KR870002035B1 - Process for preparing arylphenyl ether derivatives - Google Patents

Abstract

Compds. of formula(I) and their acid-addn. salts are prepd. Thus, mixture of 1-(p-phenoxyphenyl)-2-(1,2,4-triazolyl) ethanol nitrate, 1,2-pentanediol, P-toluenesulfonic acid, 1-pentanol, and xylene is refluxed for 6 days and treated with NaOH and H2O to give 2-[p- (phenoxy)phenyl!-2-(1H-1,2,4-triazolylmethyl)-4-n-propyl -1,3- dioxolane. (I) have (a) antimycotic activity, (b) anticonvulsant activity (3) anxiolytic activity.

Description

Method for preparing an arylphenyl ether derivative

The present invention relates to substituted arylphenyl ether derivatives of the formula (I) and acid addition salts and metal complexes thereof. The present invention also provides a method for preparing a compound of formula (I) and agrochemical compositions and pharmaceutical preparations having the at least one compound of formula (I) as an active ingredient, a method for preparing the composition and the use of the composition and formulations; And it relates to a method for treating plants to eradicate or suppress the onset by phytopathogenic microorganisms.

The arylphenyl ether derivatives of the present invention, acid addition salts and metal complexes thereof have the following structural formula:

Wherein Y is -CH = or -N =; Ra and Rb are each hydrogen, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or nitro; Ar is phenyl or naphthyl, each of which is single or polysubstituted or unsubstituted with halogen, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, nitro and / or CF ₃ ; U and V are each C ₁ -C ₁₂ alkyl, optionally substituted with halogen or C ₁ -C ₆ alkoxy, or together form one of the following alkylene bridges,

R ₁ and R ₂ is a single or multiple substituted by C ₁ -C ₁₂ alkyl, each hydrogen, C ₁ -C ₁₂ alkyl or halogen; Phenyl monophenyl or phenyl monosubstituted or polysubstituted with C ₁ -C ₃ alkyl; Or -CH ₂ -ZR ₇ ; Z is oxygen or sulfur; R ₇ is a C ₁ -C substituted by hydrogen, C ₁ -C ₈ alkyl or C ₁ -C ₂ alkoxy ₈ alkyl; C ₃ -C ₄ alkenyl, prop-2-ynyl, 3-haloprop-2-ynyl, phenyl or halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, nitro and / or CF ₃ Mono or polysubstituted phenyl; Benzyl mono or polysubstituted benzyl with halogen, C ₁ -C ₃ alkyl and / or C ₁ -C ₃ alkoxy; R ₃ , R ₄ and R ₅ are each hydrogen or C ₁ -C ₄ alkyl and the total number of carbon atoms in R ₃ , R ₄ and R ₅ does not exceed 6; R ₆ is hydrogen or C ₁ -C ₃ alkyl.

For substituted or unsubstituted phenyl or naphthyl, the substituent Ar has the following structural formula.

Wherein RC, Rd and Re are each hydrogen, halogen, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, nitro or CF ₃ .

Depending on the number of carbon atoms indicated, "alkyl" as a component of itself or another substituent means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl and isomers thereof ( Eg, isopropyl, isobutyl, t-butyl, Sec-butyl, isopentyl) and the like. Examples of alkenyl include propen-1-yl, allyl, buten-1-yl, buten-2-yl, or buten-3-yl. Halogen in the specification means fluorine, chlorine, bromine or iodine, with chlorine or bromine being preferred.

The present invention also includes complexes with acid addition salts and metal salts with the free compounds of formula (I), inorganic or organic acids.

Salts of the present invention are especially addition salts with inorganic or organic acids which are physiologically resistant.

Examples of inorganic and organic acids that can be used physiologically as plant fungicides include, but are not limited to, halogenated acids such as hydrohalic acid (e.g. hydrochloric acid, bromic or iodide, sulfuric acid, phosphoric acid, phosphorous acid, nitric acid, acetic acid, trichloroacetic acid and oxalic acid). Fatty acids or sulfonic acids such as benzenesulfonic acid and methanesulfonic acid; and the like.

Examples of physiologically tolerable acids that are useful as pharmaceuticals, ie, pharmaceutically acceptable inorganic acids (e.g. hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid, such as hydrochloric acid, bromic acid or iodic acid), pharmaceutically acceptable Carboxylic acids and sulfonic acids (eg, any hydroxylated dicarboxylic acid and aliphatic monocarboxylic acid, such as acetic acid, fumaric acid, maleic acid, malic acid or tartaric acid), and aliphatic or aliphatic sulfonic acids (eg, methane) Unsubstituted or benzene sulfonic acid lower alkanesulfonic acids such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and p-bromobenzenesulfone) as well as sulfamic acids (e.g., p-cyclohexylsulfonic acid) Can be mentioned.

Metal complexes of formula (I) consist of inorganic or organic metal salts of copper, manganese, iron, zinc and other metals (eg halides, nitrates, sulfates, phosphates, tartrates) and basic organic molecules. Metal cations may exist in other valence states.

Compounds of formula (I) are oils, resins or solids which are stable at room temperature and which have physiologically useful properties such as bactericidal properties, ie phytobactericidal and drug properties, in particular antifungal, hard and ansiolitic properties. Therefore, the compound of formula (I) is used in agriculture or related fields on the one hand to eradicate phytopathogenic microorganisms, and on the other hand, it kills parasites in warm-blooded animals and also in epilepsy, anxiety, tension and excitement. It is used as an antifungal, antifungal and ansiolitic agent in the pharmaceutical field to treat mental excitement.

An important group of fungicides useful for plant protection include compounds of formula (I), acid addition salts and metal complexes thereof, wherein each group is:

Y is -CH = or -N =; Ra and Rb are each hydrogen, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or nitro; Ar is

Rc, Rd and Re are each hydrogen, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy nitro or CF ₃ ; U and V are each C ₁ -C ₁₂ alkyl, or together

An alkylene bridge of; R ₁ and R ₂ are hydrogen, C ₁ -C ₃ alkyl or C ₁ -C ₁₂ alkyl mono- or polysubstituted with halogen, or phenyl or phenyl mono- or polysubstituted with C ₁ -C ₃ alkyl, respectively Or -CH ₂ -ZR ₇ ; Z is oxygen or sulfur; R ₇ is hydrogen, C ₁ -C ₈ alkyl, or C ₁ -C or a C ₁ -C ₈ alkyl substituted with _two alkoxy, or C ₃ -C ₄ alkenyl, prop-2-ynyl, 3-halo-Pro Phenyl-inyl, phenyl or halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyl mono- or polysubstituted with nitro and / or CF ₃ , or benzyl or halogen, C ₁ -C ₃ alkyl And / or benzyl mono- or polysubstituted with C ₁ -C ₃ alkoxy; R ₃ , R ₄ and R ₅ are each hydrogen or C ₁ -C ₄ alkyl, with no more than 6 total carbon atoms in R ₃ , R ₄ , and R ₅ ; R ₆ is hydrogen or C ₁ -C ₃ alkyl. The small group is referred to as (Ia) group.

A preferred group of agriculturally useful fungicides is that Y is -CH = or -N =; Ra and Rb are each hydrogen, halogen or C ₁ -C ₃ alkyl; Ar is

ego ; Rc, Rd and Re are each hydrogen, CF ₃ or C ₁ -C ₃ alkyl; U and V include compounds of formula (I), including salts and metal complexes thereof, as defined above in formula (I). This group is referred to as (Ib) group.

Preferred fungicides in small groups (Ib) are U and V, each being C ₁ -C ₃ alkyl, or together

An alkylene group of; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are hydrogen or C ₁ -C ₄ alkyl and include compounds of formula (I) in which the total carbon number of R ₃ , R ₄ and R ₅ does not exceed 6 . This group is referred to as the (Ic) group.

Preferred groups of agriculturally useful fungicides are those wherein Y is -CH = or -N =; Ar is as defined in formula (I); Ra, Rb, Rc, Rd and Re are chlorine, bromine, fluorine, methyl, methoxy or nitro, respectively; U and V are each C ₁ -C ₃ alkyl, or together form one of the alkylene groups as defined in formula (I); R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each hydrogen or C ₁ -C ₃ alkyl, or R ₁ is —CH ₂ -OR ₇ (R ₇ is C ₁ -C ₃ alkyl, A compound of formula (I) which is C ₂ -C ₄ alkyl substituted with C ₁ -C ₃ alkoxy, or C ₃ -C ₄ alkenyl or phenyl, said group being referred to as (Id) group.

Particularly good fungicides in the (Id) group are when U and V together form an unsubstituted or simply substituted ethylene or propylene bridge. This group is referred to as (Ie) group.

Thus, each of the following compounds may be exemplified as agriculturally useful compounds:

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -4-methyl-1,3-dioxane.

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -4-ethyl-1,3-dioxane.

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -4-methyl-1,3-dioxolane.

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -4-ethyl-1,3-dioxolane.

Important compounds of formula (I) in terms of bactericidal activity are those wherein Y is -CH = or -N =, Ra and Rb are each hydrogen, halogen or C ₁ -C ₃ alkyl, and Ar is

Rc, Rd and Re are each hydrogen, halogen, CF ₃ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, and U and V belong to the group (If) as defined in formula (I). to be.

In the subgroup (If), the sterilization in particular desirable structural formulas in the active surface (Ⅰ) compounds U and V are each C ₁ -C ₆ alkyl, halogen or C ₁ -C ₂ alkoxy which is not substituted or substituted by C ₂ -C ₄ alkyl Or combined together

Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each hydrogen or C ₁ -C ₄ , each having a group with a total carbon number of R ₃ , R ₄ and R ₅ not exceeding 6; Compound.

This group is referred to as (Ig) group.

의 알킬렌기를 형성하며, R₇은 C₁-C₄알킬, C₁-C₂알콕시로 치환된 C₂-C₄알킬, 혹은 C₃-C₄알케닐 혹은 프로프-2-이닐인 화합물이다. 이러한 그룹은 (Ih)그룹으로 지칭된다.In small groups (Ig), compounds of structural formula (I) preferred in terms of bactericidal activity, U and V together

To form an alkylene group, R ₇ is C ₁ -C ₄ alkyl, A compound, C ₁ -C ₂ alkoxy C ₂ -C ₄ alkyl, or C ₃ -C ₄ alkenyl, or prop-2-ynyl optionally substituted with to be. This group is referred to as (Ih) group.

A more preferred group of compounds of formula (I) having bactericidal activity are the Y group -CH =, Ar is as defined in formula (I), Ra and Rb are each hydrogen, methyl, chlorine or bromine, Rc, Rd And Re is hydrogen, fluorine, chlorine, bromine, methoxy, CF ₃ or nitro, and U and V are each C ₁ -C ₃ alkyl substituted or unsubstituted with C ₁ -C ₂ alkoxy or chlorine, or together Forms one of the alkylene groups defined in (I), wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are hydrogen or C ₁ -C ₃ alkyl or R is —CH ₂ OR ₇ R ₇ is a compound which is C ₂ -C ₃ alkyl or C ₃ -C ₄ alkenyl substituted with C ₁ -C ₃ alkyl, C ₁ -C ₂ alkoxy. This group is referred to as (Ii) group.

The following compounds can be exemplified as particularly good compounds having bactericidal activity:

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl] -4-methyl-5-methyl-1,3-dioxolane;

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -1,3-dioxane;

2- [p- (phenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (2,4-dimethylphenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (3-chlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (4-chlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (3-trifluoromethylphenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (4-chloro-3-methylphenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (3,4-dichlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (2,5-dichlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (3,4-dichlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-methoxymethyl-1,3-dioxolane;

2- [p- (4- (fluorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (4-fluorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-methyl-5-methyl-1,3-dioxolane;

Or each of the above pharmaceutically acceptable acid addition salts.

The compounds of the formula (Ⅰ) having an anticonvulsant activity and Y is -CH = or -N = and, Ra and Rb each is hydrogen, halogen or C ₁ -C ₃ alkyl, Ar is phenyl or C ₁ -C ₃ Alkyl C ₁ -C ₃ alkoxy CF ₃ or phenyl substituted with halogen and U and V are compounds of the group (Ii) as defined in formula (I).

In the small group (Ij), compounds of formula (I) which have particularly useful convulsive properties are those in which Y is -CH = or -N =, Ra and Rb are hydrogen, methyl, chlorine or bromine, and Ar is phenyl or halogen , Phenyl substituted with methyl or CF ₃ , and U and V are each C ₁ -C ₃ alkyl, C ₂ -C ₃ alkyl optionally substituted with C ₁ -C ₂ alkoxy, or

Forming an alkylene group of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ , each being hydrogen or C ₁ -C ₄ alkyl, wherein the total carbon number of R ₃ , R ₄ , and R ₅ is greater than 4 Compound with groups that do not. This group is referred to as group Ik.

Further preferred compounds of the group having distinct anticonvulsant properties are those in which Y is -CH = or -N =, Ra and Rb are hydrogen, this phenyl or phenyl substituted with halogen or methyl, and U and V are

Wherein R ₂ is C ₁ -C ₄ alkyl (eg methyl or ethyl), or C ₁ -C ₃ hydroxyalkyl (eg hydroxymethyl or 2-hydroxyethyl, C ₁ -C ₂ alkoxy -C ₁ -C ₂ alkyl, such as methoxymethyl or ethoxymethyl, which is referred to as group (Il).

Each of the following compounds can be exemplified as particularly preferred compounds having anticonvulsant activity:

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -1,3-dioxane;

2- [p- (4-chlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (4-chloro-2-metalphenoxy) phenyl] -2- (1-imidazolylmethyl) -4-methoxymethyl-1,3-dioxolane;

2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -4-hydroxymethyl-1,3-dioxolane;

2- [p- (4-fluorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane;

2- [p- (4-fluorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-hydroxymethyl-1,3-dioxolane;

2- [p- (4-fluorophenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -1,3-dioxane.

Also included are the respective pharmaceutically acceptable acid addition salts, preparation methods thereof, and pharmaceutical compositions.

The compound of formula (I) may be prepared by the following method:

A) condensation of a compound of formula (II) with a compound of formula (III)

(Wherein Me is hydrogen or metal cation and X is leaving group);

B) converting a carbonyl group to a group of formula (V) in a compound of formula (IV)

C) Condensation of the compounds of the following formulas (VI) and (iii) with each other so that U and V together are -CH ₂ -CH (CH ₂ ZR'7)-and R ₇ 'is a radical different from hydrogen Or a compound of

(Wherein any one of X ₁ and X ₂ radicals is a mercapto in the form of a hydroxyl or -Z-Me, the other is a leaving group X, or both X ₁ and X ₂ are hydroxyl groups) ;

D) condensation of the compounds of formulas (iii) and (iii)

Ar-X ₃ (Ⅷ)

(Wherein any one of X ₃ and X ₄ is an O-Me group (Me is hydrogen or preferably a cation), and the other is a radical which may be substituted by aryloxy);

E) The compound of the following structural formula (IV) is accompanied by decarboxylation in the molecule, and if necessary, the compound of the past is converted into another compound of the structural formula (I), or the free compound is added as an acid addition salt Convert the salt to a free compound or another acid addition salt, or convert the free compound or acid addition salt to a metal complex:

Examples of metal cations Me include alkali metal cations such as lithium, sodium or potassium cations or alkaline earth metal cations such as magnesium, strontium or barium cations. Examples of leaving groups include hydrohalic acid (e.g. fluoric acid, hydrochloric acid, bromic acid or iodide) or lower alkalsulfonic acid, unsubstituted or substituted benzenesulfonic acid or halosulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid, Reactive esterified hydroxyl groups which may be esterified with benzenesulfonic acid, p-toluenesulfonic acid or fluorosulfonic acid).

Azoles of formula (II) wherein Y is -CH = or -N = and M is a metal atom (especially an alkali metal atom) and Ar, Ra, Rb, U and V are as defined in formula (I), Of formula (III), wherein X is halogen (especially chlorine, bromine or iodine) or benzenesulfonyloxy, P-tosyloxy, trifluoroacetyloxy or preferably lower alkylsulfonyloxy (e.g. mesyloxy) The compound is relatively polar but is carried out in an inert organic solvent such as N, N-dimethyl formamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, benzonitrile, etc. These solvents are also benzene, toluene, xylene , In combination with other inert solvents such as aliphatic or aromatic hydrocarbons such as hexane, petroleum ether, chlorobenzene, nitrobenzene.

If X is chlorine or bromine, alkali iodine (such as NaI or KI) can be added to promote the reaction. The temperature is advantageously 0 ° C.-220 ° C., in particular (80 ° C.-170 ° C.). It is advantageous to heat the reaction mixture under reflux.

When Me in hydrogen (II) is hydrogen, it is preferable to carry out the reaction in the presence of a base. Examples of suitable bases include inorganic bases such as oxides, hydroxides, hydrides, carbonates and bicarbonates of alkali and earth metals and triethylamine, triethylenediamine, piperidine, pyridine 4-dimethylaminopyridine, 4-pyrrolidylpyridine Organic bases, such as a tertiary amine, such as these, are mentioned.

In this process, the intermediates and the final product are liberated from the reaction medium and can be purified by conventional methods such as extraction, crystallization, chromatography, distillation and the like as necessary.

The reaction for converting a carbonyl group to a group of formula (V) in the compound of formula IV is to prepare a compound of formula (I) wherein U and V are the same substituted or unsubstituted C ₁ -C ₁₂ alkyl group. , By reaction with orthocarboxylic acid C ₁ -C ₁₂ trialkyl esters (C ₁ -C ₁₂ alkyl groups are substituted by halogen or C ₁ -C ₆ alkoxy) or in the presence of an acid U-OH (Va) To prepare a compound of formula (I), which is carried out by reaction with at least 2 moles of monohydric alcohol having the structure of or wherein U and V together are one of the alkylene bridges as defined above It is performed by reaction with diol of formula (Vb).

HO-U…. V-OH (Vb)

In the above formula, Ar, Y, Ra, Rb, U and V are all as defined in formula (I).

The ketalization reaction is carried out by the same method as known ketalization reaction, for example, the preparation of 2-bromomethyl-2,4-diphenyl-1,3-dioxolane [synthesis, 1974 (I), 23]. Is carried out.

In a preferred embodiment of the ketalization, both reactants are heated with the azeotrope in a conventional organic solvent under reflux for several hours. Examples of suitable azeotropes include benzene, toluene, xylene, chloroform or carbon tetrachloride. In order to promote the reaction, it is preferable to add a strong acid such as p-toluenesulfonic acid. Examples of organic solvents used may in this case be aromatic hydrocarbons (eg benzene, toluene, xylene), saturated hydrocarbons (eg n-hexane) or saturated halogenated hydrocarbons (1,1,1-trichloroethane). have.

Ketalization is carried out by reacting an alkanol or diol of the structural formula (Va) or (Vb) with a ketone (IV) ketalized with another alcohol or phenol, followed by an excess of alkanol (Va) or diol (Vb). It can be carried out by transketalizing with the compound of I). Starting materials are prepared by one of the methods of A), D) and E).

In method C), the compound of formula (I) wherein U and V are -CH ₂ -CH (CH ₂ ZR ₇ )-is a compound of formula (VII) wherein X ₁ is a -ZH group and X ₂ is X and It is prepared by reacting a compound of. The reaction is preferably carried out in an inert organic solvent. Examples of suitable solvents for this reaction include N, N-dimethylformamide, N, N-dimethylacetimide, hexamethylphosphoric triamide, dimethyl sulfoxide, 4-methyl-3-pentanol and the like. Mixtures with other inert solvents, for example mixtures with aromatic hydrocarbons such as benzene, toluene, xylene and the like, can also be used. In some cases it is convenient to carry out the reaction in the presence of a base in order to increase the reaction rate. Examples of suitable bases include alkali metal hydrides or alkali metal burnts. It is also advantageous in some cases to convert the compound of formula VI into a suitable metal salt first. The reaction is carried out by reacting Structural Formula (VI) with a sodium compound (eg, sodium hydride, sodium hydroxide). The salt of formula (VI) continues to react in formula (VII). In order to increase the reaction rate it can be carried out at elevated temperature, preferably 80 ℃-130 ℃ or boiling point of the solvent.

The compounds of the formulas (VI) and (VIII) in which X ₁ is an X group and X ₂ is a -ZH group can be implemented in the same manner.

In a reaction for condensation of a compound of formula (VI) and a compound of formula (VII) wherein X ₁ and X ₂ are hydroxyl to yield a compound of formula (I) wherein Z is oxygen, the reaction is heated under reflux in a suitable solvent, Water is distilled off from the reaction mixture at azeotropy. Suitable solvents are aromatic hydrocarbons such as toluene or alcohols of HO-R ₇ . The reaction is conveniently carried out in the presence of a strong acid (eg p-toluenesulfonic acid).

In process D), the starting from the reaction of compound (iii) and ( _iii) in which X ₃ is a -OMe group, X ₄ is a leaving group or vice versa X ₃ is a leaving group, X ₄ is a -OMe group, Ra, Rb, U, V, Y and Ar are as defined in formula (I), Me is halogen. It is advantageous to carry out the reaction under the conditions described in method A).

In the method E), according to the method described in the method B), the decarboxylated compound of the compound of formula (VII), which is produced by ketalization of the following formula (XI), is an anhydrous or high boiling solvent (e.g., Diphenyl ether) is heated to a temperature of about 120 ° to 220 ° C, the compound of formula (XI) is a divalent derivative of carboxylic acid, a lower alkyl ester of halo formic acid or di-lower allyl Or by reacting with diphenylcarbamate and then with a compound of formula (XIII).

The compounds according to the invention can be converted to another compound of formula (I) by known methods.

Thus, the compound produced according to the present invention can be transketalized with another compound of formula (I). For example, in compounds of formula (I) wherein U and V are the same or unsubstituted C ₁ -C ₁₂ alkyl radicals, U is 1 mole of substituted or unsubstituted C of formula V-OH (Vc) It may be substituted by V by reaction with _1- C ₁₂ alkanol, or U may be substituted by divalent radical by reaction with diol of compound (Vb). Transalkylation is preferred in the presence of conventional methods, for example in the presence of acid condensates such as inorganic acids, sulfonic acids or strong carboxylic acids such as hydrochloric or bromic acid, sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid. Preferably by a method of removing volatile reaction products by distillation or equipotent distillation.

In addition, additional substituents may be introduced into the carbocyclic aryl moiety of the compound produced by the process of the present invention as needed. For example, halogens can be introduced by reaction with halogens or by treatment with p-chloro succinamide in the presence of Lewis acids (eg, halides of iron, zinc boron or antimony).

The nitro group can also be reduced to the amine by a suitable complex hydride such as lithium aluminium hydride, after which the amine is diazotized to a diazonium group and nitrous acid substituted according to conventional methods by halogen or alkoxy. . Halogen may also be substituted by alkyl groups by reaction with alkylmetal compounds such as alkyl lithium or alkyl magnesium halides.

If the compound of formula (I) is calculated as a base, the compounds can be converted to the corresponding salts of formula (I) with inorganic or organic acids, or to the metal complexes of formula (I) using equimolar amounts of metal salts. . In contrast, the salt of formula (I) can be converted to the free base of formula (I) by reaction with alkali carbonate or bicarbonate or alkali hydroxide.

The ketal of the structural stone (III) is a reaction tube with a diol as desired from methylaryl ketone of the following structural formula (XIV), for example, in an inert solvent such as halogenated hydrocarbon (eg methylene chloride ethylene chloride, chloroform, carbon tetrachloride). Prepared by simultaneous or sequential halogenation:

It is advantageous to accelerate the reaction by adding p-toluenesulfonic acid.

Ketones of formula (IV) can be prepared by halogenating (XIV) to (XV) and reacting azoles of formula (II) with (XV) according to the same method of method A).

Hal in the formula (XV) is chlorine or bromine.

Ketals III, VI, V and V are prepared by reacting ketones of formula (IV) with alcohols or diols according to methods B) and analogous methods.

The various methods described above constitute the object of the present invention.

Ketalization of the reaction of ketones with substituted α, β- or α, γ-diol first leads to the formation of a mixture of diastereoisomers of the ketal. Similarly, the daastero isomeric mixture of the final product of formula (I) is generally produced from ketones. Compounds of formula (I) can be calculated from the following diastereo isoforms:

The arrangement of type A is referred to herein and is classified as a "trans" -isomer.

The symbol of the three-dimensional structure is as follows:

Arrays of type B are classified as "cis" isomers. Separation of the two diastereoisomers can be accomplished by fractional crystallization or chromatography (eg thin layer chromatography, column chromatography, liquid high pressure chromatography). Both isomers have different biological properties. In practice mixtures of diastereo isomers are commonly used.

The present invention relates to all isomers of the formula (I), salts and complexes thereof.

The process for the preparation of the compounds of the formula (I) described in the processes A), B), C) and D) also constitutes an object of the present invention.

Intermediates and starting materials used in the method A) -E) are known, and others can be prepared by known methods.

1- (β-aryl) ethimidazolyl ketal, wherein aryl is phenyl or naphthyl, is described in the following literatures as fungicides and fungi: United States Patent Specification 3,575,999, 3,936,470: 4,101,664: 4,101,666: 4,156,008.

It has been found that the compounds of the present invention have bactericidal spectra that are very beneficial for pathogenic fungi and bacteria and have anticonvulsant and / or bactericidal properties that can be used in medicine. For example, the compounds of formula (I) have very good therapeutic, prophylactic and systematic pathologic treatment and can be used for the protection of horticultural crops. In the compound of formula (I), it is possible to inhibit or destroy microorganisms generated from various useful plants (fruits, flowers, leaves, stems, roots, tubers), and at the same time protect late-growing plants from the attack of such microorganisms. do.

Compounds of formula (I) are particularly effective against the following groups of pathogenic fungi: cysts (eg, Venturia grapespoata, erycife, monitinia, uncinura); Incomplete bacillus (eg, hemirea, lystokonia, fuchsia); Incomplete fungi (e.g., Botrytis, Helmintosporium, Fusathium, Septtoria, Sercosfora and Alteraria). In addition, the compounds of formula (I) have a phylogenetic action. It is also used as a seed dressing to protect seeds (fruits, tubers, grains) and fabric cut surfaces against pathogenic microorganisms and fungal infections occurring in soil. The compounds of formula (I) of the invention also have good resistance by crops.

Accordingly, the present invention relates to the use and disinfectant composition of the compound of formula (I) for the treatment of crops to eradicate phytopathogenic microorganisms, in particular fungi, and to protect crops from attack and onset by the microorganisms.

The present invention also relates to the preparation of an agrochemical composition consisting of mixing a compound of formula (I) with one or more substances. The present invention also relates to a method for treating a crop consisting of using the compound of formula (I) or a novel composition containing the compound.

Crops which are protected within the scope of this compound are as follows. Cereals (wheat, barley, rai, oats, rice, forests and related plants), root vegetables (sugar beet and fodder beet), cores and pome and sweets (apples, pears, peaches, almonds, cherries, strawberries, raspberries and blackberries) ), Legumes (peanuts, lentils, soybeans, peas), rapeseeds (flat, mustard, poppy, olives, sunflowers, coconut, castor oil, cocoa bean, peanuts), cucumbers (cucumbers, matou, melon) , Fiber crops (cotton, flax, hemp, jute), obstetrics (orange, lemon, grapes, mandarins), vegetables (spinach, blush, asparagus, cabbage, carrot, onions, tomatoes, potatoes, paprika) Cinnamon, camphor) or maize, tobacco, nuts, coffee, sugar cane, tea, vines, hops, bananas and natural rubber and garden water (compositions).

The compound of the present invention of formula (I) may generally be used in the form of a composition and may be used simultaneously or continuously in soil and crops or plants. The compounds of the present invention may be formulated with fertilizers or micronutrients or other substances that affect plant growth. That is, the other substances are selective insecticides, fungicides, herbicides, nematode insecticides, bactericides, flucisides or mixtures thereof, if necessary other surfactants or use-promoting aids which can be used in practice. Suitable carriers and auxiliaries for all formulations exist in solid or liquid form and encompass non-toxic materials commonly used in the formulation art, including natural or recycled inorganic materials, solvents, dispersants, humectants, thickeners, pressure sensitive adhesives, binders and the like. .

The preferred method of treating Structural Formula (I) and agrochemical compositions to infected plants is foliar spraying. The number of sprays and the spray rate depend on the degree of contamination of the pathogen. However, the compound of the present invention penetrates the plant through soil and roots by absorbing the liquid composition around the plant or by spraying the compound of the present invention in solid form (eg, granules for soil use) (systemic action). . The compound of formula (I) may also be applied to the seed by absorbing or evacuating the seeds with a liquid formulation or a solid formulation containing the compound of formula (I). In some cases, the plant may be selectively treated with stems or shoots.

The compound of formula (I) of the present invention is used in an unmodified form or in combination with a conventionally used adjuvant in the formulation technique, and thus, by known methods, emulsion concentrates, coating ointments, direct spray solutions, dilute solutions, dilute solutions It is formulated in the form of emulsions, wettable powders, soluble powders, dusts, granules and encapsulations (encapsulation into polymeric materials). In addition, application methods such as spraying, atomizing, dusting, scattering or fouling, such as the nature of the composition, are selected depending on the intended purpose and environment. The application rate is from 50 g to 54 kg of active ingredient per hectare, preferably from 100 g to 2 kg and most preferably from 200 g to 600 g.

Agrochemical preparations, ie compositions containing the compound of formula (I) and solid or liquid adjuvant, may be prepared by mixing the active ingredient homogeneously with an extender, for example a solvent, a solid carrier, and if necessary a surface active compound. Or by known methods of polishing.

Solid carriers used in dust and dispersible powders are natural minerals such as calcite, talc, clay, montmortillonite or attapulzaate. In order to improve the physical properties, highly dispersed silicic acid or highly dispersed adsorbent polymers may be added. Suitable granulated adsorption carriers are in porous form, such as fumis crushed brick, sepoleite or bentonite, and suitable nonadsorbent carriers are materials such as calcite or sand. In addition, numerous inorganic or organic pre-granulated materials, ie dolomite or powdered plant residues, are also used.

Depending on the nature of the compound of formula (I), nonionic cationic and / or anionic surfactants with good emulsification, dispersing and wetting properties are used as suitable surface active compounds. "Surface activity" consists of a mixture of surfactants.

Suitable anionic surfactants are water soluble soaps and water soluble synthetic surface active compounds.

Suitable soaps may be derived from alkali metal salts of high fatty acids (C ₁₀ -C ₂₂ ), alkaline earth metal salts, substituted or substituted ammonium salts (e.g. sodium or potassium salts of oleic or stearic acid), or coconut or tallow oils. Alkali metal salts, alkaline metal salts or unsubstituted or substituted ammonium salts of natural fatty acid mixtures. Also included are fatty acids and methyl taurine salts.

Synthetic surface active agents such as fatty acid sulfonates, fatty acid sulfates, sulfonated benzimidazoles, derivatives or alkylarylsulfonates are particularly often used.

Fatty acid sulfonates or sulfates are always in the form of alkali metal salts, alkaline earth metal salts, or substituted or unsubstituted ammonium salts, and contain C ₈ -C ₂₂ alkyl radicals containing alkyl components of the acyl radicals. Namely sodium or calcium form of a fatty alcohol sulfate mixture derived from lignosulfonic acid, dodecyl sulfate or natural fatty acid. These compounds consist of adducts of sulfonic acids and sulfuric acid esters / ethyleneoxides of fatty alcohols. The sulfonated benzimidazole derivatives contain one fatty acid radical having two sulfonic acid groups and 8-22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid, or naphthalenesulfonic acid / formaldehyde condensation products. Corresponding phosphates such as phosphate ester salts of addition products of 4 to 14 moles of ethylene oxide with p-nonylphenol are suitable.

Nonionic surfactants are polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, which are derivatives of 8-20 carbon atoms and alkylphenols at 3-30 glycol ether groups and (aliphatic) hydrocarbons. It contains 6-18 carbon atoms in the alkyl component.

More suitable nonionic surfactants are water-soluble adducts of polypropylene glycol, ethylenediamine propylene glycol and polyethylene polypropylene glycol having 1-10 carbon atoms in the alkyl chain and polyethylene oxide, including 20-250 ethylene glycol ether groups and 10-100 It contains propylene glycol ether groups. The compound contains 1-5 ethylene glycol units per propylene glycol unit.

Examples of nonionic surface agents include nonylphenolpolyethoxyethanol, castor oil polyglycol ether, polypropylene / polyethylene oxide adduct, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxyethoxyethanol. . Fatty acid esters of polyethylene sorbent and polyoxyethylene sorbitan trioleate are particularly suitable nonionic surface agents.

Preferred cationic surface agents are quaternary ammonium salts comprising at least one C ₈ -C ₂₂ alkyl radical as p-substituent and lower unsubstituted or halogenated alkyl, benzyl or lower hydroxyalkyl radicals as another substituent. Preferred salts are present in the form of halides, methylsulfate or ethylsulfate, ie stearyltrimethylammonium chloride or benzyl di (2-chloroethyl) ethylammonium boromid.

"McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Corp. Ringwood, New Iersey, 1979 and Sisely and Wood), "Encyclopedia of Surface Active Agents" ICheuical Publishing Co., Inc. New York, 1980).

The agrochemical composition is 0.1-99% (preferably 0.1-95%) of the compound of formula (I), 99.9-1% (preferably 9.99-5%) of 0-25% (in solid or liquid adjuvant and auxiliary) Preferably 0.1-25%) of a surfactant.

The commercial product is formulated in concentrate form while the end user uses it in dilution.

The composition also contains stabilizers, antifoams, viscosity modifiers, binders, tackifiers, fertilizers or other active ingredients to achieve a particular effect. The agrochemical composition also constitutes an object of the present invention. The bactericidal properties of pharmaceutically acceptable acid addition salts and compounds of formula (I) for the eradication of flysheet fungi in ondol are characterized by, for example, trichophytonmentaphytic by conventional microbiological test methods in vitro. , By measuring the toxic effects on the fungal strains of parasheets of warm-blooded animals such as microsporical canis, sporotricommunki, Aspergillus fumigitus and Candida albican, or in vivo In my test, after oral or topical application, it is demonstrated by measuring the therapeutic effect on experimental infections on the skin with trichophyton such as Ti rubrum.

The anticonvulsability of the present compounds and pharmaceutically acceptable acid addition salts is orally administered in vivo experiments, i.e., by pentatetrazol spasm tests in which oral administration of 10-100 mg / kg to mice, or 10-100 mg / kg orally. Can be demonstrated by an electroshock test. Angioortic properties can be demonstrated by the Gellert test and Quatre-Plaque test, orally administering 10-100 m / kg to mice and other small rodent animals. The novel compounds of the present invention also have distinct antimanic properties.

Accordingly, the present invention is a compound of formula (I) and pharmaceutical composition thereof used for the local, regional and systematic eradication of fungi of parasheets of warm-blooded animals, and for the systematic treatment of epilepsy, anxiety and mental anxiety and tension. It relates to the use of acceptable acid addition salts, in particular to the use of the pharmaceutical preparation product or pharmaceutical preparation as an active ingredient for enteric, parenteral, topical or topical application, and also to the pharmaceutical preparation of the invention.

The pharmaceutical preparation of the present invention containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is used for enteral, parenteral administration as well as topical administration such as oral or rectal of a warm-blooded animal. It contains only pharmaceutically active ingredients or pharmaceutically acceptable carriers and pharmacologically active ingredients. The dosage of active ingredient depends on the type of warm-blooded animal, the age and personal symptoms of the patient and the mode of use.

The daily dose of 75 kg of warm-blooded animals is 50-500 mg, divided into several doses as convenient.

Pharmaceutical formulations of the present invention contain 10-80% (particularly 20-60%) of active ingredient. Pharmaceutical preparations for enteral or parenteral administration are prepared in unit dosage forms of tablets, capsules, dragees or suppositories, and ampoules. It is prepared by conventional mixing, granulation, sugar coating, dissolution, lyophilization and the like. Pharmaceutical preparations for oral administration may be prepared by mixing the active ingredient with a solid carrier, optionally granulating the resulting mixture, adding an appropriate adjuvant as necessary, and then granulating the tablets or dragees or processing the mixture. Are manufactured.

Suitable carriers for tablets and / or dragees include sugars (e.g. lactose, saccharose, mannitol or sorbitol), cellulose preparations and / or fillers such as calcium phosphate (e.g. tricalcium phosphate or calcium hydrogen phosphate) or starch pastes (e.g. Maize, corn, rice or potato starch paste), gelatin tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or a combination such as polyvinylpyrrolidone, and / or the starch as needed Same dispersant, carboxymethyl starch, crosslinked polyvinyl pyrrolidone, agar, alginic acid or salts thereof. Auxiliaries are primarily lubricants and friction agents, examples being silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, polyethylene glycol. The sugar-derived tablet core uses a film that is resistant to gastric juice, the solution itself contains arabic gum, active, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, and a shellac solution of an organic solvent or mixture thereof. Silver contains a cellulose preparation such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may be added to the drag or tablet to indicate different doses of the active ingredient.

Pharmaceutical formulations for oral administration are dry filled capsules, plasticizers such as glycerol or sorbitol and soft capsules made from gelatin. Dry filled capsules contain the active ingredient in a mixture form, for example a layering agent such as lactose, a binder such as starch and / or a lubricant and stabilizer such as talc or magnesium stearate. In soft capsules, the active ingredient is dissolved or suspended in a suitable liquid (stabilizer added) such as fatty oil, paraffin oil or polyethylene glycol.

Rectal dosage forms are made by mixing the active ingredient with a suppository base. That is, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alcohols are used as suppository bases, and gelatin suppository capsules composed of active ingredients and base substances may also be used. Suitable substrates are triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, the active ingredient is in a water-soluble state or in a suspension such as an oily injection solution containing a lipophilic solvent of fatty oils (e.g., sesame oil, ethyl oleate or triglycerides such as triglycerides). It is preferred that the active ingredient be present in the presence of a water-soluble injectable suspension, or containing a substance for increasing the viscosity (eg, sodium carboxymethylcellulose, sorbitan and / or dextran) and a stabilizer.

Topical pharmaceutical preparations are creams, pastes, foams, tinctures and solutions containing 0.5% to 20% of the active ingredient. Creams are oil-water emulsions containing at least 50% water. Fatty alcohols are used as oily bases, for example lauryl, cetyl or stearyl alcohols, fatty acids (eg palmitic acid or stearic acid), liquids for solid waxes (eg isopropyl myristate, wool wax or bis) Waxes) and / or hydrocarbons (eg petroleum jelly or paraffin oil). Suitable emulsions are surface-active substances with hydrophilic properties, examples of which are fatty acid esters of polyalcohols or ethylene oxides (eg polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (twins); polyoxyethylene fatty alcohol ethers or esters) Non-ionic emulsions such as) or ionic emulsions such as alkali metal salts of fatty alcohol sulfates (e.g. sodium torylsulfate, sodium cetylsulfate or sodium stearylsulfate), such as cetylalcohol or stearyl Fatty acid alcohols such as alcohols are commonly used. Additives added to the aqueous phase include preservatives, fragrances, and the like, as well as polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycol, which reduce water through distillation.

Ointments are water-oil emulsions with up to 70%, in particular 20-50% water or aqueous solution. The oily layer mainly contains hydroxy compounds which improve hygroscopicity, such as cetyl alcohol or wool wax alcohols, or hydrocarbons containing fatty acid alcohols or esters thereof such as wool wax (eg petroleum jelly paraffin oil and / or light paraffin). do. Emulsions are lipophilic substances such as sorbitan fatty acid esters (such as sorbitan oleate or sorbitan isostearate). Aqueous additives include curbs, preservatives, fragrances and the like of polyalcohols such as glycerol, propylene glycol, sorbitol and / or polyethylene glycol.

Grease ointments are anhydrides and include hydrocarbons as substrates, for example paraffin, petroleum jelly and / or liquid paraffin, natural or synthetic fats (e.g. coconut fatty acid triglycerides, hydrated peanut oil) and or kister oils. Such as hydrogenated oils and fatty acid partial esters of glycerol (eg, glycerol mono- and distearates), and fatty alcohols, and may contain emulsions and additives to increase water absorption.

Pastes are creams and ointments containing aluminum silicate talc to bind the moisture and secretions present and powdered ingredients that adsorb secretions, such as metal oxides such as titanium oxide or zinc oxide.

Foam (foam) is administered from a pressure dispenser and is in the form of an aerosol oil-water emulsion with halogenated hydrocarbons such as chlorofluor-lower alkanes such as dichlorodifluoromethane and dichlorotetrafluoroethane. In the oil phase, paraffin oil, fatty alcohols (eg cetyl alcohol), fatty acid esters (eg isopropyl myristate) and / or other waxes are used. In emulsions, mixtures of hydrophilic emulsions such as polyoxyethylene sorbitan fatty acid esters (Tweens) and mixtures of lipophilic emulsions such as sorbitan fatty acid esters (Spans) are used. In addition, conventional additives such as preservatives are used.

Tinctures and solutions generally contain water-soluble ethanol substrates, including polyalcohols such as glycerol, glycols and / or polyethylene glycols, fatty acid esters with lower polyethylene glycols as substances for reducing water loss and for fat-maintaining, That is, a lipophilic substance dissolved in ethanol and a water-soluble mixture as a substitute for fatty substances taken from the skin, and other auxiliaries as necessary are added.

Topical pharmaceutical compositions are prepared by known methods, for example by dissolving or suspending the active ingredient in a substrate. When processing the active ingredient in solution form, dissolve the active ingredient in either of the two phases before emulsifying.When processing the active ingredient in suspension form, the active ingredient is mixed with a portion of the substrate before the emulsion and the remainder is mixed. Is added to the formulation.

The following examples illustrate the invention and are not intended to limit the invention. All parts and percentages are by weight and the pressure is in millibars (mbar).

Example 1

Preparation of 2- [p- (phenoxy) phenyl] -2- (1H-1,2,4-triazolylmethyl) -4-n-propyl-1,3-dioxolane

10.3 parts of nitrate of 1- (p-phenoxyphenyl) -2- (1,2,4-triazolyl) ethanol, 6.1 parts of 1,2-pentanediol, 6.9 parts of p-toluenesulfonic acid, 1-pentanol 20 Part and 200 parts of xylene are refluxed for 6 days under reflux on a water separator. The reaction mixture was cooled to room temperature and washed twice with 200 ml of diluted sodium hydroxide solution and twice with 200 ml of water. The organic layer is dried over sodium sulphate and filtered. Evaporating the solvent and slowly crystallizing the transcription of the oil phase yielded beige crystals with a melting point of 68.5 ° C-71 ° C.

The following compounds of formula (I) can be prepared in a similar manner to the above. (Unless otherwise noted, mixtures of diastereo isomers have different mixing ratios):

In the following table, symbol A is a diastereo isomer of Form A and B represents a diastereo isomer of Form B.

TABLE 1

Compounds of the following structural formula encompass the following isomers

TABLE 2

Compounds of the following structural formula encompass the following isomers.

TABLE 3

Compounds of the following structural formula encompass the following isomers

TABLE 4

Compounds of the following structural formula encompass the following isomers

TABLE 5

Compounds of the following structural formula encompass the following isomers

TABLE 6

Compounds of the following structural formula encompass the following isomers

TABLE 7

Compounds of the following structural formula encompass the following isomers

TABLE 8

Compounds of the following structural formula encompass the following isomers

TABLE 9

Compounds of the following structural formula encompass the following isomers

TABLE 10

Compounds of the following structural formula encompass the following isomers

Formulation Examples for Agrochemical Compositions Containing the Liquid Active Ingredient of Structural Formula (I) (Percent by Weight).

Example 4

Emulsion concentrates a) b) c)

Compounds in Tables 1-10 25% 40% 50%

Calcium Dodecyl Benzenesulfonate 5% 8% 6%

Castor oil Polyethylene glycol ether (36 moles of ethylene oxide) 5%--

Tributylphenol Polyethylene Glycol Ether (30 mol of ethylene oxide)-12% 4%

Cyclohexane-15% 20%

Xylene Mixture 65% 25% 20%

Dilution of the concentrate with water gives an emulsion with the desired concentration.

Example 5

Solutions a) b) c) d)

Compounds of Tables 1-10 80% 10% 5% 95%

Ethylene Glycol Monomethyl Ether 20%---

Polyethylene Glycol 400-70%--

N-methyl-2-pyrrolidone-20%--

Epoxidized Coconut Oil--1% 5%

Lignin (boiling range 160-190 ° C)--94%-

The solution is suitable for use in the form of microdrops.

Example 6

Mouth a) b)

5% 10% of compounds in Tables 1-10

Kaolin 94%-

Highly dispersed silicic acid 1%-

Ethanol Zite-90%

The active ingredient is dissolved in methylene chloride and the solution is sprayed onto the carrier and the solvent is subsequently evaporated off in vacuo.

Example 7

Dust a) b)

Compounds 2% 5% of Tables 1-10

Highly dispersed silicic acid 1% 5%

Talc 97%-

Kaolin-90%

Ready-to-use dusts are prepared by mixing the active ingredient with a carrier. Formulation Examples for Agrochemical Compositions Containing Solid Active Ingredient of Structural Formula I (Percent by Weight)

Example 8

Wet Powder a) b) c)

Compounds in Tables 1-10 25% 50% 75%

Sodium ligno sulfonate 5% 5%-

Sodium Lauryl Sulfate 3%-5%

Sodium Disobutylnaphthalene Sulfonate-5% 10%

Octylphenol Polyethylene glycol ether (ethylene oxide 7-8 mol)-2%-

Highly dispersed silicic acid 5% 10% 10%

Kaolin 62% 27%-

After the active ingredient is uniformly mixed with the adjuvant, the mixture is ground throughout a suitable grinding machine to obtain a wet powder which is diluted with water to give a suspension of the desired concentration.

Example 9

Fluid concentrate

10% Cyclohexanone 20% Compounds of Tables 1-10

Octylphenol polyethylene glycol ether (ethylene xylene mixture 50%

Oxide 4-5 mole) 3% cotonat oil 10%

Calcium dodecylbenzenesulfonate 3%

Castor oil polyglycol ether (ethylene

36 mol of oxide) 4%

Dilution of the concentrate with water gives an emulsion with the required concentration.

Example 10

Dust a) b)

Compounds 5% 8% of Tables 1-10

Talc 95%-

Kaolin-92%

Dust for immediate use is prepared by mixing the carrier with the active ingredient and grinding the mixture in a suitable mill.

Example 11

Extrusion

1% of compound 10% carboxymethyl cellulose of Tables 1-10

Sodium lignosulfonate 2% kaolin 87%

The active ingredient is mixed and ground with the adjuvant and the mixture is subsequently wetted with water. The mixture is extruded and dried in an air steam.

Example 12

Coated granules

Compounds 3% kaolin 94% of Tables 1-10

Polyethylene Glycol 200 3%

The finely ground active ingredient is uniformly applied to the kaolin wetted with polyethylene glycol in a mixer. Dust-free coated granules are prepared according to the present method.

Example 13

Suspension concentrate

Compounds 40% Carboxymethylcellulose 1% of Tables 1-10

Ethylene Glycol 10% 37% Aqueous Formaldehyde Solution 0.2%

Nonylphenol Polyethyleneglycol 75% Silicone oil in aqueous emulsion 0.8%

Ether (15 mol ethylene side) 6% water 32%

Sodium Renosulfonate 10%

The finely ground active ingredient is mixed with the adjuvant to obtain a suspension concentrate and then the suspension of the concentrate is diluted with water as desired.

Formulation Examples for Pharmaceutical Manufacturing

Example 14

Ointment

Ointment containing 5% 2- [p- (4-chlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-dioxolane is prepared as follows.

Furtherance

Active ingredient 5.0% Biswax 5.0%

White Petroleum Jelly 45.0% Sorbitan Sesquioleate 5.0%

Liquid paraffin 19.6% p-hydroxy benzoate 0.2%

Cetyl alcohol 5.0% 100.0% by adding demineralized water

Melt fat and emulsion together. The preservative is dissolved in water and the solution is emulsified into a melt of fat at elevated temperatures. After cooling, a suspension of the active ingredient suspended in fat melt is combined with the emulsion.

Example 15

cream

A cream containing 10% 2- [p- (chlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane is prepared by:

Furtherance

Active Ingredient 10.0% Polysorbate 6-60 3.5%

Isopropyl palmitate 8.0% 1, 2-propylene glycol 20.0%

Cetyl palmitate 1.5% acrylic acid polymer 0.5%

Silicone Oil 100 0.5% Triethanol Amine 0.7%

100.0% by adding sorbitan monostearate 3.0% demineralized water

The acrylic acid polymer is suspended in a mixture of demineralized water and 1,2-propylene glycol. Triethanol amine is stirred to obtain mucus.

The mixture of isopropyl palmitate, cetyl palmitate, silicone oil, sorbitan monostearate and polysorbate is heated to 75 ° C. and then stirred with mucus, which is heated to 75 ° C. After cooling to room temperature, the cream base is used to prepare a concentrate with the active ingredient. The concentrate is homogenized by pH using a continuous homogenizer and then added dropwise to the substrate.

A cream containing 5% 2- [p- (chlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl-1,3-dioxolane is prepared as follows:

Furtherance

Active Ingredient 5.0% Glycerol Stearate pH 4.0%

Cetyl Palmitate pH 2.0% Setomacroglobin 1000 1.0%

Cetyl Alcohol pH 2.0% Microcrystalline Cellulose 0.5%

1, 2-flophylene glycol (distilled) 20.0% of saturated medium fatty acid

Triglycerides mixture 100.0% by adding 5.0% demineralized water

Stearic acid 3.0%

Cetyl alcohol, cetyl palmitate, triglyceride mixtures, stearic acid and glycerol stearate are melted together. Microcrystalline cellulose is dispersed in water. Setomacrogol is dissolved in the remaining water and propylene glycol and mucus are mixed together. The fatty layer is stirred into the aqueous layer and the mixture is stirred and cooled. Finally, the active ingredient is ground with the above material and then mixed with the remaining cream.

Example 16

Hydrogel

A transparent hydrogel containing 5% 2- [p- (chlorophenoxy) -phenyl] -2- (1-imidazolylmethyl) -4-ethyldioxolane was prepared by the following method.

Furtherance

Active ingredient 5% hydroxypropyl methyl cellulose 2%

100% by adding 10-20% propylene glycol

Isopropanol 20%

Hydroxypropyl methyl cellulose is expanded in water. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol.

The active ingredient solution is mixed with the expanded cellulose derivatives and flavoring (0.1%) is added if necessary.

Example 17

Bubble spray

A foaming spray containing 1% 2- [p- (chlorophenoxy) phenyl] -2- (1-imidazolylmethyl) -4-ethyl dioxolane is prepared as follows.

Furtherance

Active ingredient 1.00% 1, 2-propylene glycol pH 5.00%

Cetyl Alcohol pH 1.70% Methyl Paraben 0.18%

Liquid Paraffin (Viscous) 1.00% Propyl Paraben 0.02%

Isopropyl Myristate 2.00% Chemodem 314 0.10%

Setomacroglogue 2.40% 100.00% by adding demineralized water

Sormitan Monostearate 1.50%

Cetyl alcohol, liquid paraffin, isopropyl myristate, cetomacroglo and sorbitan stearate are fused together. Methyl and propyl parabens are dissolved in hot water. Mix the melt and the solution together. After the suspension of the active ingredient suspended in propylene glycol is mixed with the substrate, chemoderm is added and water to the composition is added to the final weight.

Filler

20 ml of the composition is filled into an aluminum dispenser. Attach the dispenser with a pressure cap and fill the back gas under pressure.

Example 18

capsule

Gelatin capsules containing 200 mg of [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -1,3-dioxane as active ingredients Are manufactured:

Composition (1000 Capsules)

100 g of active ingredients

100 g of lactose (polished)

Mix the active ingredient and lactose (micronized) well. The resulting powder is sieved and packaged in 0.2 g gelatin capsules.

Example 19

refine

Tablets containing 25 mg of 2- [p- (phenoxy) phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -1,3-dioxane as active ingredients are described below. Are manufactured accordingly.

Composition (1000 tablets)

Active ingredient 25.0 g Talc 5.0 g

Lactose 100.7g Magnesium Stearate 1.8g

7.5g corn starch demineralized water slightly

Polyethylene glycol 6000 5.0 g

Produce

All solid components are passed through a 0.6 mm mesh sieve. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed together. The remaining half of the starch is suspended in 40 ml of water, the suspension is added to a boiling solution of polyethylene glycol dissolved in 1000 ml of water, and the mixture is granulated (granulated) and water is added as necessary. The granules are dried overnight at 35 ° C., then passed through a 1.2 mm sieve and pressed into tablets having a diameter of 6 mm.

Tablets containing 75 mg of 2- [p- (phenoxy) -phenyl] -2- [1- (1H-1,2,4-triazolyl) methyl] -1,3-dioxane as active ingredients are Is manufactured according to:

Composition (1000 tablets)

Active ingredient 75.0 g Talc 5.0 g

Lactose 100.0g Magnesium Stearate 1.8g

7.5g corn starch demineralized water slightly

Polyethylene glycol 6000 5.0 g

Produce

All solid components are passed through a sieve having a mesh size of 0.6 mm. Then, about half of the active ingredient, lactose, talc, magnesium stearate and starch are mixed together. The other half of starch is suspended in 40 ml of water, and the suspension is added to a boiling solution of polyethylene glycol dissolved in 100 ml of water and the mixture is granulated (granulated). If necessary, add water. The granules are dried overnight at 35 ° C., passed through a 1.2 mm sieve and pressed into 6 mm diameter tablets.

Pharmaceutical formulations containing another compound of Tables 1-10 may be prepared according to methods analogous to the above.

Biological Example

Example 20

Action on Fuchsia graminis on wheat

a) residual-protective action;

The crop is treated with a spray mixture prepared from the wet powder formulation of the active ingredient (0.06%) 6 days after sowing. After 24 hours, the treated crops are infected with the fungus Uredospuo suspension. Infected crops are incubated at 95-100% relative humidity and 20 ° C. for 48 hours and then left in a 22 ° C. green house. Deployment assessments are made 12 days after infection.

b) phylogeny

The crop is treated with a spray mixture prepared from the wet powder formulation of the active ingredient (0.06% based on soil volume) 5 days after sowing. After 48 hours the treated crops are infected with the fungus uredospoo suspension. The crops are incubated for 48 hours at 95-100% relative humidity and 20 ° C. and left in a green house at 22 ° C. Evaluation is done 12 days after infection.

The compounds of Tables 1 to 10 are very effective against Puccinia fungi. Puccinia infection is 100% on untreated infection control crops. Compound 1.9, 1.17, 1.24, 1.26, 2.17, 3.1, 3.2, 3.6-3.8, 3.12, 3.26, 3.51, 3.52, 3.54, 3.55, 3.70, 3.75, 3.78, 3.83, 3.85, 3.86, 3.127, 3.133, 3.155, 3.156 , 3.160, 3.162, 3.164, 3.168, 3.171, 3.172, 3.176, 3.177, 3.193, 3.212, 3.213, 3.220, 3.226, 3.227, 3.3.231-3.234, 3.263, 3.267, 3.274, 3.279, 3.287, 3.292, 3.311, 3.314 , 3.340, 3.348, 3.373, 3.376, 3.384, 3.386, 4.2, 4.15, 4.23, 4.50, 4.55, 4.57, 4.66, 4.70, 4.77, 4.78, 4.81, 4.89-4.94, 4.113, 4.116, 4.136, 4.138-4.147, 5.13 Residual protective treatments treated with, 5.14, 5.36, 5.40, 5.70, 5.71, 5.76, 5.78, 5.105, 5.113, 5.117, 6.8, 6.93, 7.7, 7.33 and 8.66 inhibit fungal onset to 0-5%. In addition, compounds 6.8 and 6.82 have a total systemic action (0% attack) even when diluted to a concentration of 0.006%.

Example 21

Actions on Sercos Mora arachidikora in Peanut Crops

Peanut crops 10-15 cm in height are sprayed with a spray mixture prepared from a wet powder formulation of the active compound (concentration 0.02%) and infected with a fungal condydia suspension after 48 hours. Infected crops are incubated at 21 ° C. and high humidity for 72 hours and then left in the green house until leaf spots occur. Assessment of fungal activity is made 12 days after infection, where the number and size of the spots is assessed.

Crops treated with the compounds of Tables 1-10 compared to untreated infected controls (number and spot size = 100%) show a greatly reduced invention by Sercosphora. For example, compounds 1.1, 1.4, 1.9, 1.14, 1.17, 1.24-1.27, 2.17, 3.1, 3.2, 3.6, 3.7, 3.11, 3.51, 3.52, 3.54, 3.55, 3.57, 3.78, 3.85, 3.86, 3.127, 3.133 , 3.155, 3.156, 3.162, 3.171, 3.172, 3.176, 3.177, 3.212, 3.213, 3.220, 3.221, 3.226, 3.231, 3.232, 3.233, 3.234, 3.267, 3.292, 3.314, 3.348, 3.384-3.388, 4.15, 4.23, 4.50 , 4.57, 4.59, 4.66, 4.89-4.94, 4.113, 4.116, 4.136-4.148, 5.13, 5.14, 5.36, 5.40, 5.70, 5.71, 5.73, 5.75-5.78, 5.105-5.110, 5.113-5.118, 6.1, 6.8, 6.93 , 6.94, 7.33, 7.34 and 8.72 inhibit the formation of nearly complete spots in the test.

Example 22

Action on barley Eritreci Graminis

a) residue-protection action;

A barley crop of 8 cm in height is sprayed with a spray mixture (0.02%) prepared from the active ingredient prepared as a wet powder. Treated crops are infected with fungal condydia after 3-4 hours. Infected barley crops are left in a green house at about 22 ° C. Fungal outbreaks are assessed after 10 days.

b) lineage-action

A barley crop of 8 cm in height is treated with a spray mixture (0.006% based on soil volume) prepared from the active ingredient prepared as a wet powder.

Care should be taken that the spray mixture does not come into contact with a portion of the crop on the soil. Treated fabrics are infected after 48 hours with fungi Kondia suspension. Infected barley crops are left in the greenhouse at 22 ° C and fungal infections are assessed after 10 days.

The compound of formula (I) has a good residual protective effect against erythrophage bacteria. Erysipe infection of untreated infected control crops is 100%. Compound 1.1, 1.4, 1.9, 1.14, 1.17, 1.23-1.27, 2.17, 3.1, 3.2, 3.6-3.8, 3.11, 3.12, 3.26, 3.51, 3.52, 3.54, 3.55, 3.70, 3.75, 3.78, 3.85, 3.86, 3.103 , 3.127, 3.133, 3.156, 3.160, 3.162, 3.164, 3.168, 3.171, 3.172, 3.174, 3.176, 3.177, 3.193, 3.212, 3.213, 3.220, 3.221, 3.226, 3.227, 3.231, 3.232-3.234, 3.263, 3.267, 3.274 , 3.279, 3.287, 3.292, 3.311, 3.314, 3.340, 3.348, 3.378, 3.383-3.388, 4.2, 4.15, 4.23, 4.50, 4.57, 4.59, 4.66, 4.77, 4.78, 4.81, 4.89-4.94, 4.113, 4.116, 4.137 , 4.139, 4.140, 4.141, 4.146, 4.148, 4.150, 5.13, 5.14, 5.36, 5.40, 5.70, 5.71, 5.73, 5.75-5.78, 5.106, 5.114, 6.1, 6.8, 6.17, 6.79, 6.80, 6.82, 6.93, 7.3 , 7.7, 7.21, 7.33, 7.34, 8.66, 8.72 and 10.7 inhibit fungal outbreaks by less than 5%. Compounds 4.50 and 6.82 are also effective in soil treatment (dilation) when diluted to a concentration of 0.006%.

Example 23

Residual-protective action against apple germination on Ventria in Aquarius

Apple grafts of 10-20 cm size are sprayed with a spray mixture prepared from a wet powder formulation of the active ingredient (0.06%). After 24 hours the treated crops are infected with a fungi suspension of Kondia. Crops are incubated for 5 days at 90-100% relative humidity and left for 10 days in a green house at 20 ° C-24 ° C. Skin infections are assessed 15 days after infection. Compound 1.4, 1.9, 1.17, 1.24, 1.26, 2.17, 3.1, 3.6, 3.7, 3.11, 3.52, 3.55, 3.85, 3.86, 3.156, 3.160, 3.164, 3.172, 3.176, 3.177, 3.213, 3.221, 3.233, 3.314, 3.383 -3.387, 4.15, 4.23, 4.50, 4.59, 4.66, 4.78, 4.81, 4.89, 4.90-4.94, 4.113, 4.116, 4.137-4.141, 4.146-4.150, 5.13, 5.14, 5.36, 5.40, 5.70, 5.73, 5.75, 5.76 , 5.106-5.110, 5.112, 5.114, 5.118, 6.1, 6.8, 6.93 and 10.7 inhibit fungal infections by less than 10%.

Venturi infection was 100% for untreated infected shoots.

Example 24

Soy's action on Botrytis Syria

a) residual-protective action;

A 10 cm sized soybean crop is sprayed with a spray mixture (0.002%) prepared from the active ingredient prepared as a wet powder. After 48 hours, the treated crops are infected with fungi suspension of Kondia. Infected crops are incubated for 3 days at 95-100% relative humidity and 21 ° C. and evaluated for fungal invention. The compounds of Tables 1 to 10 very strongly inhibit fungal infections in many cases.

At concentrations of 0.002%, compounds 1.1, 1.4, 1.9, 1.17, 3.6, 3.7, 3.12, 3.51, 3.55, 3.86, 3.226, 3.231, 3.267, 3.311, 4.15, 4.50, 4.59, 4.66, 4.78, 4.90 to 4.93, 4.113 , 5.13, 5.36, 5.40, 5.70, 5.71, 5.73, 5.75, 5.76, 5.78, 6.1, 6.8, 7.3, 7.33, and 8.72 were very effective (0-5% onset). Untreated, infected soybean crops had 100% infection.

Claims (1)

A method for producing a compound of formula (I), an acid addition salt thereof, or a metal complex thereof, wherein the carbonyl group is converted into a group of formula (V) in the compound of formula (IV).

In the above structure, Y is

-N =, R _a and R _b are each hydrogen, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy; Ar is naphthyl or phenyl substituted by at most three substituents selected from halogen, C ₁ -C ₃ alkyl, methoxy or CF ₃ rotor; U and V are each C ₁ -C ₃ alkyl, or together form one of the following alkylene bridges

R ₁ and R ₂ are each hydrogen, a C ₁ -C ₄ alkyl, or —CH ₂ —OR ₇ group; R ₇ is hydrogen, C ₁ -C ₄ alkyl, phenyl, halophenyl, benzyl, habenzyl, C ₃ -C ₄ alkenyl or C ₁ -C ₂ alkyl substituted by C ₁ -C ₂ alkoxy; R ₃ , R ₄ , R ₅ , R ₂₂ , R ₂₃ and R ₂₄ are each hydrogen or C ₁ -C ₃ alkyl, and the total carbon number of R ₃ , R ₄ , R ₅ , R ₂₂ , R ₂₃ and R ₂₄ is No more than 6.