IT8349185A1 - HETEROCYCLIC ETHANOL DERIVATIVES, THEIR PREPARATION AND USE AS FUNGICIDES. - Google Patents

Description

DOCUMENTATION

BOUND

BOUOj DEAR MINISTRY OF INDUSTRY, COMMERCE AND CRAFTS Central Patent Office

ROME

The Swiss company SANDOZ A.G., with registered office in Basel - Lichtstrasse 35 - and with registered office at Sandoz S.p.A. - Via Piemonte, 32 - Rome, applies for the granting of a patent for an industrial invention entitled:

"Heterocyclic derivatives of ethanol, their preparation and use as fungicides" (Case 130-3955).

W185*83 The inventor(s) of the present invention are named Dr. Fritz SCHAUB.

The right of priority arising from a previous patent application(s) in Switzerland is claimed

No. 6300/82-6 of 28 October 1982.

Attached documentation:

1) Description in duplicate copy of n. 32 pages of

series tura;

2) Certificate of payment in postal account no. 668004 made out to the 1Regional Office for Government Taxes - Rome of L. 257,000, issued by the Rome Post Office on 18 October 1983 no. 303;

3) N. 1 revenue stamp of L. 3000.=

4} Proof of payment in postal account no. 33692005 made out to CAMERA COMMERCIO-Servizi U.P.I.C.A.-Roma of L. 12,600.= issued by the Rome Post Office on 18 October 1983 no. 304.

We reserve the right to present the priority document(s) with their Italian translation(s).

Kind regards.

? A N D O Z A.Q.

Rome, October 20, 1983 ??? %

1 2w

^??????j?;

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0 ?? ??33

? USA U 0

Case 130-3955 DESCRIPTION of the industrial invention entitled:

"Heterocyclic ethanol derivatives, their preparation and use as fungicides".

Inventor: Fritz SCHAUB

SANDOZ A.G., of Swiss nationality

with headquarters in CH-4002 BASEL (Switzerland)

Filed at No.

SUMMARY OF THE INVENTION

The invention relates to ?-ary 1 -a- R^ -1 H -azol -ethanols wherein R^ represents a halogenated cyclopropyl group bonded to the carbon atom 0, either directly or through an alkyl group. These compounds can be used to combat phytopathogenic fungi in plants and to treat fungal infections in humans and animals.

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

The invention relates in particular to α-aryl-α-R.|-1H-1,2,4-triazol-1-ethanols and α-aryl-α-R-γ-1H-imidazol-1-ethanols wherein R-γ represents a halogenated cyclopropyl group bonded to the carbon atom α, either directly or through an alkyl group, as well as their ethers and esters. These compounds will be referred to in this description as the compounds of the invention.

The expression "carbon atom a" in this description designates the carbon atom of the ethanol moiety to which the R^, aryl and hydroxy groups are bonded.

The ?-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 5- or 6-chain ring having 1 or 2 heteroatoms selected from O, N and S, preferably a furyl, thienyl or pyridyl group, unsubstituted or substituted.

As an example of a particularly suitable α-aryl group, one can cite the phenyl group possibly bearing one or two substituents chosen from the halogens, N0 c?, the alkyl groups in C,1-C,b, alkenyl in C0 c-Cbc, alkynyl in C??-Cbc, alkoxy in C,1-C5 and alkylthio in C,1-Cb unsubstituted or halogenated. and the unsubstituted or substituted phenyl and phenoxy groups. As other examples of suitable α-aryl groups, one can cite heteroaromatic groups such as for example the 3-pyridyl, 2-thienyl and 2-furyl groups unsubstituted or monosubstituted with a halogen or with a C,-C,- alkyl group, for example the 5-chloro-2-1ylenyl and 5-tert.-butyl-2-furyl groups.

11 ?-aryl group ? preferably a phenyl group substituted with and R^ where R^ and R^ each mean, independently of each other, hydrogen, a halogen, a C-1-Cg alkyl group, a C-1-Cg alkenyl group, a C-2-Cg alkynyl group, an unsubstituted or halogenated C-1-Cg alkoxy or C^-Cg alkylthio group, an unsubstituted or substituted phenyl or phenoxy group, or NO,,.

When and/or they signify or contain a halogen, these are for example F, Cl or Br. As examples of suitable substituents of the phenyl group, one can cite CHO_, Cl, Br, I, CHOoO, CcDH Dc, CFO_O and C C?HD , preferably CH^, C^Hg and especially Cl. In general, substituents of the phenyl group are preferably located in the 2,4'-position (for example 2,4-di-Cl), more preferably in the 4-position (monosubstitution).

When the hydroxy group of the compounds of the invention is etherified, these ethers are for example C-1-Ccb alkyl, Co^-Crb alkenyl, C-1-Cg alkynyl or aramid ethers, such as methyl, allylic, propargylic or benzylic 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 one or more chirality centers. These compounds are generally obtained as mixtures of racemic or diastereoisomers. These mixtures can, if necessary, be separated completely or partially into individual compounds or desired mixtures of isomers according to known methods.

A class of preferred compounds includes those corresponding to the formula I

(I)

CH--C

in which

R1, R^ and Rg have the meanings given above and

Y represents CH or N.

R-j preferably represents a group G

X

where R

X-j represents H, F, CI or Br, especially CI or Br, especially C1,

represents F, CI or Br, especially CI or Br, especially CI,

R4, Rg, Rg each represent, independently of each other, an alkyl group in C-|-Cg, for example CHg, or a halogen,

A represents a CRyRg 0 CRyRg-CHRg moiety, the CRyRg-CHRg moiety being bonded to the halogenated cyclopropyl moiety via the carbon atom bearing the Rg substituent,

Ry, Rg? Rg each represent, independently of each other, H 0 an alkyl group in C-j-Cg, for example CHg, Ry and Rg can also be linked to form a cycloalkyl group in C 6-.-C,b-, and

n means 00 1.

and X^ are preferably identical.

At least one of the substituents Ry and Rg advantageously means an alkyl group in C-j-Cg or CRyRg means a cycloalkyl group.

When CRyRg means a cycloalkyl group, this group preferably contains 3 to 5 cyclic carbon atoms.

When one or more of the substituents R^, Rg and Rg denote a halogen, it is preferably F, Cl or Br, especially Cl or Br. When any of the substituents R^, Rg, Rg, R^, Rg and Rg denote an alkyl group at C-|-C8, it is preferably CH^,

n preferably means 1.

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

J (II)

M

where M represents H, a metal or a trialkyl-syl group and Y has the meaning given above,

with a corresponding 2-aryl-2-R.j-oxirane, where R-j has the meaning indicated above, or with a reactive derivative of this compound, and, if necessary, the 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 may be present in the form of a free base, a salt, or a metal complex. A salt is an addition salt with an acid, such as hydrochloride, or an alcoholate, such as sodium alcoholate. A metal complex is a complex with, for example, 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 conventional methods from the corresponding free form, and vice versa.

Compounds of formula I are obtained by reacting a compound of formula III

(Ili)

wherein R1, R? and R^ have the meanings given above, or one of its reactive functional derivatives, hereinafter referred to as reactive derivatives, with a compound of formula II as defined above, and, if necessary, subsequently etherifying or esterifying the ethanolic compounds thus obtained.

The process of the invention can, for example, be carried out by reacting a 2-aryl-2-R,-oxirane as defined above, 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 a sodium salt, in a solvent inert under the reaction conditions, for example dimethylformamide, at a reaction temperature between room temperature and the reflux temperature of the reaction mixture, or with an azole of formula II wherein M is a trialkylsilyl group, for example trimethylsilyl, in a solvent inert under the reaction conditions, for example dimethylformamide, in the presence of catalytic amounts of a base such as NaH, advantageously heating to a temperature preferably between 70 and 90°C.

The term "reactive derivatives" used in connection with the 2-aryl-2-R^-oxiranes defined above, such as the compounds of formula III, includes any de111oxirane derivative which, upon reaction with an azole, forms the ethanolic compounds of the invention. Several types of these reactive derivatives are known to those skilled in the art; as a suitable example, one can cite the corresponding halohydrins in which the halogen is, for example, Cl or Br.

The conditions under which the compounds of formula II can react with the reactive derivatives of 2-aryl-2-R-|-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 oxirane compounds, but, preferably, in the presence of an additional equivalent of a base,

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

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

The 2-aryl-2-R-|-oxiranes defined above are novel compounds. Appropriate procedures for their preparation are, for example, analogous to those given below for the preparation of the compounds of formula III.

Compounds of formula III can be obtained by known methods

a) by treatment of the corresponding halohydrins with a base,

b) by reaction of the corresponding ketones of formula IV

(IV)

where R-|, R? and R^ have the meanings given above, with a compound of formula V

<?>n (V) CHJ- N n 3 X^

where R13

n means 0 or 1,

X represents a halogen or methyl sulfate group, and R13 represents an alkyl group,

in the presence of a base, such as an alkali metal hydride or hydroxide. When R-j3 represents a Cg-C-jg alkyl group, particularly a straight-chain Cg-C-jg 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 by known methods.

Compounds of formula IVa

R, 0

? \J ? \ The X 2 (IVa) - (A)n'? CR5R6

where R^, Rg? , Rg, Rg, A, and n have the meanings given above and X1 represents F, CI or Br, can be obtained by addition of the group :CX'?X^ {where X1-j and X? have the meanings given above) to a compound of formula VI

?0^(?,?? CR^=CRgRg (VI)

where R^, Rg, R^, Rg, Rg, A and n have the meanings given above,

0 starting from compounds of formula VII

V- ^?"(A)n?CR^-CRgRg (VII) u 0R10

where ??2 , R3, R4, R^ , Rg , A and n have the meanings given above and R-JQ represents H or a protecting group of the OH group, for example a tetrahydropyranyl group, by addition of the group onto the double bond and subsequent oxidation of the alcohol function to the group

carbonyl, possibly after elimination of the protecting group. The addition of the group: C X 1 f X 2 and the oxidation can be carried out according to known methods.

Carbenes of the formula: C X 1 -p X 2 can, for example, be obtained

a) by elimination of halogenhydric acid from

from a trihalomethane with the aid of an alkaline hydroxide, for example under the conditions of a reaction

of phase transfer,

b) by thermal decomposition (decarboxylation) of a

trihaloacetate, for example sodium trihaloacetate

0 of lithium, at a temperature between 80?C and

1200C, for example in solvent mixtures containing glyme or diglyme (dimethyl ethers of ethylene glycol and diethylene glycol),

c) by thermal decomposition of CgHgHgCX^, where X is a halogen, for example in benzene, under reflux.

The starting products of formula VI, in which

n means 1 and A represents the CR7R -CHRQ group, ven-/ 8 y

are obtained for example by alkylation of an acetophenone with an allyl halide, and those of formula

VII, where (A)n represents a covalent bond or CR?Rg and R^Q represents hydrogen, are obtained for example by reacting a vinyl or allyl Grignard compound with an optionally substituted benzaldehyde.

When the preparation of the starting products is not described, these are known or can be obtained by processes analogous to the known processes or to those described in this description.

The compounds of the invention possess interesting biological properties, in particular antifungal properties, and can therefore be used therapeutically 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 different families and species of fungi, such as yeasts, molds, and dermatophytes, at concentrations between about 0.05 and about 50 µg/ml, and also by in vivo tests, for example by systemic administration, by oral administration at doses between about 10 and 100 mg/kg to mice in which an intravaginal infection with Candida albicans has been induced.

Thanks to these properties, the compounds of the injection can be used as antifungals. For their use, the dose to be administered will naturally depend on the compound used, the method of administration, and the desired treatment. However, satisfactory results are generally obtained when the compounds of the invention are administered at a daily dose of between about 1 and 100 mg/kg, advantageously in divided doses 2 to 4 times a day, or in a prolonged-acting form. In human therapeutics, the corresponding daily dose will be between 70 and 2000 mg of active substance; 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 as free bases or as salts (acid or alcohol addition salts) or as pharmaceutically or veterinaryly acceptable metal complexes. Generally, the salts have the same order of activity as the free bases.

Examples of acids that can be used for the preparation of acid addition salts include hydrochloric, hydrobromic, sulfuric, nitric, fumaric and naphthalene-1,5-disulfonic acids.

The invention therefore concerns the compounds of the invention, in the form of a free base or of pharmaceutically or veterinaryly acceptable salts or metal complexes, for use as medicinal products, particularly as antifungals. The invention also concerns a medicinal product containing, as its active substance, a compound of the invention in the form of a free base or of a pharmaceutically or veterinaryly acceptable salt or metal complex.

As medicaments, the compounds of the invention can be used in the form of pharmaceutical or veterinary compositions containing the active substance in combination with pharmaceutically or veterinaryly acceptable inert carriers or diluents and, optionally, with other excipients. Such compositions are also part of the present invention. The compounds of the invention can be administered internally in the form of tablets or capsules, or applied topically in the form of ointments or creams, or even administered in an appropriate form for the parenteral route. The concentrations of the active substance will naturally vary depending on the compound used, the desired treatment, and the chosen method of administration. In general, however, satisfactory results are obtained, for example, with topical application at concentrations between 0.05 and 5, particularly between 0.1 and 1% by weight.

The compounds of the invention can be used in a manner similar to that known for the use of known compounds such as ketoconazole. The compounds of formula I in which A represents a CR^Rg-CHRg group exhibit a particularly interesting pharmacological action.

The appropriate daily dose for a given compound of the invention will depend on several factors, namely 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-triazol-1-yl)butan-2-ol in the mouse model of vaginal candidiasis, with recovery occurring after oral administration of 4 x 12.5 mg/kg. The compounds of the invention can therefore be used at doses similar to those generally employed for ketogenic acid.

The compounds of the invention, in free form or in the form of salts (acid or alcohol addition salts) or metal complexes acceptable in agriculture, are also useful as fungicides to combat phytopathogenic fungi. Their beneficial fungicidal effect has been highlighted by in vivo tests at concentrations between approximately 0.0008 and 0.05% against Uromyces appendicuiatus (bean rust) on climbing beans, against other rust fungi (such as Hemileia, Puccinia) on coffee, wheat, geranium, snapdragon, against Erysiphe cichoracearum on cucumber and against other powdery mildews (E. graminis f.sp. tritici, E. graminis f.sp. hordei, Podosphaera leucotricha, Uncinula necator) on wheat, barley, apples, vine.

Other interesting effects have been observed, among others, in in vitro tests against Ustilago 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 per volume of substrate). Since 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 Basidioornyxetes, Ascomycetes and Deuteromycetes, in particular Basidioornyxetes of the order Uredinale (rusts) such as Puccinia spp., Hemileia spp., Uromyces spp., Ascomycetes of the order Erysiphales (powdery fungi) such as Erysiphe spp., Podosphaera spp., and Uncinula spp., as well as Phoma, Rhizoctonia and Helminthosporium.

The quantity of the 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, wetting the soil, watering, spraying, dusting, seed treatment), the purpose of the treatment (prophylactic or therapeutic), the type of fungi to be combated and the time of application.

In general, satisfactory results are obtained by applying the compounds of the invention at doses of between about 0.005 and 2.0, preferably between about 0.01 and 1 kg/hectare, in the case of a treatment for plants or soil. 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 about 0.05 and 0.5, preferably between about 0.1 and 0.3 g per kg of seed.

The term soil, as used below, designates any usual means of cultivation, natural or artificial.

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

.The compounds of the invention particularly suitable for use in agriculture are the compounds of formula I in which (A)n is a covalent bond or the CR7Rg group. Other subgroups of compounds of formula I having a particularly advantageous fungicidal effect are, among others, those in which X-j and X? represent bromine and those in which (A)n represents CH(C^-C^ alkyl)-CHRg and/or those in which R^ represents an alkyl group in for example CH^?

The present invention also relates to fungicidal compositions comprising, as the active ingredient, a compound of the invention in free form or in the form of an agriculturally acceptable salt or metal complex, in combination with an agriculturally acceptable diluent. These compositions can be obtained using conventional 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, refers to a liquid or solid substance acceptable in agriculture that can be added to the active substance to convert it into a simpler or more easily applicable form, or to dilute it to achieve a desirable or usable activity. Examples of such diluents include talc, kaolin, diatomaceous earth, xylene, or water.

Formulations used in the form of sprays, for example water-dispersible concentrates or wettable powders, may contain surfactants, such as wetting or dispersing agents, for example the condensation product of formaldehyde with a naphthalene sulfonate, an alkylaryl sulfonate, a lignosulfonate, a fatty alcohol sulfate, an alkylphenol ethoxylate and an ethoxylated fatty alcohol.

In general, these formulations contain 0.01 to 90% by weight of active ingredient, 0 to 20% of fungicide-acceptable surfactant, and 10 to 99% of one or more diluents. Concentrated forms, such as emulsifiable concentrates, generally contain about 2 to 90%, preferably 5 to 70%, of active ingredient by weight. Application forms generally contain 0.0005 to 10% by weight of a compound of the invention as the active ingredient. Conventional powder suspensions may, for example, contain 0.0005 to 0.05%, preferably 0.001 to 0.02%, of active ingredient by weight.

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

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

A) Wettable powder

Twenty-five parts of a compound of the invention are mixed with 25 parts of synthetic fine silica, two parts of sodium lauryl sulfate, three parts of sodium lignosulfonate, and 45 parts of finely divided kaolin and ground to an average particle size of approximately 5 microns. A wettable powder is obtained which is diluted in water before use as a spraying liquid and can be applied by foliar spraying as well as by root watering.

B) Graduates

0.5 parts by weight of a binder (non-ionic surfactant) are pulverized into 94.5 parts by weight of quartz sand in a drum mixer and mixed thoroughly. 5 parts by weight of a compound of the invention are then added and the mixing continues to obtain granules with a particle size between 0.3 and 0.7 mm. The granules can be applied by incorporation into the soil adjacent to the plants to be treated.

C) Emulsionable concentrate

Mix 25 parts by weight of a compound of the invention with 10 parts by weight of an emulsifier and 65 parts by weight of xylene. The concentrate is diluted with water to the desired concentration.

D) Seed treatment

Forty-five parts of a compound of the invention are mixed with 1.5 parts of diamylphenol decaglycol ether, two parts of spindle oil, 51 parts of fine talc, and 0.5 parts of the dye rhodamine B. The mixture is ground in a contraplex mill at a speed of 10,000 rpm until the average particle size is less than 20 microns. The resulting dry powder has good adhesion and can be applied to the seed, for example by stirring it for 2 to 5 minutes in a slowly rotating bowl.

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

FINAL PRODUCTS

Example 1: 2-(4-chlorophenyl)-4-(2,2-dichlorocyclopropyl)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (a) Add 5.1 g of dodecyl-dimethylsulfonium methyl sulfate to a solution of 3.0 g of 1-(4-chlorophenyl)-3-(2,2-dichlorocyclopropyl)-2,2-dimethylpropan-1-one in 30 ml of dry toluene at room temperature, and stir for 15 minutes. To the resulting suspension, add 1.1 g of powdered KOH, and the mixture is stirred for 2 hours at 35°C. The reaction mixture is cooled, poured onto ice, and extracted with diethyl ether. The organic extracts are washed three times with water, then with a saturated aqueous NaCl solution, the extracts are dried over MgSO4, and evaporated in vacuo. A residue is obtained in the form of a colorless oil containing 50% 2-(4-chlorophenyl)-2-[2-(2,2-dichlorocyclopropyl)-1,1-dimethyl-ethyl] oxirane and 50% dodecyl methyl sulfide. b) Over the course of 10 minutes, the crude oxirane thus obtained is added dropwise to a mixture of 1.0 g of 1,2,4-triazole heated to 90°C. The mixture is stirred for 18 hours, maintaining the reaction temperature at 90°C.

The reaction mixture is cooled, poured onto ice, and extracted with CH^Cl^? The organic extracts are washed successively with water and with a saturated aqueous NaCl? solution, dried over MgSO^, and the solvent is removed by evaporation in vacuo. The title compound is obtained as colorless crystals after chromatography on silica gel using, as eluent, first a mixture of hexane/ethyl acetate fraction (9:1 initially, then 1:1) and then ethyl acetate, and subsequent crystallization in a mixture of diethyl ether/hexane fraction; m.p. = 117-123? (mixture of diastereoisomers).

And examples or 2

Proceeding in a manner similar to that described in example 1, the following compounds of fora Ia are obtained:

(the) ChL-C (AL-C

reaction of an azole with the corresponding oxyrane.

Es .

(A), x^x2 Characteristics-No. that

2.1 4- CI H Cl/Cl CH N

2 CH

3 Br/Br N

4 CH

5 F/F N

6 CH

7 F/Cl N

8 CH

9 Cl/Cl N

10 2-C1 CH. CH N

11 CH

12 C(CH3)2 N Rf=0/24/ ACE*

13 CH

14 CH2 N

15 CH

16 CH(CH3) N

17 CH

18 4- CI H- C(CH3)2-CH2 Cl/Cl H H CH m.p. 140-55? 19 " Br/Br N Rf-0; 30/ Ac E* 20 CH

21 11 F/F N

22 CH

23 CH2-CH2 Cl/Cl N

24 CH

25 CH(CH3)-CH2 " " N Rf=0.28/ AcE**

20

=1 ,5598 Ex. ]

R CAI x1/x2 R4 R R Y Characteristics-No.

6 that

26 " CH

27 CI " N

28 " CH

29 C(CH3 )2-CH2 H/C I " N

30 " CH

31 Cl/Cl " N p. f. 100-8? )*

* mixture of diastereoisomers AcE ethyl acetate

** mixture of isomers

INTERMEDIATE PRODUCTS

Example 3: 1-(4-chlorophenyl)-3-(2,2-dichlorocyclopropyl)-2,2-dimethylpropan-1-one

a) To a solution of 28 g of KOH powdered in 500

ml of toluene are added while stirring, within 30 minutes and at room temperature, 45.6 g of 4-chlorophenylisopropylketone, then 8.1 g of tetrabutylammonium bromide, the internal temperature being increased to 30°C. After stirring for 2 hours, 45.6 g of 4-chlorophenylisopropylketone are added dropwise at room temperature.

28.7 g of allyl chloride in 100 ml of toluene and stir the mixture overnight at room temperature. Pour the mixture onto ice water,

it is extracted with ether, the combined organic extracts are washed subsequently with water and an ac solution

saturated NaCl, Ti are dried over MgSO^ and evaporated. Fractional distillation of the remaining crude residue gives 1-(4-chlorophenyl)-2,2-dimethyl-pent-4-en-1 -one as a colorless oil (b.p. = 95 µg/0.4 mm Hg).

b) At a temperature of 0°C, 500 g of a 50% aqueous solution of NaOH are slowly added to a solution of 64 g of 1-(4-chlorophenyl)-2,2-dimethyl-pent-4-en-1-one in 500 ml of CHCl^ and, over the course of 15 minutes, 5 g of triethylbenzylammonium chloride (TEBA) are added portionwise. When the addition is complete, the mixture is stirred for 8 hours at a temperature between 0 and 5°C and, after dilution with 500 ml of CHCl^, it is stirred again for 18 hours at room temperature. The reaction mixture is then poured onto ice, extracted with C H2^12*, the organic extracts are combined, the overall organic phase is washed with water, dried over MgSO^ and evaporated in vacuo. The title compound is obtained in its pure state by silica gel chromatography using, as eluent, a mixture of hexane/diethyl ether fraction (1-3%). Rf = 0.23 by thin-layer chromatography on silica gel using, as eluent, a mixture of hexane/diethyl ether fraction 96:4.

And examples or 4

Proceeding in a similar way to that described in example 3b), the following compounds are obtained:

formula IVa for the reaction of dihalocarbenes with the corresponding unsaturated compounds of formula VI:

Comp. (A)n ^I/^2 ^4 ^5 ^6 ^ Eluent

4.1 4-C1 H C(CH3)2CH2 Br/Br H H H 0.34 HX/AcE^1)95:5 4.2 4-C1 H CH(CH3)CH2 Cl/Cl H H H 0.31^2^ HX/AcE 9:1 4.3 4-C1 H C(CH3)2 Cl/Cl H H H 0.29 HX/AcE 9:1

(1) HX/AcE = hexane/ethyl acetate fraction

(2) mixture of diastereoisomers

Example 5: 4-chlorophenyl1-(2,2-dichloro-1-methylcyclopropyl)-ketone

To a solution of 7.0 g of 1-(4-chlorophenyl)-2-methylprop-2-en-1-one in 70 ml of chloroform, add slowly at 0? and with vigorous stirring,

16 g of a 50% aqueous solution of NaOH, then 4.3 g

of triethylbenzyl ammonium chloride. When the addition

? finished, the ice bath is removed until a

A strong exothermic reaction begins. The reaction mixture is then cooled again so that the initial reaction temperature is maintained for 1 hour.

at 34-40?, then slowly decrease to reach room temperature. After 5 hours of reaction, pour

The mixture is placed on ice and extracted with diethyl ether. The organic extracts are combined and washed.

with water, they are dried over MgSO^ and evaporated under vacuum. The residue is chromatographed on silica gel using, as eluent, a 9:1 mixture of hexane/diethyl ether fraction, which gives the title compound; 20

= 1.5689, Rf = 0.24 (thin layer chromatography using a 9:1 hexane/diethyl ether fraction mixture as eluent).

C a i n s

1) The ?-aryl-a-R]-1H-1,2,4-triazol-ethanols and the ?-aryl-a-R^-1H-imidazol-1-ethanes where R-j represents a halogenated cyclopropyl group bonded to the carbon atom a either directly or through an alkyl group, and their ethers and esters,

in free form or in the form of addition salts with acids, alcoholates or metal complexes,

2) A compound according to claim 1, characterized in that it corresponds to the formula I

(I) ChL-C

in which

R1 has the meaning indicated in claim 1, R^ and R^ each represent, independently of each other, H, a halogen, an alkyl group in Cn-Cc,

I b alkenyl in alchemy ie in ?lkoxy in C1-C5 or alkylthio in unsubstituted or halogenated, an unsubstituted or substituted phenyl or phenoxy group, or NO2. and

Y represents CH 0 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 it represents a G group

V1 (G)

(A):

in which

X-j represents H, F, CI 0 Br,

X2 represents F, CI 0 Br,

R4, R^, Rg each represent, independently of each other, H, an alkyl group and the nCn -Cc

I b 0 a halogen,

A represents a CR^R00 CR-,R0-CHRn residue, the CR^Rg-CHRg residue being bonded to the halogenated cyclopropyl group via the carbon atom bearing the Rg substituent,

Ry, Rg, Rg each represent, independently of each other, H or an alkyl group in C-|-Cg, and Rg can also be bonded to form a cycloalkyl group in C3-C^, and

n means 0 or 1,

4) A compound according to claim 3, characterized in that R0 c , Rj_, (A)n, R4., Rc, Rco, X,i, 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, CI, CI and N,

c) 4-C1, H, a covalent le game, CHg, H, H, CI, CI and N, d) 4-C 1, H, C (CH3) 2, H, H, H, CI, CI and N.

5) A compound according to claim 3, characterised in that it is 2-(4-chlorophenyl)-4-(2,2-dichlorocyclopropyl)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-11)butan-2-ol.

6) A process for the preparation of a compound according to any of claims 1 to 5, characterised in that a compound of formula II is reacted

r (II)

M

wherein M represents H, a metal or a trialkyl-s?1yl group and Y has the meaning indicated in claim 2, with a corresponding 2-aryl-2-R^-oxirane, where R^ has the meaning indicated in claim 1, ? 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 of claims 1 to 5, in free form or in the form of an agriculturally acceptable metal salt or complex, for use as a fungicide to control phytopathogenic fungi.

8) A fungicidal composition for the treatment of plants, characterised in that it contains, as active matter, a compound according to any of claims 1 to 5, in free form or in the form of an agriculturally acceptable salt or metal complex, in association with an agriculturally acceptable diluent.

9) A process for combating phytopathogenic fungi, characterised in that an effective quantity of a fungicidal compound according to any of claims 8 to 5 is applied to a growing site, in free form or in the form of a salt or metal complex acceptable in agriculture.

Claims (1)

? i ? 10) A compound according to any of claims 1 to 5, in free form or in the form of a pharmaceutically or veterinaryly acceptable metal salt or complex, for use as a medicament. 11) A medicament, characterised in that it contains, as an active ingredient, a compound according to any of claims 1 to 5, in free form or in the form of a pharmaceutically acceptable metal salt or complex. 12) A pharmaceutical or veterinary composition, characterised in that it contains a compound according to any of claims 1 to 5, in free form or in the form of a pharmaceutically or veterinary acceptable metal salt or complex, in association with a pharmaceutically or veterinary acceptable diluent or vehicle. S A N D O Z A. G.