DD296490A5 - PROCESS FOR THE PREPARATION OF NEW AMID DERIVATIVES - Google Patents

Abstract

The invention relates to a process for preparing novel amide derivatives of the following general formula wherein the substituents have the meaning given in the description. The new amide derivatives can be used as active ingredients in fungicides in agriculture and horticulture. Formula (IV) {Amide Derivatives; Production method; agents; fungicides; Agriculture; Horticulture}

Description

(II)

wherein X, Y, R ¹ and R ^{2 are} as defined above, or their reactive derivative with an aminoacetonitrile of the following general formula (III),

(III)

wherein R ^{3 is} as defined above, or a salt thereof.

Field of application of the invention

The invention relates to a process for the preparation of an amide derivative of the following general formula (IV)

_1

: -R ²

Γ Π ν '-ί

(IV)

wherein one of X and Y represents a sulfur atom and the other represents a carbon atom, each of R ¹ and R ^{2 represents} a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halomethyl group or a phenyl group, and R ³ an alkenyl group having 2 to 6 carbon atoms, a haloalkenyl group having 2 to 4 carbon atoms, a furyl group, a thienyl group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkynyloxy group having 3 to 5 carbon atoms, a pyrazolyl group or a represents unsubstituted or halogen-substituted phenyl group.

Characteristic of the known state of the art

Heretofore compounds having different chemical structures have been used as fungicides for agriculture and horticulture and contributed greatly to the control of plant diseases and, consequently, to the development of agriculture. However, these conventional fungicidal chemicals proved insufficient in their controlling activity and safety. For example, some dithiocarbamate fungicides, such as zinc ethylene

bis (dithiocarbamate) / zineb /, manganese ethylene bis (dithiocarbamate) / maneb /, a complex of manganese ethylene bis (dithiocarbamate) and zinc ethylene bis-dithiocarbamate) / mancozeb / and dizink bis (dimethyldithiocarbamate) ethylenebis (diethiocarbamate) / Polycarbamates /, N-haloalkylthioimide fungicides such as N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide / captan /, N-i'.T ^ '^' - tetrachloroethylthio ^ -cyclohexane-i-dicarboximide / captofol / and N-trichloromethylthiophthalimide / folpet /, inorganic copper fungicides such as cuprisulfate, basic cuprisulfate, basic cupric chloride and cupric hydroxide, tetrachloroisophthalonitrile / TPI \ l /, N- (dichlorofluoromethylthio) -N ', N-dimethyl-N-phenylsulfamide / dichlofluanide / and S- Chloro-N-β-chloro-S-trifluoromethyl-pyridyl-O.-e-dinitro-trifluoromethylaniline / fluazinam /, an excellent controlling activity for diseases in plants such as fruit trees and vegetables, and are widely used as agricultural and horticultural fungicides used. However, these chemicals are predominantly preventive and are not expected to have a healing effect. Therefore, they have the serious shortcoming that when observing the occurrence of plant diseases, one can not expect sufficient efficacy from these chemicals. Considering, in a given situation, the use of chemicals to control plant diseases, these chemicals are sprayed more or less after the onset of symptoms of the plant disease and the above chemicals are difficult for complete control of the diseases. Furthermore, the concentrations of these chemicals in which they have a controlling effect are very high so that they are safe to use with difficulty, and some of these chemicals have a non-negligible toxicity to fish.

To remedy this deficiency, extensive research has been carried out on new controlling agents. For example, acylalanine fungicides such as N- (2,6-dimethylphenyl) -N- (2'-methoxyacetyl) alanine methyl ester / methalaxyl /, N- (2,6-dimethylphenyl) -N- (2-furoyl) - alanine methyl ester / furalaxyl /, N- (2,6-dimethylphenyl) -N- (phenylacetyl-alanine methyl ester / benalaxyl /, 2-chloro-N- (2,6-dimethylphenyl) -N- (tetrahydro-2-) oxo-3-furanyl) -acetamide / ofurace / and 2-methoxy-N- (2,6-dimethylphenyl) -N- (2-oxo-1,3-oxazolidin-3-yl) -acetamide / oxadixyl, as Agents for the control of plant diseases caused by Oomycetes, which also have excellent curative properties and have been put into practical use world-wide, have already been stated to be resistant to these chemicals, and their control effect consequently decreased.

Numerous active benzylamide compounds have been found and used as herbicides or fungicides. For example, known substituted benzamide derivatives include ethyl N-benzoyl-N- (3,4-dichlorophenyl) -2-aminopropionate / benzoylprop-ethyl / as a herbicide and N- (3-isopropoxyphenyl) -2-methylbenzamide / mepronil / as a fungicide. BP-2094786, BP-2095237 and BP 2107308 disclose a herbicide and a fungicide comprising a substituted benzylamide derivative having a 4-pyridylcarbonyl, 2-furylcarbonyl, 2-thienylcarbonyl or 2-benzofurylcarbonyl group, however, faces its phytotoxicity Crops are a problem.

Object of the invention

The aim of the invention is. To provide a process for the preparation of a compound which is free from the aforementioned shortcomings of the prior art and has excellent properties as a fungicide for agriculture and horticulture. In particular, the invention relates to a simple process for producing a compound in high yield, which has a preventive and curative effect on a wide range of plant diseases, such as diseases of fruit trees and vegetables, an excellent control effect against resistant fungi, a wide range of applications and a has long residual activity, no phytotoxicity to crops and shows very low toxicity to warm-blooded animals and fish.

Explanation of the essence of the invention

It has been found that amide derivatives having a thiazole or isothiazole ring have a biological activity which was by no means predictable due to the compounds exemplified above and an excellent control over a wide range of plant diseases, and in particular that these amide derivatives are both preventive and curative Have effect in controlling various crop diseases such as late blight and downy mildew

 The amide derivatives prepared by the processes of the invention have the following general formula (IV)

N / I ^ xT CK

/ K Λ. ! '(IV)

\ / ί ti -. .-, - ITI, - ^! i

ti 'Il "Ovji'iiiL.1 I

wherein one of X and Y represents a sulfur atom and the other represents a carbon atom, each of R ¹ and R ^{2 represents} a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halomethyl group or a phenyl group, and R ^{3 represents} a Alkenyl group having 2 to 6 carbon atoms, a haloalkenyl group having 2 to 4 carbon atoms, a furyl group, a thienyl group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkynyloxy group having 3 to 5 carbon atoms, an alkynylthio group having 3 to 5 carbon atoms, a pyrazolyl group or an unsubstituted or halogen-substituted phenyl group. In the amide derivatives of the general formula (IV), examples of the alkyl group of R ¹ and R ^{2 are} methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert. Butyl, n-pentyl and n-hexyl groups. Examples of the halomethyl group are

Chloromethyl and trifluoromethyl groups. The alkenyl group of R ³ is, for example, a vinyl, allyl, propen-1-yl, 2-methyl-propene-1-yl, 1-methyl-propen-1-yl, 1,2-dimethyl-propene-1-yl , 2-ethyl-propene-1-yl or 2-n-propyl-propene-1-yl group. The haloalkenyl group is e.g. a 2-chloroethenyl, 2-chloropropen-1-yl or i-methyl-2-chloropropen-i-yl group. Examples of the alkoxy group are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy groups. Examples of the alkylthio group are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio groups. Examples of the alkinyloxy group are propyn-2-yloxy, S-methylpropy ^ -yloxy and 3-ethylprop-2-yloxy groups. Examples of the alkynylthio groups are propin-2-ylthio, 3-methylprop-2-yl-thio, 3-ethyl-2-propyl-2-yl-thio groups. The halogen atom may be, for. B. to act fluorine, chlorine, bromine or iodine

 The compounds of general formula (IV) are new

 The present invention relates to a process for the preparation of an amide derivative of the general formula (IV)

(IV)

L> Li ^<- lni _>! "; \

wherein one of X and Y represents a sulfur atom and the other represents a carbon atom, each of R ¹ and R ^{2 represents} a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halomethyl group or a phenyl group, and R ³ for an alkenyl group having 2 to 6 carbon atoms, a haloalkenyl group having 2 to 4 carbon atoms, a furyl group, a thienyl group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkynyloxy group having 3 to 5 carbon atoms, an alkynylthio group having 3 to 5 carbon atoms, a pyrazolyl group or an unsubstituted or halogen-substituted phenyl group, which is the reaction of a heterocyclic, 5-membered carboxylic acid of the general formula (II)

(II)

wherein X, Y, R ¹ and R ² are as defined above, or a reactive derivative thereof with an aminoacetonitrile represented by the following general formula (III)

(III)

wherein R ^{3 is} as defined above, or with its salt.

The processes of the invention for the preparation of the amide derivatives are represented by the following Reaction Schemes (a) + (b).

KsaktionsDchciüa \ z

Y "" \

ι Ι, - Γ \ ^ -; ι

r, J

(II) or vata

reive deri-

(IV)

In this scheme, the amide derivatives of the general formula (IV) can be prepared by reacting the heterocyclic, 5-membered carboxylic acid of the general formula (II) or its reactive derivative (such as an acid chloride or an acid anhydride) with the aminoacetonitrile of the general formula (III) or whose salt is converted. Various methods are available for carrying out the reaction according to scheme (a) and are described below with reference to the following reaction schemes (a) -1 to (a) -5.

Reaction scheme (a) -1

Process comprising the conversion of the carboxylic acid to a chloride and its reaction with aminoacetonitrile:

SOCl.

OCl

HN-CN (III)

(IV)

Usually, the carboxylic acid derivative (II) is heated in an excess of thionyl chloride. After the reaction, excess thionyl chloride is evaporated off to obtain the acid chloride. Sometimes the reaction in thionyl chloride does not go well. In such a case, the carboxylic acid (II) is treated with an almost weight equivalent amount of phosphorus pentachloride in an inert solvent. This makes the reaction smooth. After the reaction, low boiling materials are evaporated to give the acid chloride. The resulting acid chloride is reacted in an inert solvent with the aminoacetonitrile (III) or its salt in the presence of a weight-equivalent amount or a slight excess of a base to easily give the amide derivative (IV). If the salt of the aminoacetonitrile is used, the base is additionally fed in an amount which is necessary for the neutralization of the salt. The inert solvent is inert to the chloride and the aminoacetonitrile. Specific examples are ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene and ligroin, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, esters such as ethyl acetate and ethyl propionate, and aprotic polar solvents such as Ν , Ν-dimethylformamide, dimethylsulfoxide and 1,3-dimethylimidazolidinone. Pyridine can be used as the base and solvent. Examples of the base may be organic bases such as triethylamine, dimethylaniline, pyridine and DBU, and inorganic bases such as ammonia, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide and ammonium carbonate, although these examples are not restrictive. It is undesirable to carry out this reaction at too high a temperature because the thermal stability of the aminoacetonitrile derivative intermediate (III) is low. Preferred reaction temperatures are 10 to 50 ^° C. After the dropwise addition of the aminoacetonitrile derivative (III), the mixture is continuously stirred at room temperature to complete the reaction. The reaction time, which varies depending on the reaction temperature, is usually 0.5 to 4 hours. After the reaction, the crude reaction product is obtained by a conventional method. The resulting desired amide derivative can be easily isolated and purified by a conventional method such as recrystallization or column chromatography.

Reaction scheme (a) -2

A process comprising reacting an anhydride of the carboxylic acid with the aminoacetonitrile.

(II)

HN-CN (III)

CN

ONHCH

CN ^R

(IV)

The amide derivative (IV) can be obtained by carrying out the same reaction as in Reaction Scheme (a) -1 except that the acid anhydride is used in place of the acid chloride.

Reaction scheme (a) -3

A process comprising reacting a mixed acid anhydride of the carboxylic acid with the aminoacetonitrile.

^{: 0} 2 ^H

ClCO ₂ R

N (II)

X / ^R ~ 0

-C-O-C-OR '

CN

HN-CN

(III)

CN * "3

(IV)

(In the above scheme, R ^{4 is} a lower alkyl group.)

The carboxylic acid derivative (II) is dissolved in an organic solvent, and in the presence of a base, a chloroformate ester is added to form a mixed acid anhydride. Addition of the aminoacetonitrile (III) to the mixed acid anhydride gives the amide derivative (IV). The organic solvent and the base may be the same as in the reaction scheme (a) -1. The reaction temperature is -50 to 20 ° C, preferably -10 to 10 ⁰ C, for the reaction of the carboxylic acid with the chloroformate, and 0 to 50 ° C, preferably 10 to 30 "C, for the reaction of the mixed anhydride with the aminoacetonitrile. The Isolation and purification of the final product can be easily done according to a conventional method, as in the case of Reaction Scheme (a) -1.

Reaction scheme (a) -4

Process comprising the use of carbonyldiimidazole (CDI).

N ^:

(CDI)

^{: 0} 2 ^H

(II)

O O

-C-O-C-N

CN

(III)

(IV)

-6- 296 493

The carboxylic acid derivative (II) is dissolved in an organic solvent and carbonyldiimidazole is added. This is followed at 0 to 50 ° C, preferably 0 to 30 ⁰ C, the addition of aminoacetonitrile (III) to give the amide derivative (IV). The organic solvent used may be the same as that used in the reaction of Reaction Scheme (a) -1. The isolation and purification of the final product may be readily accomplished in a conventional manner in the same manner as described for the reaction in Reaction Scheme (a) -1. _r

Reaction scheme (a) -5

Process comprising the use of dicyclohexylcarbodiimide (DCC).

K (II)

^{: 0} 2 ^H

Q-N = C =

(DCC)

CN

R-

(III)

(IV)

.CN R ³

The carboxylic acid derivative (II) is dissolved in an organic solvent and dicyclohexylcarbodiimide is added to the solution. While cooling the solution with ice-water, the aminoacetonitrile (III) is added to obtain the amide derivative. The organic solvent used in this reaction may be the same as those exemplified in the reaction scheme (a) -1. The isolation and purification of the final product can be done easily by a conventional method.

In addition to the reactions shown in Reaction Schemes (a) -1 to (a) -5, methods for the preparation of the arhid derivatives of the invention can be used as commonly used in the field of peptide synthesis. When R ³ in the general formula (IV) is an alkoxy, alkylthio, alkynyloxy, alkynylthio or pyrazolyl group, the amide derivative (IV) can be prepared by the following process (b).

Γίώί., <Ti OHS S C Γ: 3ü .;

(B)

or οι /. unr. r. toy I-, accta ~ t sib R ~

Luburioa- \

, V ^A "

/'.,-. i . i'Utir- I Ί

ύ r

(IV

; <'(VII)

Tui trtii

Y (

An N-cyanomethylcarboxyamide (V) corresponding to the formula (IV) in which R ^{3 is} a hydrogen atom is used as a synthesis; Intermediate for a compound of general formula (IV) in which R ^{3 is} an alkoxy, alkylthio, alkynyloxy, alkynylthio ^; or pyrazolyl group, very important.

Treatment of the N-cyanomethylcarboxyamide (V) with a halogenating agent in a suitable solvent gives a halogenated intermediate (VI). Bromine or N-bromosuccinimide can be used as halogenating agent. Examples of solvents are aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,4-dichloroethane, and aliphatic carboxylic acid esters such as methyl acetate, ethyl acetate, isopropyl acetate and ethyl propionate. The reaction temperature is 20 to 80 ° C, preferably 30 to 50 ⁰ C. This reaction may be carried out in an inert gas atmosphere. Since the halogenation intermediate (VI) is unstable, it is immediately reacted with HR ³ (VII). This reaction takes place in the presence of an acid acceptor. Examples of the acid acceptor are tertiary amines such as triethylamine and dimethylaniline, although they are not limitative. It is desirable; that this reaction is carried out in a solvent or diluent. It is desirable to avoid high temperatures in carrying out this reaction because the thermal stability of the intermediate is low. Desirably, it is done under cooling because it is exothermic. The desired amide derivative (IV) can be purified in a conventional manner by recrystallization, column chromatography, etc.

The thioamide derivative (VIII) can be obtained by reacting the compound (IV) with gaseous hydrogen sulfide in the presence of a catalytically effective amount of a tertiary amine in an inert solvent, e.g. Aliphatic, halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,4-dichloroethane, or aliphatic carboxylic esters, such as methyl acetate, ethyl acetate, isopropyl acetate and ethyl propionate. The isolation and purification of the desired product can be easily carried out in a conventional manner by recrystallization, column chromatography, etc.

Methods of synthesizing the heterocyclic 5-membered carboxylic acid (II) used as a starting material in the invention will be described below with reference to citations.

(1) Thiazo1-4-carboxylic acids (Journal of Chemical Society, 1946, page 87) s o

+ BrCH ₂ C-CO ₂ C ₂ H ₅

24 h reflux in benzene

Kaoh

CO ₂ H

(2) Thiazole-5-carboxylic acids (Chemical Abstracts, Volume 40, page 4056)

+ R ² -C-CH-CO ₂ C ₂ H ₅

shark

R "

NaOH _s

This is the so-called Hantzsch reaction.

(3) Isothiazolecarboxylic acids (Journal of Chemical Society, 1959, page 3061)

1 Sandmeyer-] _

^R \ reaction ^R \

^V S NH.

br

R ¹ R ¹

CuCN _v ^ _r _ NaOH _N ^

(4) 2-Halothiazole-5-carboxylic acids (Journal of Heterocyclic Chemistry, Volume 22, page 1621, 1985)

,? SOCl S

RC-CH ₂ CO ₂ C ₂ H ₅ ± - ^ R ₁ -C-CH ₂ CO ₂ C ₂ H ₅

ci

NH-C-NH- ^N - ^ /

J 1 1 , ™ ₂ \

j CO ₂ C ₂ H

J (HNO + CuCl ₉ ) or

^ + Cu ₇ Cl) or (HNO ₂ + Naj)

N < S T 1 R 2 C ₂ H N - ^ v. Hal- < _s CO X R ¹ 2 H Hal- CO

The aminoacetonitrile (III) can be easily obtained by the so-called Strecker reaction as shown below.

Λ - L. Γι ¹ J 7 ''^{; j} ~ '-> ⁿ ·

-7

(IX) (X) (111)

(In the above scheme, Hai means a halogen atom.)

Specifically, it can be obtained by reacting an aldehyde of the general formula (IX) with hydrogen cyanide ([X], M = H) or an alkali metal cyanide ([X], M = alkali metal) and ammonia or ammonium chloride in water or in a two-layer, consisting of water and an organic solvent system. The order of addition of the aldehyde (IX), the cyanide (X) and the ammonia or ammonium chloride is arbitrary. In any case, this reaction proceeds more efficiently in the presence of a phase transfer catalyst. The resulting aminoacetonitrile is desirably immediately subjected to the next step because it is unstable. However, when converted to a mineral acid salt, it becomes a stable solid and can be stored for a long period of time.

The amide derivatives according to the invention of the following general formula (IV)

"1, 2

/ (IV)

Yi

wherein one of X and Y represents a sulfur atom and the other represents a carbon atom, each of R ¹ and R ^{2 represents} a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halomethyl group or a phenyl group, and R ^{3 represents} a Alkenyl group having 2 to 6 carbon atoms, a haloalkenyl group having 2 to 4 carbon atoms, a furyl group, a thienyl group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkynyloxy group having 3 to 5 carbon atoms, an alkynylthio group having 3 to 5 carbon atoms, a pyrazolyl group or an unsubstituted or halogen-substituted phenyl group can be used as an active ingredient in fungicidal agents.

-9- 296 49Of

If the compound is used as a fungicide for agriculture and horticulture, it shows an excellent control effect; against a wide range of plant diseases. It is especially effective against late blight and downy mildew §§ of various crops caused by Oomycetes, effective. The essential to be controlled -f |

Diseases include potato herb rot (Phytophthora infestans), tomato herb rot (Phytophthora infestans), 3 |

Tobacco black rot (Phythophthora nicotiana var. Nicotiana), strawberry red rot (Phytophthora sp.). Stems and roots of soybean (Phytophthora megasperma var. Sojae), powdery mildew (Plasmopara viticola), cucumber downy mildew (Pseudoperonospora cubensis), false hop powdery mildew (Pseudoperonospora humuli), false spinach powdery mildew Φ-

(Peronospora spinaciae) and fouling or seedling mildew or rot of various crops caused by

Aphanomyces, Pythium, etc. Another essential feature of the amide derivatives of the invention is that when applied to crops, they show little phytotoxicity observed in other amide derivatives. The compounds prepared by the process according to the invention are applied, for example, by seed pickling, spraying on the foliage, soil treatment, etc. The compounds prepared by the methods of the invention exhibit sufficient activity when applied by methods commonly used by those skilled in the art. The rate of application of the compound of the invention and the concentration at which it is applied may depend on the crop and the disease being treated, the extent of the disease's appearance, the formulation of the compound, the method of application and various environmental conditions. When sprayed, the suitable amount of the compound as the active ingredient is 50 to 5000 g / ha, preferably 100 to 2000 g / ha. When the formulation is diluted and sprayed with water as a wettable powder or emulsifiable concentrate, the dilution ratio is preferably 200 to 10,000, preferably 500 to 5,000.

The fungicidal composition for agriculture and horticulture can be used or formulated together with another agricultural chemical, such as another fungicide, an insecticide or a ί

Plant growth regulator, a soil conditioner or a fertilizer substance. I

The compound prepared according to the invention may be used as such, but preferably in the form of a composition comprising a carrier (which is intended to include a solid or liquid diluent as well). The carrier used herein means a synthetic or natural, inorganic or organic substance which is incorporated to aid in the contact of the active ingredient at the site to be treated and to facilitate the storage, transport and handling of the compound as an active ingredient.

Suitable solid carriers include e.g. As clays such as montmorillonite and kaolinite, inorganic substances such as Dfatomeenerde, terra alba, talc, vermiculite, gypsum, calcium carbonate, silica gel and ammonium sulfate, vegetable, organic substances such as soybean meal, sawdust and wheat flour, and urea.

Suitable liquid carriers include e.g. aromatic hydrocarbons such as toluene, xylene and cumene, paraffinic hydrocarbons such as kerosene and mineral oils, halogenated hydrocarbons such as carbon tetrachloride, chloroform and dichloroethane, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and tetrahydrofuran, alcohols such as methanol, ethanol, propanol and ethylene glycol, dimethylformamide, dimethyl sulfoxide and water.

In order to increase the potency of the compound prepared according to the invention, the adjuvants described below may be used alone or in combination, depending on the type of formulation, the situation of use, etc.

For purposes of emulsification, dispersion, distribution, wetting, bonding and stabilization, for example, anionic surfactants such as lignosulfonates, alkylbenzenesulfonates, alkylsulfuric acid ester salts, polyoxyalkylene alkyl sulfates and polyoxyalkylene alkyl phosphoric acid ester salts; nonionic surfactants such as polyoxyalkylene alkyl ethers, polyoxyalkylene alkylaryl ethers, polyoxyalkylene alkylamines, polyoxyalkylene alkylamides, polyoxyalkylene alkyl thioethers, polyoxyalkylene fatty acid esters, glycerine fatty acid esters, sorbitan fatty acid esters, polyoxyalkylene sorbitan fatty acid esters, and polyoxypropylene / polyoxyethylene block copolymers; Lubricants, such as calcium stearate and waxes; Stabilizers, such as isopropyl hydrogen phosphate and methyl cellulose, carboxymethyl cellulose, casein and gum arabic, are used. These components should not be limited to the specific examples given above. Usually, the amount of the active ingredient in the composition of the present invention is 0.5 to 20 wt% for a dust, 5 to 20 wt% for an emulsifiable concentrate, 10 to 90 wt% for a wettable powder, 0.1 to 20 wt. % for granules and 10 to 90% by weight for a flowable agent. The amount of carrier in the formulation is usually 50 to 99% by weight , for a dust, 60 to 95% for an emulsifiable concentrate, 10 to 90% by weight for a wettable powder, 80 to 99% by weight for granules and 10 to 90% by weight of a flowable agent. The amount of the adjuvant is usually 0.1 to 20% by weight for a dust, 1 to 20% by weight for an emulsifiable concentrate, 0.1 to 20% by weight for a wettable powder, 0.1 to 20% by weight. % for granules and 0.1 to 20% by weight for a flowable agent.

The compound prepared in accordance with the present invention has both preventive and curative effects against a wide range of diseases in fruit trees and vegetables, and exhibits an excellent control effect against those plant diseases in which pathogenic fungi have acquired resistance to conventional fungicidal chemicals. Furthermore, the composition according to the invention has a sufficiently long residual action and has no phytotoxicity. It also has extremely low toxicity to warm-blooded animals and "

Fishing. ί

As a fungicide for agriculture and horticulture, the composition according to the invention has a controlling effect on a wide range of plant diseases. Examples of plant diseases to which the composition of the present invention shows an excellent control effect include frost rot (Glomerella cingulata), anthracnose (Elsinoe ampelina), powdery mildew (Uncinula necator). Rust or fire (Phacospora ampelopsidis) and powdery mildew {Plasmopara viticola) of the grape; Rust (Gymnosporangium yamadae), Alternaria leaf spot (Alternaria mali), fruit spot (Mycosphaerella pomi), scab (Venturia inaequalis) and powdery mildew (Podosphaera leucotricha) of the apple; Anthracnose (Colletotrichum lagenarium), powdery mildew (Sphaerotheca fuliginea), rubbery stem rot {Mycosphaerella melonis), downy mildew (Pseudoperonospora cubensis), Phytophthora rot (Phytophthora melonis), scab (Cladosporium cucumerinum) and bacterial spots (Pseudomonas lachrymans) in squash; Early rot (Alternaria solani), leaf mold (Cladosporium fulvum), Phytophthora rot (Phytophthora capsici).

-10- 296 4 £ Ό

Late blight (Phytophthora infestans) and powdery mildew (Erysiphe cichoracearum) at tomato; Alternaria leaf spots (Alternaria japonica), white spots (Cercosporella brassicae) and downy mildew in cruciferous animals; Rust (Puccinia aiii) and downy mildew (Peronospora destructor) green onion; downy mildew (Peronospora spinaciae) in spinach; Scab (Elsinoe glycines), purple spots (Cercospora kikuchii) and downy mildew (Peronospora manshurica) of soybean; Anthracnose (Colletotrichum lindemuthianum) and rust (Uromnyces appendiculatus) of the white bean; downy mildew (Peronospora viciae) in field beans; Black rot (Phytophthora nicotiana var. Nicotiana) of tobacco; Early blight (Alternaria solani) and late blight (Phytophthora infestans) in potato; downy mildew (Pseudoperonospora humuli) in hops; Phytophthora rot (Phytophthora cinnamomi) in the pineapple; Phytophthora rot of the green pepper (Phytophthora capsici); powdery mildew (Sphaerotheca humuli) and red rot (Phytophthora fragerie) of strawberry; and gray mold (Botrytis cinerea), Sclerotinis disease (Sclerotinia sclerotiorum), and putrefaction (by pythium, etc.) of various crops.

The compounds prepared according to the invention are z. B. by seed pickling, spraying on the foliage, soil treatment, etc. applied. The compounds of the invention exhibit sufficient activity when applied by methods commonly used by those skilled in the art. The rate of application of the compounds of the invention and the concentrations at which they are applied may depend on the crop and the disease being treated, the extent of the disease's appearance, the formulation of the compound, the method of application, and various environmental conditions. When sprayed, the suitable amount of the compound as the active ingredient is 50 to 5,000 g / ha, preferably 100 to 2,000 g / ha. If it is to be sprayed as a wettable powder or as an emulsifiable concentrate diluted with water, the dilution ratio is preferably 200 to 10,000, preferably 500 to 5000.

The fungicidal composition for agriculture and horticulture may be used or formulated with other agricultural chemicals such as another fungicide, insecticide or plant growth regulator, soil conditioner or fertilizer substance.

The compounds prepared according to the invention can be applied as such, but preferably in the form of a composition with a carrier (this also includes solid or liquid diluents). The carrier used herein means a synthetic or natural, inorganic or organic substance incorporated to assist in the contact of the active agents at the site to be treated and to facilitate the storage, transport and handling of the compound as an active ingredient.

Suitable solid carriers and liquid carriers as well as adjuvants may be the same as those exemplified above.

Either way, the amount of active ingredients in the composition of the invention is 0.5 to 20% by weight for a dust, 5 to 20% by weight for an emulsifiable concentrate, 10 to 90% by weight for a wettable powder, 0.1 to 20 wt .-% in granulation and 10 to 90 wt .-% at a flowable agent. The amount of carrier in the formulation is usually 50 to 99 wt% for a dust, 60 to 95 wt% for an emulsifiable concentrate, 10 to 90 wt% for a wettable powder, 80 to 99 wt% for granules and 10 to 90% by weight with a flowable agent. The amount of the adjuvant is usually 0.1 to 20 wt% for a dust, 1 to 20 wt% for an emulsifiable concentrate, 0.1 to 20 wt% for a usable powder, 0.1 to 20 wt% in the case of granules and 0.1 to 20% by weight with a flowable agent. The ratio of the fungicide as the second active ingredient to the amide derivative of the invention can be freely changed between 0.1 and 30.

embodiment

The processes of the present invention for preparing the amide derivatives of the general formula (IV) are illustrated below by the following Synthesis Examples.

Synthetic Example 1

Synthesis of N-fa-Cyanofurfury O ^ -chloro-methylthiazole-B-carboxyamide (Compound No. 37) 8.8 g of 2-chloro-4-methylthiazole-5-carboxylic acid were suspended in 7 mL of thionyl chloride and treated with 1 drop of N, N Dimethylformamide. The mixture was heated at reflux for 1 h and then excess thionyl chloride was evaporated under reduced pressure. 10 ml of benzene are added and the mixture is evaporated under reduced pressure. This procedure was repeated three times to give 9.7 g of 2-chloro-4-methylthiazole-5-carboxylic acid chloride, which was used in the following reaction without purification.

The 2-chloro-4-methylthiazole-5-carboxylic acid chloride (1.6 g) was suspended in 30 ml of pyridine and admixed with 1.3 g of a- (2-furyl) -aminoacetonitrile hydrochloride. The mixture was stirred for 2 h at room temperature. After the reaction, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography. Elution with hexane / ethyl acetate gave 1.79 g (yield 75.2%) of the desired N- (α-cyano-fururfuryl-7-2-chloro-4-methylthiazole-5-carboxylic acid amide.

Synthesis Example 2 Synthesis of N- (α-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide (Compound No. 2)

9.30 g of 2,4-dimethylthiazole-5-carboxylic acid were suspended in 90 ml of toluene and mixed with 15.0 g of phosphorus pentachloride. The mixture was refluxed for 1 h. Under reduced pressure, the resulting phosphorus oxychloride and toluene were evaporated to give 2,4-dimethylthiazole-5-carboxylic acid chloride, which was used in the following reaction without purification.

6.2 g of α- (2-furyl) -a-aminoacetonitrile and 6.0 g of triethylamine were dissolved in 120 ml of ethyl acetate, and 2,4-dimethylthiazole-5-carboxylic acid chloride was added dropwise to the solution while stirring, and the mixture was stirred at room temperature for 1 hour. 150 ml of water were added and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water

and dried over sodium sulfate. The dried ethyl acetate layer was distilled under reduced pressure to remove the solvent. The residue was recrystallized from isopropyl ether to obtain 11.65 g (yield 90.0%) of desired N- (α-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide.

Synthesis Example 3

Synthesis of N-ta-cyanofurfuryl J ^^ - diethylthiazole-B-carboxylic acid amide (Compound No. 12) According to the procedure of Synthesis Example 2, 2,4-diethylthiazole-5-carboxylic acid and phosphorus pentachloride were reacted to give 2: 4-diethylthiazole-5 to obtain carboxylic acid chloride quantitatively. The 2,4-diethylthiazole-5-carboxylic acid chloride was used in the following reaction without purification.

2.80 g of α- (2-furyl) -α-aminoacetonitrile and 6.0 g of triethylamine were dissolved in 50 ml of ethyl acetate and 2.1 g of the 2,4-diethylthiazole-5-carbonyl chloride were added dropwise with stirring and the mixture was stirred for 1 h room temperature. 150 ml of water were added and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water and dried over sodium sulfate. The dried ethyl acetate layer was evaporated under reduced pressure to remove the solvent. The residue was recrystallized from η-hexane to obtain 2.41 g (yield 80.0%) of desired N- (α-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide.

Synthesis Example 4

Synthesis of N- (α-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide (Compound No. 2) using a mixed acid anhydride

4.71 g of 2,4-dimethylthiazole-5-carboxylic acid were suspended in 70 ml of tetrahydrofuran and added with 6.67 g of triethylamine. The mixture was stirred. Cooled to -10 to -5 ° C, 4.10g of n-butyl chloroformate was added, and the mixture was stirred at that temperature for 30 minutes, after which it was treated with 4,03ga- (2-furyl) -a-aminoacetonitrile hydrochloride. The mixture was stirred at room temperature for 5 h and then allowed to stand overnight. The precipitate was separated by filtration and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane / ethyl acetate added 4.20 g (53.6% yield) of the desired N- (a-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide.

Synthesis Example 5. , ,

Synthesis of N- (α-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide (Compound No. 2) according to the CDI method 4.0 g a- (2-furyl) -α-aminoacetonitrile hydrochloride and a mixture of 3, 70 g of a 50% aqueous solution of NaOH and 50 ml of isopropyl ether were stirred for 1 h at 40 ⁰ C under nitrogen gas. The isopropyl ether layer was separated. Separately, while 4.71 g of 2,4-dimethylthiazole-5-carboxylic acid and 4.88 g of carbonyldiimidazole (CDI) were stirred in 50 ml of methylene chloride, α- (2-furyl) -a-aminoacetonitrile in isopropyl ether was added dropwise under ice cooling. The mixture was allowed to stand at room temperature overnight and distilled under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, separated, washed with water and dried over sodium sulfate. The ethyl acetate layer was distilled under reduced pressure to remove the solvent. The residue was recrystallized from isopropyl ether to give 5.51 g (yield 70.4%) of desired N- (α-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide.

Synthetic Example 6

Synthesis of N- (α-cyanofurfuryl) -2,4-dimethylthiazole-5-carboxylic acid amide (Compound No. 2) by the DCC method 3.0 g of α- (2-furyl) -α-aminoacetonitrile hydrochloride and a mixture of 70 g of a 50% aqueous solution of NaOH and 30 ml of methylene chloride were stirred for 1 h at 40 ⁰ C under nitrogen gas. Thereafter, the methylene chloride layer was separated.

Separately, while 2.50 g of 2,4-dimethylthiazole-5-carboxylic acid and 3.10 g of dicyclohexylcarbodiimide (DCC) were stirred in 50 ml of methylene chloride, α- (2-furyl) -a-aminoacetonitrile was added dropwise under cooling with ice-water over 1 hour , After |

the mixture was stirred for 1 h under ice-cooling, allowed to stand overnight at room temperature and

distilled under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, separated, washed with water and dried over sodium sulfate. The ethyl acetate layer was removed under reduced pressure to remove. distilled of the solvent. The residue was purified by silica gel column chromatography. Elution with hexane / |

Ethyl acetate gave 1.85 g (yield 47.3%) of the desired N-ta-CyanofurfuryO ^^ - dimethylthiazole-S-carboxamide. J

Ά Synthesis Example 7

Synthesis of N-la-Cyanofurfury O-S-methylisothiazoM-carboxylic acid Amide (Compound No. 32), '

1.2 g of α-β-FuryO-α-aminoacetonitrile hydrochloride were dissolved in 10 ml of pyridine and stirred at room temperature.

1.1 g of S-MethylisothiazoM-carboxylic acid chloride was added dropwise. After dropwise addition, the mixture was stirred for 1 h and added under

reduced pressure to remove the pyridine distilled. The residue was dissolved in ethyl acetate, separated, washed with water, and dried over sodium sulfate. The ethyl acetate layer was removed under reduced pressure to remove the

Solvent distilled. The residue was purified by silica gel column chromatography. Elution with benzene / *

Ethyl acetate gave 1.2 g (yield 70%) of the desired N-la-Cyanofurfury D-S-methylisothiazoM-carboxylic acid amide. }

Synthesis Example 8 '. i

Synthesis of N-fa Cyanofurfyury O-S-methylisothiazole-S-carboxamide (Compound No. 34) 5.0 g of α- (2-furyl) -a-aminoacetonitrile hydrochloride were treated with sodium hydroxide in ethyl acetate according to the same procedure as in the above Synthesis Example 6 subjected to a hydrogen chloride elimination. 2.5 g of pyridine were added and further added dropwise with an ethyl acetate solution of 4.0 g of S-methylisothiazole-δ-carboxylic acid chloride. After the addition, the mixture was stirred for 1 hour. The reaction mixture was washed with water, dilute hydrochloric acid and dilute aqueous sodium carbonate solution. Sodium sulfate and charcoal were added to the reaction mixture ^;

dehydrate and discolor. The solvent was removed under reduced pressure and the residue was washed with ethyl ether to give 4.5 g (yield 74%) of the desired N-fa-cyanofurfuryl J-S-methylisothiazole-B-carboxylic acid amide.

Synthetic Example 9

Synthesis of NO-cyano-S-methyl -buteno-O-methylisothiazole-S-carboxamide (Compound No. 36) To a mixture of 30 ml of water and 30 ml of ethyl ether was added 3 ml of 28% aqueous ammonia, 2.0 g Sodium cyanide, 4.5 g of ammonium chloride and 0.5 g of triethylbenzylammonium chloride, and the mixture was cooled to 5 ° C. While stirring, a solution of 2.8 g of 3-methyl-2-butenal was added dropwise. After the dropwise addition, the mixture was stirred continuously at 15 to 20 ^° C. for 5 hours. The ether layer was separated, washed with water and dried over sodium sulfate to give an ether solution of 1-cyano-3-methyl-2-butenylamine. 1.0 g of triethylamine was added to the solution and added dropwise with stirring at room temperature with an ethyl acetate solution of 1.1 g of S-methylisothiazole-δ-carboxylic acid chloride. After the addition, the mixture was stirred for 1 hour, washed with water and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with benzene / ethyl acetate gave 1.0 g (63% yield); desired N- (1-cyano-3-methyl-2-butenyl) -3-methylisothiazole-5-carboxylic acid amide.

  Synthetic Example 10

Synthesis of N-fa-CyanobenzyO-Z-methylisothiazole-S-carboxamide (Compound No. 35) 1.2 g of a-benzyl-α-aminoacetonitrile hydrochloride was suspended in 20 mL of ethyl acetate and 7 mL of 10% NaOH was kept at a temperature below 10 ° C C added dropwise. The mixture was stirred for 10 min at this temperature and was added dropwise an ethyl acetate solution of 0.8 g of S-methylisothiazol-S-carboxylic acid chloride at 0 C to ^c. After the addition, the mixture was stirred for 30 minutes. The ethyl acetate layer was washed with water and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with benzene / ethyl acetate gave 1.0 g (77% yield) of the desired N-fa-cyanobenzyO-S-methylisothiazole-S-carboxamide.

Synthetic Example 11

Synthesis of N-ta-cyano-α-ti-pyrazoly-O-methyl-S-methylisothiazole-S-carboxamide (Compound No. 46) 0.7 g of N-t-cyanomethyl-S-methylisothiazole-B-carboxylic acid amide was dissolved in 30 ml of ethyl acetate. 0.8 g of bromine was added and the mixture was stirred for 30 minutes and then cooled over an ice bath. A mixture of 0.3 g of pyrazole, 1.0 g of triethylamine and 5 ml of ethyl acetate was added to the reaction mixture with stirring. The mixture was stirred for 30 minutes. The ethyl acetate layer was washed with water and distilled under reduced pressure to remove the solvent.

The residue was purified by silica gel column chromatography. Elution with benzene / ethyl acetate gave 0.75 g (78% yield) of the desired N-ta-cyano-α-d-pyrazoly-O-methyl-S-methylisothiazole-S-carboxylic acid amide.

Synthetic Example 12

Synthesis of N-fa-cyano-a-li-pyrazoly-O-methyl-β-dimethylthiazole-B-carboxylic acid amide (Compound No. 38)

(1) Synthesis of N-cyanomethyl ^^ - dinethylthiazole B-carboxylic acid amide

A mixture of 10 g of 2,4-dimethylthiazole-5-carboxylic acid, 13.6 g of thionyl chloride and 70 ml of toluene was cooled with ice and mixed with stirring with 8.4 g of Ν-dimethylformamide. The mixture was stirred at 3 to 5 ° C for 3 hours and then at 20 ° C for 1 hour, and 200 ml of toluene and 37 g of triethylamine were added. An ethyl acetate solution of aminoacetonitrile prepared from aminoacetonitrile sulfate using ethyl acetate and NaOH was gradually added to the reaction mixture under ice-cooling. The mixture was stirred for 1 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane / ethyl acetate gave 6.6 g (53% yield) N -cyanomethyl ^^ - diethylthiazole-S-carboxamide.

(2) Synthesis of N-Ca-cyano-α-ti-pyrazoly-O-methyne-dimethylthiazole-S-carboxylic acid amide

1.0 g of N-cyanomethyl-1-dimethylthiazole-B-carboxylic acid amide was dissolved in 30 ml of ethyl acetate. 0.3 ml of bromine was added and the mixture was refluxed until the disappearance of the dark brown color of the bromine. The reaction mixture was cooled over an ice-bath and 0.5 g of pyrazole, 2.0 g of triethylamine and 10 ml of ethyl acetate were added at the above temperature. The mixture was stirred for 2 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane / ethyl acetate gave 0.74 g (54.9% yield) of the desired N-ta-cyano-a-pyrazolyl-1-methyl-1-dimethylthiazole-S-carboxylic acid amide.

Synthetic Example 13

Synthesis of N-ia-cyano-a-ethoxymethyO ^^ - dimethylthiazole-S-carboxamide (Compound No. 39) 1.0 g of N-cyanomethyl-W-dimethylthiazole-S-carboxylic acid amide was dissolved in 30 ml of ethyl acetate. 0.3 ml of bromine was added and the mixture was heated to reflux until the disappearance of the dark brown color of the bromine. The reaction mixture was cooled over an ice-bath and treated with 1.0 g of ethanol, 2.0 g of triethylamine and 10 ml of ethyl acetate at the above temperature. The mixture was stirred for 2 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, dried and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane / ethyl acetate gave 0.53 g (43.1% yield) of desired N-fa-cyano-a-ethoxymethyl-W-dimethyl-thiazole-B-carboxylic acid amide.

Table 1 below shows typical examples of amide derivatives of general formula (IV) prepared according to the invention. The terms (a) and (b) in the column "Process" mean the processes (a) and (b) as described above.

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Claims (1)

Claim: Process for the preparation of an amide derivative of the following general formula (IV) (IV) wherein one of X and Y represents a sulfur atom and the other represents a carbon atom, each of R ¹ and R ^{2 represents} a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halomethyl group or a phenyl group, and R ^{3 represents} an alkenyl group 2 to 6 carbon atoms, a haloalkenyl group having 2 to 4 carbon atoms, a furyl group, a thienyl group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an alkynyloxy group having 3 to 5 carbon atoms, an alkynylthio group having 3 to 5 carbon atoms , a pyrazolyl group or an unsubstituted or halogen-substituted phenyl group, characterized in that it comprises the reaction of a heterocyclic, 5-membered carboxylic acid of the following general formula (II)