from 0, N and S, preferably a furyl, thienyl or pyridyl group, unsubstituted or substituted.



   As an example of an a-aryl group in particular
 EMI2.1
 suitable may be mentioned the phenyl group optionally carrying one or two substituents from halogens, NO2, selected groups C1-C5alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-Cg alkoxy and Ci-cas alkylthio unsubstituted or halogenated, and the phenyl and phenoxy groups unsubstituted or substituted. As other examples of suitable a-aryl groups, mention may be made of heteroaromatic groups such as 3-pyridyl, 2-thienyl and 2-furyl groups which are unsubstituted or monosubstituted by a halogen or by a C1-C5 alkyl group, for example the groups 5-chloro-2-thienyl and 5-tert. butyl-2-furyl.



   The a-aryl group is preferably a phenyl group substituted by R2 and R3, where R2 and R3 each signify, independently of one another, hydrogen, halogen, a

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 C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C6 alkoxy or C1-C5 unsubstituted or halogenated alkylthio, an unsubstituted or substituted phenyl or phenoxy group, or NO2.



   When R2 and / or R3 signify or contain a halogen, it is for example F, Cl or Br. As examples of suitable substituents of the phenyl group, mention may be made of CH3, Cl, Br, I, CH30, C6H5, CF30 and C2H5, preferably CH3, C6H5 and especially Cl. In general, the substituents of the phenyl group are preferably located in position 2.4 (for example 2, 4-di-Cl), more preferably in position 4 (monosubstitution).



   When the hydroxy group of the compounds of the invention is etherified, these ethers are for example alkyl ethers in
 EMI3.1
 Cl-Cs, C3-C5 alkenyls, C3-C5 alkynyls or aralkyls, such as methyl, allyl, propargyl or benzyl ethers; when this hydroxy group is esterified, these esters are for example derivatives of aliphatic carboxylic acids, such as acetates.



   The compounds of the invention contain 1 or more centers of chirality. Such compounds are generally obtained in the form of racemic mixtures or of diastereoisomers. These mixtures can, if necessary, be completely or partially separated into individual compounds or desired mixtures of isomers according to known methods.



   A class of preferred compounds includes those
 EMI3.2
 corresponding to formula I
 EMI3.3
 
 EMI3.4
 in which Ri, R2 and R3 have the meanings given above and Y represents CH or N.



  Ri preferably represents a group G
 EMI3.5
 

  <Desc / Clms Page number 4>

 
 EMI4.1
 in which Xi represents H, F, Cl Br, especially Clou Br, in particular Cl, X2 represents F, Clou Br, especially CI or Br, in particular Cl,
 EMI4.2
 R4, Rs, R6 each represent, independently of one another, H, a C1-C5 alkyl group, for example
CH3, or a halogen, A represents a CR7R8 or CR7R8-CHR9 residue, the remainder
CR7R8-CHR9 being linked to the halogenated cyclopropyl residue by the carbon atom carrying the substituent Rg, R7, Ra, Rg each independently represent
 EMI4.3
 others, H or a C1-C5 alkyl group, for example CH3, R7 and Rg can also be linked to form a C3-C6 cycloalkyl group, and n signifies o or 1.



   X1 and X2 are preferably identical.



   At least one of the substituents R7 and R8 advantageously signifies a C1-C4 alkyl group or else CR7R8 signifies a cycloalkyl group.



   When CR7R8 signifies a cycloalkyl group, this group preferably contains from 3 to 5 cyclic carbon atoms.



   When one or more substituents R4, Rg and R6 signify a halogen, it is preferably F, Cl or Br, in particular Cl or Br. When any of the substituents R4,
 EMI4.4
 Rs, R6, R7, R8 and Rg signify a C1-C5 alkyl group, it is preferably CH3. n preferably means 1.



   The invention also relates to a process for the preparation of these compounds, a process in which a compound of formula II is reacted
 EMI4.5
 

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 in which M represents H, a metal or a trialkylsilyl group and Y has the meaning given above, with a corresponding 2-aryl-2-Rl-oxirane, in which R 1 has the meaning given above, or with a reactive derivative of this compound, and, if necessary, the ethanolic ethanolic compounds thus obtained are etherified or esterified.



   When M represents H in formula II, the reaction is preferably carried out in the presence of a base.



   The compounds of the invention can be in the form of a free base, a salt or a metal complex. By salt is meant an addition salt with an acid, for example the hydrochloride, or an alcoholate, for example sodium alcoholate. The metal complex is a complex for example with a metal such as Cu or Zn, and with anions such as chlorides, sulfates and nitrates.



   Acid addition salts, alcoholates and metal complexes can be obtained by the usual methods from the corresponding free form, and vice versa.



   The compounds of formula I are obtained by reacting a compound of formula III
 EMI5.1
 
 EMI5.2
 in which Ri, R2 and R3 have the meanings given above, or one of its reactive functional derivatives, hereinafter designated reactive derivatives, with a compound of formula II as defined above, and, if necessary, by etherifying or then esterifying the ethanolic compounds thus obtained.



   The process of the invention can for example be carried out by reaction of a 2-aryl-2-Ri-oxirane as defined above,

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 for example a compound of formula III, with an azole of formula II as such (M = H) or in the form of a metal salt (M = metal), preferably in the form of an alkali metal salt, for example of sodium, in an inert solvent under the reaction conditions, for example in dimethylformamide, at a reaction temperature between room temperature and the reflux temperature of the reaction mixture, or with an azole of formula II in which M is a group trialkylsilyl, for example trimethylsilyl, in an inert solvent under the reaction conditions, for example in dimethylformamide, in the presence of catalytic amounts of a base such as NaH,

   advantageously by heating to a temperature preferably between 70 and 900C.



     The term "reactive derivatives" used in connection with
 EMI6.1
 the 2-aryl-2-Rl-oxiranes defined above, such as the compounds of formula III, includes any derivative of oxirane which, by reaction with an azole, forms the ethanolic compounds of the invention. Various types of these reactive derivatives are known to those skilled in the art; as an appropriate example, mention may be made of the corresponding halohydrins in which the halogen is for example Clou Br.



   The conditions under which the compounds of formula II can react with the reactive derivatives of the 2-aryl-2-Rl-oxiranes defined above, are also known per se. The reaction of the compound of formula II with the halohydrin of the compound of formula III can be carried out under the conditions indicated for the reaction with the oxirane compounds, but preferably in the presence of an additional equivalent of a based.



   The esters and ethers of the compounds of the invention can be obtained according to known methods of esterification and etherification from the corresponding ethanolic compounds.



   The compounds of the invention can be isolated from the reaction mixture and purified according to the methods known per se.



   The 2-aryl-2-Rl-oxiranes defined above are new compounds. The processes suitable for their preparation are, for example, analogous to those indicated below for the

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 preparation of the compounds of formula III.



   The compounds of formula III can be obtained according to known methods a) by treatment of the corresponding halohydrins with a base, b) by reaction of the corresponding ketones of formula IV
 EMI7.1
 in which Ri, R2 and R3 have the meanings given above, with a compound of formula V
 EMI7.2
 where n means 0 or 1
X represents a halogen or a methyl sulphate group, and R13 represents an alkyl group, in the presence of a base, such as an alkali metal hydride or hydroxide. When R13 represents a C8-C18 alkyl group, in particular a C8-C18 straight chain alkyl group, for example an n-dodecyl group, the compound of formula V can also serve as a phase transfer catalyst.



   The compounds of formula IV can also be obtained according to known methods.



   The compounds of formula IVa
 EMI7.3
 in which R2, R3, R4, R5, R6, A, X2 and n have the meanings given above and X'l represents F, Cl or Br, can be obtained by addition of the group: CX'lX2 (in which X ' l and X2 have the meanings given above) to a compound of formula VI

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 EMI8.1
 
 EMI8.2
 in which R2, R3, R4, Rg, R6, A and n have the meanings given above, or starting from compounds of formula VII
 EMI8.3
 
 EMI8.4
 in which R2, R3, R4, Rs, R6, A and n have the meanings given above and Rio represents H or a protective group of the OH group, for example a tetrahydropyrannyl group, by addition of the group: CX'lX2 on the double bonding and subsequent oxidation of the alcohol function to a carbonyl group, possibly after removal of the protective group.

   The addition of the group: CX'lX2 and the oxidation can be carried out according to known methods.



   The hulls of formula: CX'lX2 can, for example, be obtained a) by elimination of hydrohalic acid from a trihalomethane using an alkali hydroxide, for example under the conditions of a transfer reaction phase, b) by thermal decomposition (decarboxylation) of a trihaloacetate, for example a tri ha 1 sodium or lithium oacetate, at a temperature between 800C and 120 C, for example in mixtures of solvents containing glyme or diglyme (dimethyl ethers of ethylene glycol and diethylene glycol), c) by thermal decomposition of CgHgHgCXg, where X is a halogen,

   for example in benzene, at reflux.



   The starting materials of formula VI, in which n signifies 1 and A represents the group CR7R8-CHRg, are obtained for example by alkylation of an acetophenone with a halide

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 allyl, and those of formula VII, in which (A) n represents a covalent bond or CR7RB and Rio represents hydrogen, are obtained for example by reaction of a vinyl or allylic Grignard compound with an optionally substituted benzaldehyde.



   When the preparation of the starting materials is not described, these are known or can be obtained by methods analogous to the known methods or to those described in the present application.



   The compounds of the invention have interesting biological properties, in particular antifungal properties and can therefore be used in therapy for the treatment of fungal infections in humans and animals. This antifungal activity can be demonstrated by in vitro tests, for example by serial dilution tests on various families and species of fungi, such as yeasts, molds and dermatophytes, at concentrations of between approximately 0.05 and approximately 50 g / ml, and also by in vivo tests, for example systemic, by oral administration of doses of between approximately 10 and 100 mg / kg to mice to which an intravaginal infection with Candida has been transmitted. albicans.



   Thanks to these properties, the compounds of the invention can be used as antifungals. For their use, the dose administered will naturally depend on the compound used, the mode of administration and the treatment desired. However, satisfactory results are generally obtained when the compounds of the invention are administered at a daily dose of between approximately 1 and 100 mg / kg, advantageously in divided doses 2 to 4 times per day, or in a delayed-release form. . In human therapy the corresponding daily dose will be between 70 and 2000 mg of active substance; the appropriate unit doses for oral administration include, for example, between 17.5 and 1000 mg of active substance.



   The compounds of the invention can be prepared and used in the form of a free base or in the form of salts (salts

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 addition of acids or aloolates) or metal complexes, acceptable from the pharmaceutical or veterinary point of view. In general, the salts have the same order of activity as the free bases. Examples of acids which can be used for the preparation of acid addition salts include hydrochloric, hydrobromic, sulfuric, nitric, fumaric and
 EMI10.1
 Naphthalene-1,5-disulfonic acid.



   The invention therefore relates to the compounds of the invention, in the form of a free base or of salts or of metal complexes acceptable from the pharmaceutical or veterinary point of view, for use as medicaments, in particular as antifungals. The invention also relates to a medicament containing, as active substance, a compound of the invention in the form of a free base or of a salt or of a metal complex acceptable from the pharmaceutical or veterinary point of view.



   As medicaments, the compounds of the invention can be used in the form of pharmaceutical or veterinary compositions containing the active substance in association with inert carriers or diluents acceptable from the pharmaceutical or veterinary point of view and, optionally, with other excipients . Such compositions also form part of the present invention. The compounds of the invention may be administered internally in the form of tablets or capsules, or be applied locally in the form of ointments or creams, or alternatively be administered in a form suitable for the parenteral route. The concentrations of active substance will naturally vary depending on the compound used, the treatment desired and the mode of administration chosen.

   In general, satisfactory results are however obtained, for example, by topical application at concentrations of between 0.05 and 5, in particular between 0.1 and 1% by weight.



   The compounds of the invention can be used in a manner analogous to that known for the use of known compounds such as ketoconazole. The compounds of formula I in

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 which A represents a CRyRg-CHRg group have a particularly interesting pharmacological action.



   The appropriate daily dose for a given compound of the invention will depend on various factors, i.e., its relative activity. This has for example been established for 2- (4-chlorophenyl) -4- (2, 2-dichlorocyclopropyl) -3, 3-dimethyl-1- (1H- 1, 2, 4-triazole-1-yl) butane -2-ol in the vaginal candidiasis model in mice, healing appeared after oral administration of 4 x 12.5 mg / kg. The compounds of the invention can therefore be used in doses analogous to those generally used for ketoconazole.



   The compounds of the invention, in free form or in the form of salts (addition salts of acids or alcoholates) or of metal complexes acceptable in agriculture, are also useful as fungicides for combating phytopathogenic fungi. Their advantageous fungicidal effect has been demonstrated in in vivo tests at concentrations between approximately 0, 0008 and 0.05% against Uromyces appendiculatus (bean rust) on row beans, against other rust fungi ( such as Hemileia, Puccinia) on coffee, wheat, geranium, snapdragons, against Erysiphe cichoracearum on cucumber and against other powdery mildew (E. graminis f. sp. tritici, E. Graminis f. sp. hordei, Podosphaera
 EMI11.1
 leucotricha, Uncinula necator) on wheat, barley, apples, vines.

   Other interesting effects have been observed among others in in vitro tests against Ustilago

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 maydis at concentrations between approximately 0.8 and 200 ppm, and in vivo against Rhizoctonia solani at concentrations between approximately 10 and 160 ppm (calculated by volume of substrate).

   Whereas these tests also indicate good plant tolerance and good systemic action, the compounds of the invention are suitable for the treatment of plants, seeds and soil to combat phytopathogenic fungi such as Basidiomycetes, Ascomycetes and Deuteromycetes, in particularly the Basidiomycetes of the order Uredinalia (rust) such as Puccinia spp, Hemileia spp, Uromyces spp, the Ascomycetes of the order of Erysiphales (odiums) such as Erysiphe spp, Podosphaera spp, and Uncinula spp, as well as Phoma, Rhizoctonia, and
 EMI12.1
 Helminthosporium.



   The amount of compound of the invention to be applied will depend on various factors such as the compound used, the type of treatment (plants, soil, seeds), the method of treatment (for example watering the soil or the plant, spraying, dusting , treatment of seeds), the objective of the treatment (prophylactic or therapeutic), the type of fungi to fight and time
 EMI12.2
 of application.



   In general, satisfactory results are obtained by applying the compounds of the invention at doses of between approximately 0.005 and 2.0, preferably between approximately 0.01 and 1 kg / ha, in the case of a treatment for plants. or ground. The treatment can, if necessary, be repeated, for example at intervals of 8 to 30 days. When the compounds of the invention are used to treat seeds, satisfactory results are generally obtained by using the compounds at doses of between approximately 0.05 and 0.5, preferably between approximately 0.1 and 0.3 g per kg of seed.

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   The expression soil, as used below, designates any usual culture medium, natural or artificial.



   The compounds of the invention can be used on a large number of cultivated plants, such as soybeans, coffee, ornamental plants (such as geraniums, roses), vegetables (for example peas, cucumbers, celery, tomatoes and beans), beets at
 EMI13.1
 sugar, sugarcane, cotton, flax, corn, vines, pome and stone fruits (such as pears and plums), and are particularly suitable for cereals (such as wheat, oats, barley), especially wheat.



   The particularly suitable compounds of the invention
 EMI13.2
 for use in agriculture are the compounds of formula 1 in which (A) n is a covalent bond or the group CR7R8. The other subgroups of compounds of formula 1 having a particularly advantageous fungicidal effect are, inter alia, those in which Xi and X2 represent bromine and those in which (A) n represents CH (C1-C6-alkyl) and / or those in which R4 represents a C1-C4 alkyl group, for example Chug.



   The present invention also relates to fungicidal compositions comprising, as active material, a compound of the invention in free form or in the form of a salt or metal complex acceptable in agriculture, in association with a diluent acceptable in agriculture. These compositions can be obtained according to the usual methods, for example by mixing a compound of the invention with a diluent and optionally with other ingredients such as surfactants.



   The term diluent as used below denotes a liquid or solid material acceptable in agriculture which can be added to the active material respectively to transform it

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 in a simpler or more easily applicable form, or to dilute it in order to obtain a desirable or usable activity. Examples of such diluents include talc, kaolin, diatomaceous earth, xylene and water.



   The formulations used in the form of a spray, such as concentrates dispersible in water or wettable powders, may contain surfactants such as wetting or dispersing agents, for example the condensation product of formaldehyde with a naphthalenesulfonate, a alkylarylsulfonate, a ligninesulfonate, a fatty alcohol sulfate, an ethoxylated alkylphenol and an ethoxylated fatty alcohol.



   In general, these formulations contain from 0.01 to 90% by weight of active material, from 0 to 20% of surfactant acceptable for a fungicide and from 10 to 99, 99% of one or more diluents.



  Concentrated forms, for example emulsifiable concentrates, generally contain from about 2 to 90%, preferably between 5 and 70% by weight of active material. The application forms generally contain from 0.0005 to 10% by weight of a compound of the invention as active material. The suspensions for conventional sprays can contain, for example, from 0.0005 to 0.05, preferably from 0.001 to 0.02% by weight of active material.



   In addition to the usual diluents and surfactants, the compositions of the invention may contain other additives having specific effects, for example stabilizers, deactivators (for solid formulations on active surface supports), agents to improve adhesion to plants, corrosion inhibitors, anti-foaming agents and dyes. In addition, other fungicides with similar or complementary fungicidal activity, or other beneficial materials, such as insecticides, may be present in

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 the formulations.



   The following examples illustrate the preparation of fungicidal formulations for the treatment of plants.



  A. Wettable powder
25 parts of a compound of the invention are mixed with 25 parts of synthetic fine silica, 2 parts of sodium laurylsulfate, 3 parts of sodium ligninesulfonate and 45 parts of finely divided kaolin and are ground to a medium size. particles of about 5 microns. A wettable powder is obtained which is diluted in water before use in the form of a spray liquor, and which can be applied by foliar spraying as well as by watering the roots.



  B. Granules
0.5 part by weight of a binder (non-ionic surfactant) is sprayed onto 94.5 parts by weight of quartz sand in a drum mixer and the whole is mixed thoroughly. 5 parts by weight of a compound of the invention are then added and mixing is continued thoroughly to obtain a granule whose particle size is between 0.3 and 0.7 mm. The granules can be applied by incorporation into the soil adjacent to the plants to be treated.
 EMI15.1
 



  C. Emulsifiable concentrate
25 parts by weight of a compound of the invention are mixed with 10 parts by weight of an emulsifying agent and 65 parts by weight of xylene. The concentrate is diluted with 1% water to the desired concentration.



  D. Seed treatment
45 parts of a compound of the invention are mixed with 1.5 parts of diamy1pheno1 decaglycolic ether, 2 parts of pin oil, 51 parts of fine talc and 0.5 part of the rhodamine dye B. mixing in a contraplex mill operating at 10,000 revolutions per minute until the average particle size is less than 20 microns. Dry powder

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 The resulting has good adhesion and can be applied to seeds, for example by mixing it for 2 to 5 minutes in a slowly rotating container.



   The following examples describe the preparation of the compounds of the invention; temperatures are given in degrees Celsius.



  FINAL PRODUCTS Example 1:
 EMI16.1
 2- 2,4-triazole-1-yl) butane-2-ol a) 5.1 g of dodecyl dimethylsulfonium methyl sulfate are added to a solution of 3.0 g of 1- (4-chlorophenyl) -3- (2,2-dichloro-cyclopropyl) -2,2-dimethyl-propane-1-one in 30 ml of dry toluene at room temperature, and the mixture is stirred for 15 minutes. To the resulting suspension is added 1.1 g of pulverized KOH and the mixture is stirred for 2 hours at 35. The reaction mixture is cooled, poured onto ice and extracted with ethyl ether. The organic extracts are washed 3 times with water, then with a saturated aqueous NaCl solution, the extracts are dried over MgSO 4 and they are evaporated in vacuo.

   A residue is obtained in the form of an oil.
 EMI16.2
 colorless containing 50% 2- 2-dichlorocyclopropyl) -l, and 50% dodecyl and methyl sulfide. b) In the course of 10 minutes, the raw oxirane thus obtained is added dropwise to a mixture of 1.0 g of 1, 2, 4-triazole which has been heated to 90, and the mixture is stirred for 18 hours while maintaining the reaction temperature at 90.



  The reaction mixture is cooled, poured onto

  <Desc / Clms Page number 17>

 ice and extracted with CH2Cl2. The organic extracts are washed successively with water and with a saturated aqueous NaCl solution, they are dried over MgSO 4 and the solvent is eliminated by evaporation under vacuum. The title compound is obtained in the form of colorless crystals after chromatography on silica gel with a fraction of hexane / ethyl acetate first (9: 1 originally, then 1: 1) as eluent. then
 EMI17.1
 with acetate and subsequent crystallization from a mixture of diethyl ether / hexane fraction; F = (mixture of diastereoisomers).



  Example 2
By proceeding in a similar manner to that described in Example 1, the following compounds of formula la are obtained
 EMI17.2
 by reaction of an azole with the corresponding oxirane:
 EMI17.3
 
 <tb>
 <tb> Ex. <SEP> R2 <SEP> R3 <SEP> (A) n <SEP> X1 / X2 <SEP> R4 <SEP> R5 <SEP> R6 <SEP> Y <SEP> Character. <SEP> 3 <SEP> n <SEP> ristiaues <SEP>
 <tb> 2.

    <SEP> 1 <SEP> 4-Cl <SEP> H <SEP> - <SEP> Cl / Cl <SEP> CH3 <SEP> H <SEP> H <SEP> N
 <tb> 2 <SEP> " <SEP> " <SEP> - <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 3 <SEP> " <SEP> " <SEP> - <SEP> Br / Br <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 4 <SEP> " <SEP> " <SEP> - <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 5 <SEP> " <SEP> " <SEP> - <SEP> F / F <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 6 <SEP> " <SEP> " <SEP> - <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 7 <SEP> " <SEP> " <SEP> - <SEP> F / Cl <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 8 <SEP> " <SEP> " <SEP> - <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 9 <SEP> " <SEP> " <SEP> - <SEP> Cl / Cl <SEP> H <SEP> " <SEP> " <SEP> N
 <tb>
 

  <Desc / Clms Page number 18>

 
 EMI18.1
 
 <tb>
 <tb> Ex. <SEP> R2 <SEP> R3 <SEP> (A) <SEP> n <SEP> X1 / X2 <SEP> R4 <SEP> R5 <SEP> R6 <SEP> Y <SEP> CharacterNo.

    <SEP> ristics
 <tb> 10 <SEP> " <SEP> 2-Cl <SEP> - <SEP> " <SEP> " <SEP> " <SEP> CH3 <SEP> CH3 <SEP> N
 <tb> 11 <SEP> " <SEP> " <SEP> - <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 12 "H <SEP> C <SEP> (CH3) <SEP> 2 <SEP> " <SEP> " <SEP> " <SEP> H <SEP> H <SEP> N <SEP> Rf = 0.24 /
 <tb> 13 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH <SEP> AcE *
 <tb> 14 <SEP> " <SEP> " <SEP> CH2 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 15 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 16 <SEP> " <SEP> " <SEP> CH <SEP> (CH3) <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 17 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 18 <SEP> 4-Cl <SEP> H <SEP> C (CH3)

  2-CH2 <SEP> Cl / Cl <SEP> H <SEP> H <SEP> H <SEP> CH <SEP> F = 140-55
 <tb> 19 <SEP> " <SEP> " <SEP> " <SEP> Br / Br <SEP> " <SEP> " <SEP> " <SEP> N <SEP> Rf = 0, <SEP> 30í
 <tb> 20 <SEP> It <SEP> fi <SEP> CH <SEP> AcE *
 <tb> 21 <SEP> " <SEP> " <SEP> " <SEP> F / F <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 22 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 23 <SEP> " <SEP> " <SEP> CH2-CH2 <SEP> Cl / Cl <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 24 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 25 <SEP> " <SEP> " <SEP> CH <SEP> (CH3) -CH2 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> N <SEP> Rf = 0.28ACE
 <tb> n20D <SEP> = <SEP> 1.5598
 <tb> 26 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 27 "" "" "ci" "N
 <tb> there <SEP> ci <SEP>
 <tb> 29 <SEP> " <SEP> " <SEP> C <SEP> (CH3)

  2-CH2 <SEP> H / Cl <SEP> " <SEP> " <SEP> " <SEP> N
 <tb> 30 <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> " <SEP> CH
 <tb> 31 <SEP> " <SEP> " <SEP> " <SEP> Cl / Cl <SEP> CH3 <SEP> " <SEP> " <SEP> N <SEP> F = 100-8 *
 <tb>
 * mixture of diastereoisomers-AcE = ethyl acetate ** mixture of isomers

  <Desc / Clms Page number 19>

 INTERMEDIATE PRODUCTS Example 3: 1- (4-chlorophenyl) -3- (2, 2-dichlorocyclopropyl) -2, 2-dimethylpropane-1 one a) To a solution of 28 g of KOH sprayed in 500 ml of toluene is added under stirring, in 30 minutes and at room temperature, 45.6 g of 4-chlorophenyl-isopropylketone then, 8.1 g of tetrabutylammonium bromide, the internal temperature rising to
300.

   After stirring for 2 hours, 28.7 g of allyl chloride in 100 ml of toluene are added dropwise at room temperature and the mixture is stirred overnight at room temperature. The mixture is poured into ice water, extracted with ether, the combined organic extracts are washed successively with water and a saturated aqueous NaCl solution, dried over MgSO4 and evaporated.

   The fractional distillation of the residue in the remaining raw state gives 1- (4-chlorophenyl) -2, 2-dimethyl-pent-4-ene-1-one in the form of a colorless oil (E = 950/0, 4 mmHg). b) At a temperature of 0, slowly add 500 g of a solution
 EMI19.1
 aqueous 50% NaOH to a solution of 64 g of 1- (4-chorophenyl) -2, 2-dimethyl-pent-4-ene-1-one in 500 ml of CHCl3 and, within 15 minutes , 5 g of triethylbenzylammonium chloride (TEBA) are added in portions. When the addition is complete, the mixture is stirred for 8 hours at a temperature between 0 and 50 and, after dilution with 500 ml of CHCl 3, it is further stirred for 18 hours at room temperature.

   The reaction mixture is then poured onto ice, extracted with CH2Cl2, the organic extracts are combined, the overall organic phase is washed with water, dried over MgSO4 and evaporated in vacuo. The title compound is obtained in the pure state by chromatography on silica gel with, as eluent, a fraction of hexane / diethyl ether (1-3%). Rf = 0.23 by thin layer chromatography on silica gel with ----------------------------------

  <Desc / Clms Page number 20>

 eluting a mixture of hexane / diethyl ether 96: 4.



  Example 4
By proceeding in a manner analogous to that described in Example 3b), the following compounds of formula IVa are obtained by reaction of the dihalocarbons with the corresponding unsaturated compounds of formula VI:
 EMI20.1
 
 <tb>
 <tb> Comp. <SEP> R2 <SEP> R3 <SEP> (A) <SEP> n <SEP> X1 / X2 <SEP> R4 <SEP> R5 <SEP> R6 <SEP> Rf <SEP> Eluent
 <tb> 4.1 <SEP> 4-Cl <SEP> H <SEP> C <SEP> (CH3) <SEP> 2CH2 <SEP> Br / Br <SEP> H <SEP> H <SEP> H <SEP> 0.34 <SEP> HX / AcE <SEP> (1) <SEP> 95 <SEP>: <SEP> 5
 <tb> 4.2 <SEP> 4-Cl <SEP> H <SEP> CH <SEP> (CH3) <SEP> CH2 <SEP> Cl / Cl <SEP> H <SEP> H <SEP> H <SEP> 0.31 <SEP> (2) <SEP> HX / AcE <SEP> 9 <SEP>: <SEP> 1
 <tb> 4.3 <SEP> 4-Cl <SEP> H <SEP> C <SEP> (CH3) <SEP> 2 <SEP> Cl / Cl <SEP> H <SEP> H <SEP> H <SEP> 0.29 <SEP> HX / AcE <SEP> 9 <SEP>:

    <SEP> 1
 <tb>
 (1) HX / AcE = fraction of hexane / ethyl acetate (2) mixture of diastereoisomers Example 5:
 EMI20.2
 4-chlorophenyl- To a solution of 7, Og of 1-prop-2-ene-1-one in 70 ml of chloroform, 16 g of an aqueous solution of NaOH at 50 are slowly added to 0 and with vigorous stirring %, then 4.3 g of triethylbenzylammonium chloride. When the addition is complete, the ice bath is removed until a strong exothermic reaction begins. The reaction mixture is then cooled again so that the reaction temperature is
 EMI20.3
 originally maintained for 1 hour at 34-40, then slowly drops to room temperature. After 5 hours of reaction, the mixture is poured onto ice and extracted with diethyl ether.

   The organic extracts are combined, washed with water, dried over MgSO4 and evaporated in vacuo. The residue is chromatographed on silica gel using as
 EMI20.4
 eluting a 9: 1 hexane / diethyl ether mixture to give the title compound; n60 = 1.5689, Rf = 0.24 (thin layer chromatography D with a fraction of hexane / diethyl ether 9: 1 as eluent).


    

Claims (13)

 EMI21.1   CLAIMS 1. The 2, 4-triazole-1-ethanols and 'x. in which R 1 represents a carbon cyclopropyl group either directly or via an alkyl group, and their ethers and esters,  EMI21.2  in free form or in the form of addition salts of alcoholates or metal complexes. 2. A compound according to claim 1, characterized in that it corresponds to formula I  EMI21.3    EMI21.4  in which R1 has the meaning given in claim 1, acids, R2 and R3 each represent, independently of one another, H, a halogen, a C1-C5 alkyl group, C2-CS alkenyl, C2-C5 alkynyl, C1-C5 alkoxy or C1-C5 alkylthio unsubstituted or halogenated, an unsubstituted phenyl or phenoxy group or  EMI21.5  substituted, or NO2, and Y represents CH or N, and its ethers and esters, in free form or in the form of an acid addition salt, an alcoholate, or a metal complex.  3. A compound according to claim 2, characterized in that R1 represents a group G  EMI21.6    <Desc / Clms Page number 22>  in which Xl represents H, F, Cl or Br, X2 represents F, Cl or Br, R4, RS, R6 each represent, independently of one another, H, a C1-C6 alkyl group or a halogen, A represents a CRyRs or CR7R8-CHR9 remainder, the rest CR7R8-CHR9 being linked to the halogenated cyclopropyl group by the carbon atom carrying the substituent Rg, R7, Ra, Rg each represent, independently of each other, H or a C1-C5 alkyl group, R7 and Rg can also be linked to form a C3-C6 cycloalkyl group, and n signifies 0 or 1.  4. A compound according to claim 3, characterized in that R2, R3, (A) n, R4, R5, R6, Xi, X2 and Y represent respectively: a) 4-C1, H, C (CH3) 2- CH2, H, H, H, Br, Br and N, b) 4-C1, H, CH (CH3) -CH2, H, H, H, C1, C1 and N, c) 4-C1, H, a covalent bond, CH3, H, H, C1, Cl and N, d) 4-C1, H, C (C3) 2, H, H, H, Cl, C1 and N.  5. A compound according to claim 3, characterized in that it is 2- (4-chlorophenyl) -4- (2,2-dichlorocyclopropyl) - 3, 3-dimethyl-l- (1H-1, 2, 4-triazole-1-yl) butane-2-o1.  6. A process for the preparation of a compound according to any one of claims 1 to 5, characterized in that a compound of formula II is reacted  EMI22.1    <Desc / Clms Page number 23>  in which M represents H, a metal or a trialkylsilyl group and Y has the meaning given to claim 2, with a corresponding 2-aryl-2-Rl-oxirane, in which R 1 has the meaning given to claim 1, or with a reactive functional derivative of such an oxirane, and, if necessary, the ethanolic compounds thus obtained are etherified or esterified, and the compounds thus obtained are recovered in free form or in the form of an acid addition salt, an alcoholate or a metal complex.  7. A compound according to any one of claims  EMI23.1  1 to 5, in free form or in the form of a metal complex or acceptable in agriculture, for use as a fungicide to combat phytopathogenic fungi.  8. A fungicidal composition for the treatment of plants, characterized in that it contains, as a material  EMI23.2  active, a compound according to any one of claims 1 to 5, in free form or in the form of a salt or a metal complex acceptable in agriculture, in combination with a diluent acceptable in agriculture.  9. A method for combating phytopathogenic fungi, characterized in that an effective amount of a fungicidal compound according to any one of claims 1 to 5 is applied to a place of culture, in free form or in the form of a salt or a metal complex acceptable in agriculture.    10. A compound according to any one of claims  EMI23.3  1 to 5, in free form or in the form of a salt or a metal complex acceptable from the pharmaceutical or veterinary point of view, for use as a medicament. 11. A medicament, characterized in that it contains, as active principle, a compound according to any one of claims 1 to 5, in free form or in the form of a salt or an acceptable metallic complex from the point of pharmaceutical view.  <Desc / Clms Page number 24>    12. A pharmaceutical or veterinary composition, characterized in that it contains a compound according to any one of claims 1 to 5, in free form or in the form of a salt or a metal complex acceptable from the pharmaceutical point of view or veterinary, in combination with a diluent or vehicle acceptable from the pharmaceutical or veterinary point of view.    13.-Products and processes in substance as above described with reference to the examples cited.