PL224003B1

Method of producing 2-pyridyl ethyl benzamide derivative

Abstract

Compound of general formula (I) in which p is an integer equal to 1, 2, 3 or 4; q is an integer equal to 1, 2, 3, 4 or 5; each substituent X is chosen, independently of the others, as being halogen, alkyl or haloalkyl, at least one of the substituents being a haloalkyl; each substituent Y is chosen, independently of the others, as being halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, amino, phenoxy, alkylthio, dialkylamino, acyl, cyano, ester, hydroxy, aminoalkyl, benzyl, haloalkoxy, halosulphonyl, halothioalkyl, alkoxyalkenyl, alkylsulphonamide, nitro, alkylsulphonyl, phenylsulphonyl or benzylsulphonyl; as to the N-oxides of 2-pyridine thereof; with the exception of N-{2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-ethyl}-2,6-dichlorobenzamide. Method for preparing the compound of general formula (I). Fungicidal composition comprising the compound of general formula (I). Method for treating phytopathogenic diseases.

PL224003B1, drawing sheet 1 — Sheet 1 of 15

Term

Term ended

Expired 8 August 2023, 3.1 years ago.

2 claims: 1 independent, 1 dependent

1
Preparation of the compound of formula (I):1. Sposób wytwarzania związku o wzorze (I): w którym: wherein: X is independently halo or haloalkyl and is present twice, preferably at the 3- and 5-position of the pyridine ring, and at least one of X is haloalkyl;X niezależnie oznacza fluorowiec lub fluorowcoalkil i występuje dwukrotnie, korzystnie w pozycji 3 i 5 pierścienia pirydyny i co najmniej jeden z X oznacza fluorowcoalkil;PL 224 003 B1 PL 224 003 B1 Y is independently halogen, alkyl, haloalkyl, alkoxy, amino, alkylthio, cyano, ester, hydroxy, benzyl, haloalkoxy, halosulfonyl, alkylsulfonamide, nitro, or alkylsulfonyl, and occurs 1, 2, 3 or 4 times in the benzene ring where the alkyl alone or in combination contains 1 to 10 carbon atoms, with the exception of N- {2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -2,6-dichlorobenzamide;which method includes: Y niezależnie oznacza fluorowiec, alkil, fluorowcoalkil, alkoksyl, grupę aminową, alkilotio, cyjanową, estrową, hydroksylową, benzyl, fluorowcoalkoksyl, fluorowcosuIfonyl, alkilosulfonoamid, grupę nitrową lub alkilosulfonyl i występuje 1, 2, 3 albo 4 razy w pierścieniu benzenu, przy czym alkil sam lub w kombinacji zawiera 1 do 10 atomów węgla, z wyjątkiem N-{2-[3-chloro-5-(trifluorometylo)-2-pirydynylo]etylo}-2,6-dichlorobenzamidu;który to sposób obejmuje: - etap pierwszy, w którym związek o wzorze ogólnym (la), w celu podstawienia go w sposób selektywny w pozycji 2, poddaje się reakcji w obecności zasady w aprotycznym polarnym rozpuszczalniku;- the first step in which the compound of general formula (Ia) is reacted in the presence of a base in an aprotic polar solvent to selectively displace it in the 2-position;* albo z grupą alkilocyjanooctanu typu (NC-CH2-CO2Alk) z wytworzeniem związku o wzorze ogólnym (Ib) zgodnie ze schematem: * or with an alkylcyanoacetate group of the type (NC-CH2-CO2Alk) to obtain a compound of general formula (Ib) according to the scheme: gdzie: where: - X has the meaning given above - X ma znaczenie podane powyżej - Alk is an alkyl group having 1 to 10 carbon atoms;- Alk oznacza grupę alkilową mającą 1 do 10 atomów węgla;- Q is a nucleofugic group, the compound of general formula (Ib) thus obtained is then dealkyloxycarboxylated in the presence of an alkali metal halide, such as Li-halogen, K-halogen or Na-halogen, at the reflux temperature of a mixture of water and sulfoxide d imethyl according to the Krapcho reaction to obtain a compound of general formula (Ic), according to the scheme: - Q oznacza grupę nukleofugową, po czym tak otrzymany związek o wzorze ogólnym (Ib) poddaje się dezalkiloksykarboksylowaniu w obecności halogenku metalu alkalicznego, jak Li-fluorowiec, K-fluorowiec lub Na-fluorowiec, w temperaturze wrzenia pod chłodnicą zwrotną mieszaniny wody i sulfotlenku d imetylowego, zgodnie z reakcją Krapcho, z wytworzeniem związku o wzorze ogólnym (Ic), zgodnie ze schematem: * or with acetonitrile to directly give a compound of formula (Ic) according to the scheme: *albo z acetonitrylem, z bezpośrednim wytworzeniem związku o wzorze (Ic) zgodnie ze schematem: - etap drugi, w którym poddaje się redukcji związek o wzorze ogólnym (Ic) z wytworzeniem pirydyloetanoaminy o wzorze ogólnym (Id), lub jej odpowiedniej soli amoniowej, w zależności od tego, czy środowisko jest, czy nie jest kwaśne, pod ciśnieniem wodoru, w obecności katalizatora metalicznego, w protonowym rozpuszczalniku, zgodnie ze schematem: second step in which a compound of general formula (Ic) is reduced to give a pyridylethanamine of general formula (Id) or its corresponding ammonium salt, depending on whether or not the medium is acidic, under a hydrogen pressure, in the presence of a metal catalyst, in a protic solvent, according to the scheme: PL 224 003 B1 PL 224 003 B1 - etap trzeci, w którym przekształca się związek o wzorze ogólnym (Id) w związek o wzorze ogólnym (I) przez poddawanie reakcji z halogenkiem benzoilu, w obecności zasady, zgodnie ze schematem: - the third step, where the compound of general formula (Id) is converted into a compound of general formula (I) by reacting with a benzoyl halide in the presence of a base according to the scheme: gdzie Y ma znaczenie podane powyżej. where Y is as defined above.

392 paragraphs in 8 sections, as filed

Description of the invention

The invention relates to a process for the preparation of novel compounds with fungicidal properties suitable for use in fungicidal compositions and for use in agriculture as fungicides.

Patent application WO 01/11 965 describes a large family of compounds with fungicidal properties, the general formula comprising the compounds of the present invention. However, in this patent application the presently claimed compounds are not described and their activity as fungicides has not been tested.

Nevertheless, it is always useful in agriculture to use compounds that are more active than those already known to those skilled in the art in order to reduce the amount of active ingredient used by the farmer, but at the same time maintaining an effectiveness at least equivalent to that of the compounds already known.

It has now been found that a number of compounds selected from the large family of compounds have the above-mentioned advantages.

The invention relates to a process for the preparation of a compound of formula (I):

wherein:

X is independently halo or haloalkyl and is present twice, preferably at the 3- and 5-position of the pyridine ring, and at least one of X is haloalkyl;

Y is independently halogen, alkyl, haloalkyl, alkoxy, amino, alkylthio, cyano, ester, hydroxy, benzyl, haloalkoxy, halosulfonyl, alkyl sulfonamide, nitro, or alkylsulfonyl, and occurs 1, 2, 3 or 4 times in the benzene ring where the alkyl alone or in combination contains 1 to 10 carbon atoms, with the exception of N- {2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -2,6-dichlorobenzamide; which method includes:

- the first step in which the compound of general formula (Ia) is reacted in the presence of a base in an aprotic polar solvent to selectively displace it in the 2-position;

* or with an alkylcyanoacetate group of the type (NC-CH2-CO2Alk) to obtain a compound of general formula (Ib) according to the scheme:

where:

- X has the meaning given above

- Alk is an alkyl group having 1 to 10 carbon atoms;

- Q is a nucleofug group, then the compound of general formula (Ib) obtained in this way is dealkyloxycarboxylated in the presence of an alkali metal halide, such as Li-halogen, K-halogen or Na-halogen, under reflux of a mixture of water and dimethyl sulfoxide , according to the Krapcho reaction, to give a compound of the general formula (Ic), according to the scheme:

PL 224 003 B1

* or with acetonitrile to directly give a compound of formula (Ic) according to the scheme:

second step in which a compound of general formula (Ic) is reduced to give a pyridylethanamine of general formula (Id) or its corresponding ammonium salt, depending on whether or not the medium is acidic, under a hydrogen pressure, in the presence of a metal catalyst, in a protic solvent, according to the scheme:

- the third step, where the compound of general formula (Id) is converted into a compound of general formula (I) by reacting with a benzoyl halide in the presence of a base according to the scheme:

where Y is as defined above.

Preferably, in the process of the invention, the nucleofugic group Q is a halogen or a trifluoromethanesulfonate.

For the purposes of the present invention, the term "halogen" means chlorine, bromine, iodine or fluorine.

For the purposes of the present invention, each alkyl or acyl present in the molecule has from 1 to 10 carbon atoms, preferably from 1 to 7 carbon atoms, more preferably from 1 to 5 carbon atoms, which may be straight or branched chain.

The second step of the described process is carried out in the presence of a metal catalyst. Preferably, the metal catalyst is a nickel, platinum or palladium based catalyst.

PL 224 003 B1

The third step of this process is carried out in the presence of a benzoyl halide. Preferably, the benzoyl halide is benzoyl chloride.

Preferred compounds according to the invention have the following characteristics:

- the substituents with the symbols X and X are in the positions as in the formula below:

- q is 1 or 2, wherein the substituent (s) of the symbol (Y) is in the ortho position of the benzene ring.

Another preferred subfamily of such compounds is represented by the general formula (I '):

wherein XIY are as defined above.

More preferably, X1 is halogen and X2 is haloalkyl.

Another preferred subfamily of such compounds consists of compounds of general formula (I "):

Where X and Y are as defined above.

More preferably, the compounds of general formula (I ") have the following characteristics:

- X1 is halogen and X2 is haloalkyl;

1

- Y1 is halogen or haloalkyl.

More preferably, haloalkyl is trifluoromethyl.

Particularly preferred such compounds are:

N- {2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -2-trifluoromethylbenzamide;

N- {2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -2-iodobenzamide;

N- {2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -2-bromobenzamide;

From the compound of general formula (I) obtained by the above-described method, those skilled in the art will be able to prepare 2-pyridine N-oxide derivatives by known methods. Thus, for example, a compound of general formula (I) obtained by the process described herein may be treated with excess metachloroperbenzoic acid (also called m-CPBA) in the presence of a solvent, which may be chloroform, at a temperature ranging from 60 to 80 ° C. C.

The compounds prepared by the claimed process can be used in a fungicidal composition containing an effective amount of an active substance of general formula (I). Such a fungicidal composition comprises, as an active ingredient, an effective amount of the above-defined compound of general formula (I) and an agriculturally acceptable support, carrier or filler.

The term "carrier" as used herein denotes a natural or synthetic organic or inorganic substance with which the active substance is combined for easier application, especially to parts of plants. Generally, such a carrier is inert and should be agriculturally acceptable. The carrier can be a solid or a liquid. Examples of suitable carriers are clays, natural or synthetic silicates, silica, resins, waxes, solid fertilizers, water, alcohols, in particular butanol, organic solvents, minerals, plants and products derived therefrom. Mixtures of such carriers can also be used.

The composition may also contain additional ingredients. In particular, the composition may further contain a surfactant. The surfactant may be an emulsifier, dispersant or wetting agent of the ionic or non-ionic type, or a mixture of such surfactants. Examples include, for example, polyacrylic acid salts, ligninsulfonic acid salts, phenolsulfonic acid or naphthalenesulfonic acid salts, polycondensation products of ethylene oxide with fatty alcohols or fatty acids or fatty amines, substituted phenols (in particular alkylphenols or arylphenols), ester salts sulfosuccinic acid, taurine derivatives (in particular alkyl taurates), phosphoric esters of polyoxyethylene alcohols or phenols, fatty acid polyol esters and derivatives of the above compounds containing sulfate, sulfonate and phosphate functional groups. In general, the presence of at least one surfactant is essential when the active ingredient and / or the inert support are water-insoluble or when the vector agent for the application is water. Preferably, the surfactant content is in the range of 5% to 40%, based on the weight of the composition.

Optionally, additional ingredients may also be included, e.g. protective colloids, tackifiers, thickeners, thixotropic agents, penetration enhancers, stabilizers, masking agents. Generally speaking, the active ingredients may be combined with any solid or liquid additive according to the usual formulation technique for such formulation.

In general, such a composition may contain from 0.05 to 99 wt. % of active substance, preferably from 10 to 70% by weight.

The compositions can be used in a variety of forms and methods of application. These include means such as an aerosol dispensing device, an encapsulated suspension, a cold fogging concentrate, a dusting powder, an emulsifiable solution, an oil-in-water emulsion, a water-in-oil emulsion, an encapsulated granule, fine granules, a free-flowing concentrate. flow-off for seed treatment, pressurized gas, gas-generating product, granules, heat misting concentrate, macrogranules, microgranules, oil dispersible powder, free-flowing oil-miscible concentrate, oil-miscible liquid, paste, fine plant forms, dry seed treatment powder, pesticide-coated seed, soluble concentrate, soluble powder, seed treatment solution, suspending concentrate ( free-flowing concentrate), ultra-low-volume spraying fluid (ulv), ultra-low-volume spraying suspension (ulv), water-dispersible granules or tablets, water-dispersible powder for treatment with suspension, water-soluble granules or tablets, water-soluble powder for seed treatment, and wettable powder.

Such compositions include not only ready-to-apply compositions to plants or seeds treated with suitable equipment such as spray or dusting apparatus, but also concentrated commercial compositions that must be diluted prior to application to a crop.

The compounds according to the invention can also be mixed with one or more insecticides, fungicides, bactericides, acaricide attractants or pheromones, or other compounds with biological activity. The mixtures prepared in this way have a broadened spectrum of activity. Mixtures with other fungicides are particularly preferred.

The fungicidal compositions described herein can be used for the curative or preventive control of plant pathogenic fungi in crops. Thus, a method of curative or preventive control of plant pathogenic fungi in crops is characterized by:

That the above-described fungicidal composition is applied to the seeds, plants and or fruit of the plant, or to the soil in which the plant grows or is desired to grow.

The composition used against plant pathogenic fungi in crops comprises an effective and non-phytotoxic amount of an active ingredient of general formula (I).

The expression "effective and nonphytotoxic amount" means an amount of the composition sufficient to control or destroy the fungi present or capable of appearing on the crops and not causing any significant symptom of phytotoxicity to those crops. This amount may vary widely depending on the type of fungus to be controlled, the type of crop, climatic conditions and the nature of the compounds contained in a given fungicidal composition.

The amount can be determined from the results of systematic field trials performed, which is within the capabilities of one of ordinary skill in the art.

The method of treatment described is useful for the therapeutic treatment of propagation material, such as tubers or rhizomes, as well as seeds, cuttings or cuttings, and pierced plants or plants. Such a curative effect may also prove useful in treating the roots. The treatment may prove useful for treating aerial parts of plants, such as trunks, stems or shoots, leaves, flowers and fruit of plants.

The plants that can be protected in this way include: cotton, flax, grapevines, plants in fruit crops, such as Rosaceae sp. (E.g. pome fruits, such as apples and pears, as well as stone fruits, such as apricots, almonds and peaches), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraecae sp., Oleaecae sp., Actinidaceae sp., Lauraecae sp., Musaecae sp. (E.g. banana trees etc.), Rubiaceae sp. , Theaceae sp., Stereuliecae sp., Rutaecae sp. (E.g. lemons, oranges and grapefruits), legumes, plants such as Solanaeeae sp. (e.g. tomatoes), Liliacee sp., Asteraecae sp. (e.g. lettuce), Umbelliferae sp., Crueiferae sp., Chenopodiaecae sp., Cucurbitaecae sp. sp., Papilionaecae sp. (e.g. peas, Rosaecae sp. (e.g. strawberries), large-crop plants such as Graminae sp. (e.g. maize, cereals such as wheat, rice, barley and triticale), Asteraceae sp. ( e.g. sunflower), Crueiferae sp., e.g. rapeseed, Papilionaeeae sp. (e.g. soybean), Solanaceae sp. (e.g. potato), Cheno podiaecae sp. (e.g. fodder beet), horticultural and forestry crops, as well as genetically modified homologues of the above plants.

Among plants and possible diseases of these plants protected by the described method, the following plants, crops and diseases can be mentioned:

- wheat, in terms of controlling the following grain diseases: fusariosis (Microdochium nivale and Fusarium roseum), foul-smelling wheat (Tilletia caries, Tilletia controuersa or Tilletia indica), Septoria nodorum and pollen knives;

- wheat, in terms of controlling the following diseases of the aerial parts of the plant: cereal stalk fragility (Tapesia yallundae, Tapesia acuiformis), blade stalk gangrene (Gaeumannomyces graminis), foot blight fusariosis (F. culmorum, F. graminearum), cereal rhizoctoniosis Rhizoctonia cerealis), powdery mildew (Erysiphe graminis form specie tritici), rusts (Puccinia striiformis, Puccinia recondita) and septoria (Septoria tritiei and Septoria nodorum);

- wheat and barley, with a view to combating bacterial and viral diseases: e.g. barley yellow mosaic;

- barley, with regard to the control of the following grain diseases: net blotch of barley leaves (Pyrenophora graminea, Pyrenophora teres and Cochliobolus satiuus), pollen head (Ustilago nuda) and fusariosis (Microdochium niuale and Fusarium roseum);

- barley, in terms of controlling the following diseases of overhead parts of the plant: cereal stalk fragility (Tapesia yallundae), net blotch of barley leaves (Pyrenophora teres and Cochliobolus satiuus), powdery mildew (Erysiphe graminis forma specie hordei), dwarf rust (Puccinia hordei) rynchosporiasis (Rhynchosporium seealis);

- potato, for the control of tuber diseases (in particular: Helminthosporium solani, Phoma tuberosa, Rhizoctonia solani, Fusarium solani, potato blight (Phytophthora infestans) and certain viruses (virus Y);

- potato, with regard to controlling the following foliar diseases: potato blight (Altenaria solanii), potato blight (Phytophthora infestans);

- cotton, in terms of combating the following diseases of young plants growing from seeds:

seedling gangrene and vascular fusariosis (Rhizoctonia solani and Fusarium oxysporum) and black root rot (Thielauiopsis basicola);

PL 224 003 B1

- the cultivation of protein-providing plants, e.g. peas, for controlling the following seed diseases: anthracnose (Ascochyta pisi, Mycosphaerella pinodes), fusarium disease (Fusarium oxysporum), gray mold (Botrytis einerea) and pea downy mildew (Pyrenospora pisi);

- the cultivation of oilseeds, e.g. rapeseed, with a view to controlling the following seed diseases:

Phoma lingam, Altemaria brassieae and Selerotinia selerotiorum;

- maize, for the control of grain diseases: Rhizopus sp., Penicillium sp., Triehoderma sp., Aspergillus sp. and Gibberella fugikuroi);

- flax, for the control of seed diseases: Altemaria linicola;

- forest trees, with a view to combating seedlings (Fusarium oxysporum, Rhizoctonia solani);

- rice with the aspect of controlling the following diseases of the aerial parts of the plant: rice blight (Magnaporthe grisea), rhizoctonia solani (Rhizoctonia solani);

- the cultivation of legumes in terms of controlling the following diseases of seeds or young plants growing from seeds: gangrene of seedlings and vascular fusariosis (Fusarium oxysporum, Fusarium roseum, Rhizoctonia solani, Pythium sp.);

- the cultivation of legumes for the control of the following diseases of the aerial parts of the plant: gray mold (Botrytis sp.), powdery mildew (in particular Erysiphe cichoracearum, Sphaerotheca fuliginea and Leveillula taurica), fusarium disease (Fusarium oxysporum, Fusarium roseum, cladosporium sp.) , altemariosis (Altemaria sp.), anthracnose (Colletotrichum sp.), septoriosis (Septoria sp.), rhizoctoniosis (Rhizoctonia solani), downy mildew (e.g. Bremia lactucae),

Peronospora sp., Pseudoperonospora sp., Phytophthora sp.);

- fruit trees, for diseases of the aerial parts of the plant: moniliosis (Monilia fructigenae, M. Iaxa), apple scab (Venturia inaequalis), powdery mildew (Podosphaera leucotricha);

- grapevines, as regards foliage diseases, in particular gray mold (Botrytis cinerea), grapevine mildew (Uncinula necator), black rot (Guignardia biwellt) and downy mildew (Plasmopara viticola);

- fodder beet, in terms of controlling the following diseases of the aerial parts of the plant: beet leaf spot (Cercospora beticola), powdery mildew (Erysiphe beticola), beetroot ramulariosis (Ramularia beticola).

The described fungicidal composition can also be used against fungal diseases prone to development on and in wood. The term "timber" covers all types of wood and all types of treatment of wood intended for construction work (eg solid wood, high density wood, laminated wood and plywood). The method of treating wood is by bringing it into contact with one or more compounds of the invention, or a composition containing such a compound, and includes, for example, direct application, spraying, dipping, injection, or any other suitable method.

In the case of a foliar application, the dose of active ingredient usually applied in such a method is preferably and generally in the range from 10 to 800 g / ha, more preferably from 50 to 300 g / ha.

In the case of a seed treatment treatment, the dose of active ingredient applied will generally and preferably be in the range from 2 to 200 g / 100 kg of seed, more preferably from 3 to 150 g / 100 kg. It is easy to understand that the dosages indicated above are merely exemplary to illustrate the solution. One skilled in the art will know how to adapt the doses used according to the nature of the crop treated.

The described fungicidal composition can also be applied to genetically modified organisms by using the compounds according to the invention or the agrochemical compositions containing them. Genetically modified plants are plants into the genome of which a heterologous gene encoding a protein of interest has been introduced and permanently integrated. The term "heterologous gene encoding a protein of interest" generally refers to genes which impart new agronomic properties to the transformed plant, or to genes which provide an improvement in the agronomic quality of the transformed plant.

The described composition can also be used for the preparation of a composition useful for the curative or preventive control of fungal diseases in humans and animals, such as, for example, mycoses, dermatoses, sheath mycoses and yeasts, or diseases caused by Aspergillus spp., For example Aspergillus fumigatus.

PL 224 003 B1

The present invention is explained below with reference to the following tables (with compounds shown therein) and examples. The following AIB tables illustrate, in a non-limiting manner, examples of compounds with fungicidal properties. In the tables and examples below, M + 1 represents the peak of the molecular ion plus or minus 1 amu, respectively (atomic mass units) according to the results of the analysis by mass spectroscopy and M (Apcl +) is the molecular ion peak found by mass spectroscopy under chemical ionization conditions under atmospheric overpressure.

Table A.

<td>Relationship no</td><td>X1</td><td>X2</td><td>X3</td><td>X4</td><td>Y1</td><td>Y2</td><td>Y3</td><td>Y4</td><td>Y5</td><td>M + 1</td>

<td>A-11</td><td>Cl</td><td>CF3</td><td>H.</td><td>H.</td><td>H.</td><td>H.</td><td>Those</td><td>H.</td><td>H.</td><td> 363</td>

PL 224 003 B1 cont. table A

PL 224 003 B1 cont. table A

PL 224 003 B1 cont. table A

<td>A-110</td><td>Those</td><td>CF3</td><td>H.</td><td>H.</td><td>Br</td><td>H.</td><td>H.</td><td>Cl</td><td>H.</td><td> 441</td>

<td>A-119</td><td>Cl</td><td>CF3</td><td>H.</td><td>H.</td><td>O-CFj-CHFCl</td><td>H.</td><td>H.</td><td>Cl</td><td>H.</td><td> 495</td>

<td>A-120</td><td>Cl</td><td>CF3</td><td>H.</td><td>H.</td><td>O-allyl</td><td>H.</td><td>H.</td><td>Cl</td><td>H.</td><td> 419</td>

<td>A-121</td><td>Cl</td><td>CF3</td><td>H.</td><td>H.</td><td>Oallil</td><td>H.</td><td>H.</td><td>H.</td><td>H.</td><td> 385</td>

PL 224 003 B1 cont. table A

PL 224 003 B1 cont. table A

Table B.

X3

<td>Relationship no</td><td>X1</td><td>X1</td><td>X3</td><td>X4</td><td>Y1</td><td>Y2</td><td>Y3</td><td>Y4</td><td>Y5</td><td>M + 1</td>

The following compound preparation examples are provided to illustrate the invention and should not be considered as limiting its scope in any way.

PL 224 003 B1

Preparation of methyl [3-chloro-5- (trifluoromethyl) -2-pyridinyl] (cyano) acetate

Procedure: 116 g (2.91 mol,

1.8 eq) of sodium hydride (60% oil suspension). The suspension formed is cooled in an ice-water bath and a solution of 160 g (1.616 mol, 1.0 eq.) Of methyl cyanoacetate in 200 ml of DMF is added dropwise with stirring. After the evolution of gas has ceased completely, 350 g (1.616 mol, 1.0 eq.) Of 2,3-dichloro-5- (trifluoromethyl) pyridine are added with stirring. The mixture thus obtained is stirred overnight at ambient temperature, then 50 ml of methanol are added and the reaction mixture is poured into 5 liters of water. The pH is adjusted to 3-4 with concentrated hydrochloric acid. The yellow precipitate formed, methyl [3-chloro-5- (trifluoromethyl) -2-pyridinyl] cyano) acetate, is filtered off and washed with water and pentane.

Preparation of [3-chloro-5- (trifluoromethyl) -2-pyridinyl] acetonitrile

Procedure: 314 g (1.13 mol, 1 eq.) Of methyl [3-chloro-5- (trifluoromethyl) -2-pyridinyl] (cyano) acetate are dissolved in a solution of 44 ml of water and 1.1 liters of dimethyl sulfoxide. and 22 g (0.38 mol, 0.33 eq.) of sodium chloride. The reaction mixture thus formed is stirred and heated at 160 ° C until all gas evolution has ceased, and then cooled to ambient temperature. Then, 1 liter of water and 0.5 liters of dichloromethane are introduced. After separation of the phases, the aqueous phase is extracted twice with 0.5 liter of dichloromethane, and the organic phase is washed with twice 0.5 liter of water and dried with magnesium sulphate. After concentration, the crude product is diluted in 100 ml of dichloromethane and eluted over a silica pad with 20:80 ethyl acetate / heptane. The resulting filtrate was concentrated to give [3-chloro-5- (trifluoromethyl) -2-pyridinyl] acetonitrile.

Preparation of 2- [3-chloro-5- (trifluoromethyl-2-pyridinyl] ethanamine acetate

Procedure: 113 g (0.51 mol, 1 eq.) Of [3-chloro-5- (trifluoromethyl) -2-pyridinyl] acetonitrile are diluted in 2.5 liters of acetic acid and 30 g of palladium (5% on active carbon) are added. ). The reaction mixture thus formed is stirred at ambient temperature under pressure5 hydrogen of 5 x 105 Pa (5 bar). The progress of the reaction is followed by TLC. After [3-chloro-5- (trifluoromethyl) -2-pyridinyl] acetonitrile is completely depleted, the mixture is filtered through Celite pad and then concentrated to dryness to give 2- [3-chloro-5- (trifluoromethyl) -2- acetate. pyridinyl] ethanamine.

PL 224 003 B1

Procedure: 0.100 g (0.00037 mol, 1.0 eq.) Of 2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethanamine acetate is diluted in 3 ml of dichloromethane, then 0.500 g of polyurethane is added. (4-vinylpyridine). The mixture thus formed was stirred at ambient temperature for 1/2 hour.

Then, 1.2 equivalents of the desired carboxylic acid chloride are added and the reaction mixture is stirred at ambient temperature overnight, then filtered and concentrated to dryness. The crude product is purified by reverse phase HPLC to give the corresponding amide.

In order to compare the activity of the compounds of general formula (I) with the activity of the compound described in WO 01/11 965, the following biological activities were tested on a number of fungal diseases.

In vivo test for activity against Alternaria brassicae (Alternaria brassicae)

An aqueous solution of the active substance with a concentration of 2 g / liter to be tested is prepared by grinding it in solution 1 or 2.

Solution 1

- water,

- Tween 80 diluted to 10% in water; 5 μΐ / mg of active substance,

- sufficient clay to obtain: active substance + clay = 100 mg.

Solution 2

A concentrated solution containing surfactants and commonly used adjuvants; 200 μl / mg of active substance.

The aqueous solution is diluted with water to the desired concentration.

Radish of the Pernot variety is sown in 50:50 pozzolana / peat substrate and kept at 18-22 ° C. Treatment is carried out by spraying with an aqueous suspension. Untreated control plants are sprayed with water. 24 hours after treatment, the plants are inoculated by spraying with a solution containing Alternaria brassicae spores (40,000 spores / ml) from a 12-day culture. Thereafter, the radish plants are kept at 18-20 ° C in a humid atmosphere. After 7-8 days of incubation, the efficacy of the test compounds is assessed in comparison with the control plants.

In vivo activity test against Botrytis cinerea in cucumbers

An aqueous solution of the active substance with a concentration of 2 g / liter to be tested is prepared by grinding it in solution 1 or 2.

Solution 1

- water,

- Tween 80 diluted to a concentration of 10% in water; 5 μl / mg of active substance,

- sufficient clay to provide: active substance + clay = 100 mg.

Solution 2

A concentrated solution containing surfactants and commonly used adjuvants; 200 μl / mg of active substance.

The aqueous solution is diluted with water to the desired concentration.

Marketer cucumbers are sown in 50:50 pozzolana / peat substrate and kept at 18-22 ° C. Treatment is carried out by spraying with an aqueous suspension. Untreated control plants are sprayed with water. 24 hours after treatment, the plants are inoculated by spraying with a solution containing Botrytis cinerea spores (150,000 spores / ml) from a 15-day-old culture.

PL 224 003 B1

Thereafter, the cucumber plants are kept at 11-15 ° C in a humid atmosphere. After 7-8 days of incubation, the efficacy of the test compounds is assessed in comparison with the control plants.

In vivo test for activity against Pvrenovhora teres (Net blotch on barley leaves)

An aqueous solution of the active substance with a concentration of 2 g / liter to be tested is prepared by grinding it in solution 1 or 2.

Solution 1

- water,

- Tween 80 diluted to a concentration of 10% in water; 5 μl / mg of active substance,

- sufficient clay to provide: active substance + clay = 100 mg.

Solution 2

A concentrated solution containing surfactants and commonly used adjuvants; 200 μl / mg of active substance.

The aqueous solution is diluted with water to the desired concentration.

Barley of the Express variety is sown in 50:50 pozzolana / peat substrate and kept at 12 ° C. Treatment is carried out at the first leaf (10 cm) stage by spraying with an aqueous suspension. Untreated control plants are sprayed with water. 24 hours after treatment, the plants are inoculated by spraying with a solution containing Pyrenophora teres spores (10,000 spores / ml) from a 10-day-old culture.

Thereafter, the barley plants are kept at 18 ° C in a humid atmosphere. After 8-15 days of incubation, the efficacy of the test compounds is assessed in comparison with the control plants.

In vivo test for activity against Septoria tritici (wheat septoria)

An aqueous solution of the active substance with a concentration of 2 g / liter to be tested is prepared by grinding it in solution 1 or 2.

Solution 1

- water,

- Tween 80 diluted to a concentration of 10% in water; 5 μl / mg of active substance,

- sufficient clay to provide: active substance + clay = 100 mg.

Solution 2

A concentrated solution containing surfactants and commonly used adjuvants; 200 μl / mg of active substance.

The aqueous solution is diluted with water to the desired concentration.

Scipion wheat is sown in 50:50 pozzolana / peat substrate and kept at 12 ° C. Treatment is carried out at the first leaf (10 cm) stage by spraying with an aqueous suspension. Untreated control plants are sprayed with water. 24 hours after treatment, the plants are inoculated by spraying with a solution containing Septoria tritici spores (500,000 spores / ml) from a 7-day-old culture.

Thereafter, the wheat plants are kept at 18-20 ° C in a humid atmosphere for 72 hours and then under a relative humidity of 90%. 21-28 days after infection, the efficacy of the test compounds is assessed in comparison with the control plants.

The efficacy of the test compounds is estimated at doses of 500 g / ha, 250 g / ha or 330 ppm, as percentage of control with respect to untreated plants. Under these conditions, good efficacy is defined as greater than 80% efficacy. Average efficacy is defined as efficacy ranging from 50 to 80%. Poor Efficacy is defined as efficacy ranging from 10-50%, and Zero Efficacy is defined as less than 10% efficacy.

When used at a concentration of 500 g / ha, the following compounds showed good to medium efficacy against pathogenic fungi:

Alternaria brassicae: A-2, A-4, A-6, A-7, A-9, A-13, A-14, A-20, A-25.

Botrytis cinerea: A-2, A-7, A-9, A-20, A-25.

Pyrenophora teres: A-2, A-4, A-5, A-6, A-7, A-9, A-20, A-25, A-27.

Septoria tritici: A-2, A-4, A-5, A-6, A-7, A-16, A-18, A-20, A-21, A-22, A-23, A-24 , A-25.

When used at a concentration of 250 g / ha, the following compounds showed good to medium efficacy against pathogenic fungi:

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Alternaria brassicae: A-20, A-28, A-29, A-41, A-45, A-46, A-73, A-173.

Botrytis cinerea: A-20, A-45, A-46, A-73.

Pyrenophora teres: A-20, A-45, A-46, A-73.

The following compounds used at a concentration of 330 ppm showed good to medium efficacy against pathogenic fungi:

Alternaria brassicae: A-20, A-44, A-45, A-46, A-47, A-48, A-49, A-52, A-60, A-61, A-62, A-71, A- 72, A-73, A-74, A-75, A-76, A-77, A-79, A-80, A-83, A-84, A-85, A-86, A-87, A-89, A-92, A-92, A-96, A-98, A-99, A-100, A-107, A-110, A-112, A-113, A-117, A- 122, A-123, A-124, A-125, A-127, A-128, A-133, A-134, A-135, A-136, A-137, A-138, A-139, A-140, A-141, A-142, A-143, A-144, A-146, A-147, A-148, A-150, A-151, A-152, A-156, A- 157, A-158, A-159, A-162, A-165, A-166, A-167, A-168, A-169, A-170, A-171, A-173, A-174, A-175, A-176, A-177, A-178, A-179, A-180, A-181, A-182, A-183, A-184, A-185, A-186, A-187, A- 188, A-189, A-194, B-1.

Botrytis cinerea: A-20, A-45, A-46, A-73, A-170, A-172, A-173, A-174, A-175, A-187.

Pyrenophora teres: A-20, A-44, A-46, A-45, A-61, A-73, A-83, A-87, A-89, A-96, A-117, A-125 , A-133, A-134, A-140, A-167, A-173, A-174, A-187, B-1.

Under these conditions:

- N- {2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -2,6-dichlorobenzamide at a concentration of 330 ppm and 250 g / ha showed poor and no efficacy, respectively, against Alternaria brassicae and at a concentration of 250 g / ha and 330 ppm, zero efficacy against Botrytis cinerea;

- N- {methylcarbamoyl-2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -4-phenylbenzamide, disclosed in WO 01/11 965 (see compound 316 in Table D), in at a concentration of 250 g / ha, it showed poor efficacy against Alternaria brassicae and Septoria tritici and zero efficacy against Botrytis cinerea;

- N- {1-ethylcarbamoyl-2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -nitrobenzamide also disclosed in WO 01/11 965 (see compound 307 in Table D) at a concentration of 250 g / ha showed zero efficacy against Alternaria brassicae and Botrytis cinerea;

- N- {1-ethylcarbamoyl-2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl] benzamide and N- {1-methylcarbamoyl-2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl ] ethyl} benzamide, also disclosed in WO 01/11 965 (see compounds 304 and 314 in Table D), at a concentration of 250 g / ha showed poor efficacy against Septoria tritici and zero efficacy against Botrytis cinerea; and

- N- {1-ethylcarbamoyl-2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -4-chlorobenzamide, N- {1-ethylcarbamoyl-2- [3-chloro-5- (trifluoromethyl) ) -2-pyridinyl] ethyl} -2-bromobenzamide and N- {1-methylcarbamoyl-2- [3-chloro-5- (trifluoromethyl) -2-pyridinyl] ethyl} -4-methoxybenzamide, also disclosed in Patent Application No. WO 01/11 965 (see compounds 306, 310 and 315 in Table D) at a concentration of 250 g / ha showed zero efficacy against Botrytis cinerea.

Contents8

54 members in 31 offices

This recordMember, by publication datePriority claim21 more offices are in the list below

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Priority claims
Document	Office	Kind	Date
02356159	European Patent Office (EPO)	A	2002-08-12
02356159	European Patent Office (EPO)	A	2002-08-12
0305233	France	A	2003-04-29
0305233	France	A	2003-04-29
023561590	–	–	–
0305233	–	–	–
EP20020356159	–	–	–
FR20030005233	–	–	–

Members54

Family members, oldest first
Document	Office	Kind
EP1389614A1	European Patent Office (EPO)	A1	2004-02-18
CA2492173A1	Canada	A1	2004-02-26
WO2004016088A2	World Intellectual Property Organization (WIPO)	A2	2004-02-26
AU2003266316A1	Australia	A1	2004-03-03
WO2004016088A3	World Intellectual Property Organization (WIPO)	A3	2004-03-25
TW200415991A	Taiwan Province of China	A	2004-09-01
AR040852A1	Argentina	A1	2005-04-20
MXPA05001580A	Mexico	A	2005-04-25
MA27335A1	Morocco	A1	2005-05-02
EP1531673A2	European Patent Office (EPO)	A2	2005-05-25
KR20050071476A	Republic of Korea	A	2005-07-07
BR0313340A	Brazil	A	2005-07-12
RU2005106877A	Russian Federation	A	2005-07-20
ECSP055594A	Ecuador	A	2005-08-11
CN1674784A	China	A	2005-09-28
US2005234110A1	United States of America	A1	2005-10-20
JP2005535714A	Japan	A	2005-11-24
PL375269A1	Poland	A1	2005-11-28
EP1531673B1	European Patent Office (EPO)	B1	2006-01-04
IL166335A0	Israel	A0	2006-01-16
IL166335D0	Israel	D0	2006-01-16
AT314808T	Austria	T	2006-02-15
ATE314808T1	Austria	T1	2006-02-15
DK1531673T3	Denmark	T3	2006-03-06
DE60303147D1	Germany	D1	2006-03-30
ES2250921T3	Spain	T3	2006-04-16
HK1080329A	Hong Kong, China	A	2006-04-28
HK1080329A1	Hong Kong, China	A1	2006-04-28
NZ537608A	New Zealand	A	2006-04-28
SI1531673T1	Slovenia	T1	2006-06-30
ZA200500294B	South Africa	B	2006-08-30
DE60303147T2	Germany	T2	2006-08-31
OA19202A	African Intellectual Property Organization (OAPI)	A	2006-10-13
UA78361C2	Ukraine	C2	2007-03-15
CN1319946C	China	C	2007-06-06
AU2003266316B2	Australia	B2	2007-10-25
RU2316548C2	Russian Federation	C2	2008-02-10
KR100853967B1	Republic of Korea	B1	2008-08-25
US7572818B2	United States of America	B2	2009-08-11
IL166335A	Israel	A	2010-11-30
CA2492173C	Canada	C	2011-04-26
TWI343785B	Taiwan Province of China	B	2011-06-21
JP4782418B2	Japan	B2	2011-09-28
FR14C0045I1	France	I1	2014-07-18
LU92504I2	Luxembourg	I2	2015-01-02
FR14C0045I2	France	I2	2015-01-09
PL410411A1	Poland	A1	2015-03-16
PL410412A1	Poland	A1	2015-03-16
BRPI0313340B1	Brazil	B1	2015-08-18
PL222168B1	Poland	B1	2016-07-29
PL224002B1	Poland	B1	2016-11-30
PL224003B1This record	Poland	B1	2016-11-30
HUS1400037I1	Hungary	I1	2017-08-28
BE2014C015I2	Belgium	I2	2022-08-09

Method of producing 2-pyridyl ethyl benzamide derivative

Abstract

Term

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Priority claims8

Members54

Numbers

Titles2

Classification