EP2812310A1

EP2812310A1 - Method for producing substituted anthranilic acid derivatives

Info

Publication number: EP2812310A1
Application number: EP13704756.9A
Authority: EP
Inventors: Thomas Himmler; Sergii Pazenok; Frank Volz; Norbert Lui
Original assignee: Bayer Intellectual Property GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2012-02-07
Filing date: 2013-02-06
Publication date: 2014-12-17
Also published as: JP2018027964A; KR20140124810A; MX2014009317A; MX363730B; TW201336811A; WO2013117601A1; TWI644888B; BR112014019487A2; US20150011772A1; KR102032979B1; IL233945A0; CN104245666A; CN104245666B; US9969717B2; US9670182B2; CN109970707A; US20160046607A1; JP2015511229A; JP6438551B2; US20170217934A1

Abstract

The invention relates to a method for producing substituted anthranilic acid derivatives of formula (I), in which R¹, R², R³, and R⁴ have the meanings specified in the description, by reacting the compounds of general formula (IV) in the presence of a palladium catalyst and carbon monoxide. The invention further relates to compounds of general formula (IV).

Description

i

Process for the preparation of substituted anthranilic acid derivatives

The present invention relates to a novel process for the preparation of substituted anthranilic acid derivatives of the formula (I)

is optionally mono- or polysubstituted, identically or differently, by fluorine or chlorine-substituted Ci-C6-alkyl, or C6-Cio-aryl, or represents a hetaryl radical of the general formula (II),

is preferably C 1 -C 3 -alkyl, Ce-aryl or a hetaryl radical of the general formula (II), particularly preferably C 1 -C 2 -alkyl or a hetaryl radical of the general formula (II) where

^R8 is Ci-Ce-alkyl, C ₃ -C ₆ cycloalkyl, Ci-C ₄ alkoxy, Ci-C ₄ alkylthio, Ci-C ₄ -Alkylsulfmyl, C ₁ -C4- alkylsulfonyl, which is optionally monosubstituted or may be the same or different, may be substituted by chlorine or fluorine, or is fluorine, chlorine, cyano, alkylamino, dialkylamino, cycloalkylamino or C 3 -C 6 -trialkylsilyl,

R ^{8 is} preferably fluorine, chlorine or C 1 -C ⁶ -alkyl,

R ⁸ particularly preferably represents fluorine or chlorine,

Z is CH or N,

Z is preferred and particularly preferably N, and Y is hydrogen, fluorine, chlorine, optionally mono- or polysubstituted, identical or different, by chlorine or fluorine-substituted Ci-C6-alkyl, C3-C6-cycloalkyl, Ci-C i-alkoxy, C ₁ -C4-alkylthio, Ci C4-alkylsulfmyl, Ci-C4-alkylsulfonyl, or is cyano, alkylamino, dialkylamino, cycloalkylamino, C3-C6-trialkylsilyl or a radical of the general formula (III)

stands,

in which

R> 9 is C 1 -C 5 -alkyl which may optionally be monosubstituted or polysubstituted, identically or differently, by halogen,

R ^{9 is} preferably C ₁ -C 3 -purylalkyl, R ^{9 is} particularly preferably CF 3 or C ₂ F ₅ ,

R ^{2 is} a radical OR ⁵ or NR ⁶ R ⁷ ,

R ^{2 is} preferred and particularly preferably represents OR ⁵ ,

R ^{2 is} also preferably and more preferably NR ⁶ R ⁷ , wherein R ⁵ , R ⁶ and R ^{7 are} independently hydrogen, Ci-C6-alkyl, or C6-Cio-aryl, R ⁵ , R ⁶ and R ⁷ independently of one another preferably represent hydrogen, C ₁ -C ₃ -alkyl or C 6 -aryl, R ⁵ , R ⁶ and R ⁷ independently of one another particularly preferably represent hydrogen or C ₁ -C ₂ -alkyl,

R ^{3 is} hydrogen, optionally mono- or polysubstituted, identically or differently by fluorine or chlorine-substituted Ci-C6-alkyl, Ci-C6-alkoxy or C3-C6-cycloalkyl, R ^{3 is} also halogen,

R ^{3 is} preferably GC ₅ -alkyl,

R ³ particularly preferably represents methyl, ethyl or tert-butyl,

R ^{3 is} also preferred and particularly preferably represents chlorine,

R ^{4 is} hydrogen, fluorine, chlorine, cyano, for optionally mono- or polysubstituted, the same or various C 1 -C 4 -alkyl substituted by fluorine or chlorine, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylamino, di- (C 1 -C 4 -alkylthio) alkyl) amino, C 3 -C 6 -cycloalkylamino, (C 1 -C 4 -alkoxy) imino, (C 1 -C 4 -alkyl) (C 1 -C 4 -alkoxy) imino, SF 5 or C 3 -C 6 -trialkylsilyl,

4 preferably represents hydrogen, chlorine or cyano, particularly preferably represents chlorine or cyano, characterized in that derivatives of the formula (IV)

in which the radicals R ¹ , R ³ and R ^{4 have} the abovementioned meaning,

and

X is chlorine, bromine or iodine, preferably bromine or iodine, particularly preferably bromine, in the presence of a palladium catalyst and optionally a phosphine ligand simultaneously ohlenmonoxid and a compound of general formula (V)

R ⁵ -OH (V), in which R ^{5 has} the abovementioned meanings, or a compound of the general formula (VI)

HNR ⁶ R ⁷ (VI) in which R ⁶ and R ^{7 have} the meanings given above, are reacted.

It has already been claimed in the literature that substituted anthranilic acid derivatives of formula (I) are prepared by reacting anthranilic acid derivatives of general formula (VII)

with carboxylic acids of the general formula (VIII)

R ^ COOH (VIII), in the presence of agents that activate the carboxyl group for the desired reaction, such as thionyl chloride, oxalyl chloride, phosgene, methanesulfonyl chloride or toluenesulfonic acid chloride can be obtained (WO 2003/015519, WO 2003/106427, WO WO2006 / 0672978, WO2008 / 010897, WO2008 / 070158, WO2008 / 082502, WO2009 / 006061, WO2009 / 061991, WO2009 / 085816, WO2009 / 111553, Bioorg. & Med. Chem. Lett. 15 (2005) 4898-4906; Biorg. & Med. Chem. 16 (2008) 3163-3170).

The known reactions can be illustrated by the following reaction schemes, wherein R ¹ , R ³ , R ⁴ , R ⁶ and R ^{7 have,} for example, the meanings given above

a) ⁵ with R ⁵ not equal to H, or NR ⁶ R ⁷

b) R ² = OR ⁵ with R ⁵ = H

These known methods for the preparation of substituted anthranilic acid derivatives of the formula (I) require the availability of the corresponding substituted anthranilic acid derivatives of the general formula (VII). These substituted anthranilic acid derivatives of the general formula (VII) are either known or can be prepared by known methods of organic chemistry. However, these substituted anthranilic acid derivatives of the general formula (VII) can be produced in part only in a complex manner, in many stages and at high costs, which can lead to uneconomically high costs for the end products as a result of unavoidable losses in yield.

Substituted anthranilic acid derivatives of the formula (I) are known as compounds having known insecticidal activity (see, for example, Bioorg. & Med. Chem. Lett. 15 (2005) 4898-4906; Biorg. & Med. Chem. 16 (2008) 3163-3170 ) of high interest. It has also already become known to prepare substituted anthranilic acid derivatives of the general formula (VII) by reacting substituted anthranilic acid derivatives of the general formula (IX) in the presence of a palladium catalyst, a ligand, a primary amine and a base with carbon monoxide (WO 2012/103436). However, it has not been disclosed that substituted anthranilic acid derivatives of the general formula (IV) in a similar way.

The object of the present invention is therefore to provide a new, more economical Verfalirens for the preparation of substituted anthranilic acid derivatives of the formula (I).

The object has been achieved according to the present invention by a process for the preparation of anthranilic acid derivatives of the general formula (I), characterized in that substituted anthranilic acid derivatives of the general

in which X, R ³ and R ^{4 have} the meanings given above,

with acids of the general formula (VIII) to the substituted anthranilic acid derivatives of the formula (IV)

be reacted, and then in the presence of a palladium catalyst and optionally phosphine ligands simultaneously with carbon monoxide and a compound of general formula (V)

HNR ⁶ R ⁷ (VI), in which R ⁶ and R ^{7 have} the meanings given above, are converted to the substituted anthranilic acid derivatives of the general formula (I).

The method according to the invention can be illustrated by the following scheme step 2

CO

(IV) (I)

Also subject matter of the present en the general formula (IV)

in which the radicals R ¹ , R ^J , R ⁴ and X have the meanings given above. Preference is given to compounds of the general formula (IV) in which

R ^{1 is} optionally mono- or polysubstituted, identically or differently, by fluorine or chlorine-substituted C 1 -C 6 -alkyl, or C 6 -C 10 -aryl, or is a hetaryl radical of the general formula (II),

in which

optionally mono- or polysubstituted, identically or differently, by fluorine or chlorine-substituted Ci-Ce-alkyl, C ₃ -C ₆ cycloalkyl, Ci-C ₄ alkoxy, Ci-C ₄ alkylthio, _Ci-C4 alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, or is fluorine, chlorine, cyano, alkylamino, dialkylamino, cycloalkylamino or C 3 -C 6 -trialkylsilyl, preferably fluorine, chlorine or C 1 -C 6 -alkyl, particularly preferably fluorine or chlorine, is CH or N, preferably N, and

Y is hydrogen, fluorine, chlorine, optionally mono- or polysubstituted by identical or different substituents, chloro or fluorine-substituted G-C6-alkyl, C3-C6-cycloalkyl, Ci-C i-alkoxy, C ₁ -C4-alkylthio, Ci C4-alkylsulfinyl, Ci-C4-alkylsulfonyl, or is cyano, alkylamino, dialkylamino, cycloalkylamino, -C6-trialkylsilyl or a radical of the general formula (III)

stands,

in which R ⁹ is C 1 -C 5 -alkyl which may be mono- or di-mono-, identical or different, substituted by Halogi,

R ^{9 is} preferably C 1 -C ³ -perfluoroalkyl,

R ⁹ particularly preferably represents CF 3 or C 2 F 5,

R ^{3 is} chlorine,

R ^{3 is} also methyl,

R ^{4 is} chlorine or cyano, and

X is bromine or iodine.

Particular preference is given to compounds of the general formula (IV) in which

R ^{1 is} a hetaryl radical of the general formula II),

in which

R ^{8 is} fluorine or chlorine, Z is N, and

Y is hydrogen, fluorine, chlorine or a radical of the general formula (III)

stands

in which

R ^{9 is} CF ₃ or C ₂ F ₅ , R ^{3 is} methyl, R ^{4 is} chlorine or cyano, and

X stands for bromine.

Examples of the particularly preferred compounds of the general formula (IV) which may be mentioned are: N- (2-bromo-4-cyano-6-methylphenyl) -1- (3-chloro-2-yl) -3- 5- (trifluoromethyl) -2H-tetrazol-2-yl] methyl} -1 H -pyrazole-5-carboxamide

N- (2-bromo-4-chloro-6-methylphenyl) -1- (3-chloropyridin-2-yl) -3- {[5- (pentafluoroethyl) -2H-tetrazol-2-yl] methyl} -1 H-pyrazole-5-carboxamide.

General Definitions: Alkyl groups (= fluoro or chloroalkyl groups) substituted with one or more fluorine or chlorine atoms are, for example, selected from trifluoromethyl (CF 3), difluoromethyl (CHF ₂ ), CC ₁ ₃ , CFCl ₂ , CF ₃ CH ₂ , C 1 CH ₂ , CF3CCI2.

Alkyl groups are in the context of the present invention, unless otherwise defined, linear or branched hydrocarbon groups.

The definition of alkyl and Ci-Ci ₂ alkyl includes, for example, the meanings methyl, ethyl, n-, iso- propyl, n-, iso-, sec- and t-butyl, n-pentyl, n-hexyl, 1,3- Dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl.

Cycloalkyl groups are in the context of the present invention, unless otherwise defined, annular saturated hydrocarbon groups.

Aryl radicals in the context of the present invention, unless otherwise defined, are aromatic hydrocarbon radicals which may have one, two or more heteroatoms selected from O, N, P and S and may optionally be substituted by further groups ,

Arylalkyl groups and arylalkoxy groups are in the context of the present invention, unless otherwise defined, substituted by aryl groups alkyl or alkoxy groups which may have an alkylene chain. Specifically, the definition of arylalkyl includes, for example, the meanings benzyl and phenylethyl; the definition of arylalkoxy, for example, the meaning benzyloxy.

Alkylaryl groups (alkaryl groups) and alkylaryloxy groups are in the context of the present invention, unless otherwise defined, by alkyl groups substituted aryl groups, or aryloxy groups which may have a C 1-8 alkylene chain and in the aryl skeleton or Aryloxygerüst one or more heteroatoms selected from O, N, P and S, may have.

Step 1

Anthranilic acid (IV) can be prepared as follows:

(IX)

(IV)

The reaction is carried out in the presence of a condensing agent. All agents customary for such coupling reactions are suitable for this purpose. Examples which may be mentioned are acid halide formers such as phosgene, phosphorus tribromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or thionyl chloride; Anhydride formers such as ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate or methanesulfonyl chloride; Carbodiimides, such as Ν, Ν'-dicyclohexylcarbodiimide (DCC) or other conventional condensing agents, such as phosphorus pentoxide, polyphosphoric acid, 1, 1 'carbonyldiimidazole, 2-ethoxy-N-ethoxycarbonyl-1, 2-dihydroquinol in (EEDQ), T r is iphenylphosphine / carbon tetrachloride, bromotripyrrolidinophosphonium hexafluorophosphate, bis (2-oxo-3-oxazolidinyl) phosphinochloro o of the toTzotriazol-1-oxy-tris (dimethylamino) phosphonium hexafluorophosphate. For polymer, supported reagents such as e.g. polymer-bound cyclohexylcarbodiimide can also be used. Bervozugt are phosgene, mesyl chloride and thionyl chloride.

If appropriate, process step 1 can be carried out in the presence of an inert organic diluent customary for such reactions. These include, preferably, aliphatic, alicyclic or aromatic hydrocarbons, such as, for example, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; Ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; Ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; Nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; Amides, such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide or mixtures thereof.

The process step 1 is usually carried out in the presence of a base.

Suitable bases are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as Na2CÜ3, K2CO3 and acetates such as NaOAc, KOAc, LiOAc, and -Alkoholate such as NaOMe, NaOEt, NaOt-Bu, KOt-Bu. Also suitable Bases include organic bases such as trialkylamines, alkylpyridines, phosphazenes and 1,8-diazabicyclo [5.4.0] undecene (DBU). Preferred are organic bases such as pyridines, alkylpyridines such as 2,6-dimethylpyridine, 2-methyl-5-ethylpyridine or 2,3-dimethylpyridine.

The process step 1 according to the invention is preferably carried out within a temperature range from 20 ° C to + 100 ° C, more preferably at temperatures of 30 ° C to +80 ° C, particularly preferably at 30-60 ° C.

The process step 1 according to the invention is generally carried out under atmospheric pressure. Alternatively, it is also possible to work in a vacuum or under pressure in an autoclave.

The reaction time can be chosen in a range between 1 hour and several hours, depending on the batch size and the temperature.

If appropriate, process step 1 can be carried out in the presence of a catalyst. Examples which may be mentioned are 4-dimethylaminopyridine or 1-hydroxy-benzotriazole.

step 2

Substituted anthranilic acid derivatives of the general formula (I) can be prepared according to process step 2 as follows:

step 2

CO

R ⁵ -OH

(IV) (I)

The reaction is carried out in the presence of a palladium catalyst. Palladium catalysts used in the process according to the invention are palladium (II) salts, such as, for example, palladium chloride, bromide, iodide, acetate, acetylacetonate, which are optionally replaced by further ligands, for example. B. Pd (0) species such as palladium on activated carbon, Pd (PPli3) 4, bis (dibenzylideneacetone) palladium or tris (dibenzylideneacetone) dipalladium used. Preference is given to bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, palladium chloride, palladium bromide and palladium acetate; Particularly preferred are bis (dibenzylideneacetone) palladium, palladium chloride and palladium acetate.

The amount of palladium catalyst used in the process according to the invention is 0.001 to 20 Mol percent, based on substituted anthranilic acid derivative of the general formula (IV). Preferably, 0.005 to 10 mole percent are used; particularly preferred are 0.01 to 5 mole percent.

As phosphine ligands in the process according to the invention, ligands of the general formula (X)

PR ¹⁰ R ^U R ¹² (X)

used

wherein the radicals R ¹⁰ , R ¹¹ and R ¹² independently of one another are hydrogen, linear or branched C 1 -C 6 -alkyl, vinyl, aryl or heteroaryl from the series pyridine, pyrimidine, pyrrole, thiophene or furan, which in turn with further Substituents from the series linear or branched Ci-C8-alkyl or C6-Cio-aryl, linear or branched G-Cg-alkyloxy or Ci-Cio-aryloxy, halogenated linear or branched Ci-C8-alkyl or halogenated C6-Cio-aryl , C6-Cio-aryloxycarbonyl, linear or branched Ci-C8-alkylamino, linear or branched Ci-Cs-dialkylamino, Ci-Cs-arylamino, Ci-Cs-Diarylamino, hydroxy, carboxyl, cyano, or halogen such as fluorine or chlorine substituted could be.

Furthermore, chelating bisphosphines are suitable as phosphine ligands. Examples of this for this 1, 2-bis (diphenylphosphino) ethane, 1, 2-bis (diphenylphosphino) propane, 1, 2-bis (diphenylphosphino) butane, 2,2 'bis (diphenylphosphino) - 1, 1' -binaphthyl and 1, 1 'bis (diphenylphosphino) fenOcen called.

Preferred phosphine ligands are trialkylphosphines such as tri-tert-butylphosphine in ad trimeradamantylphosphine, as well as triarylphosphines such as triphenylphosphine, tri (ortho-tolyl) phosphine or tri (para-methoxyphenyl) phosphine. Particularly preferred is triphenylphosphine.

Alternatively, it is also possible to use defined palladium complexes which have been previously produced from the abovementioned ligands in one or more process steps.

In the process according to the invention, 1 to 20 molar equivalents of phosphine are used, based on the amount of palladium used. Preference is given to using 2 to 15 molar equivalents.

Process step 2 of the process according to the invention is carried out in the presence of carbon monoxide (CO). The carbon monoxide is usually introduced as a gas, so that the reaction is usually carried out in an autoclave. Usually one works with 0, 1 to 50 bar CO pressure, preferably at 1 to 25 bar.

It is alternatively possible in principle to introduce the carbon monoxide in the form of suitable metal-carbonyl complexes such as di-cobalt octacarbonyl or molybdenum hexacarbonyl. Preference is given to working with gaseous carbon monoxide.

Process 2 is usually carried out in the presence of a base. Suitable bases include organic bases such as trialkylamines, alkylpyridines, phosphazenes and 1,8-diazabicyclo [5.4.0] undecene (DBU). Preference is given to organic bases such as triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, alkylpyridines such as, for example, 2,6-dimethylpyridine, 2-methyl-5-ethylpyridine or 2,3-dimethylpyridine.

The compounds of the general formula (V) or (VI) required for the preparation of the substituted anthranilic acid derivatives of the general formula (I) are usually used in an excess, based on the substituted anthranilic acid derivative of the general formula (IV). It is also possible to use the compounds of general formula (V) or (VI) in such an amount that they simultaneously serve as a solvent.

Preparation Examples The following preparation examples illustrate the invention without limiting it. example 1

2-acetamido-5-cyano-3-methylbenzoesäur

In a 30 ml autoclave under nitrogen as protective gas 2.54 g [10 mmol] of N- (2-bromo-4-cyano-6-methylphenyl) acetamide, 3.89 g [21 mmol] of tri-n-butylamine , 0, 131 g [0.5 mmol] of triphenylphosphine, 0.035 g [0.05 mmol] of bis (triphenylphosphine) palladium (II) chloride and 2 g of water. After sealing, the autoclave is purged with carbon monoxide, heated to 1 10 ° C and maintained a carbon monoxide pressure of 10 bar. After 18 hours, allowed to cool to room temperature, the autoclave, the reaction mixture is stirred with methylene chloride, filtered through diatomaceous earth, the filtrate washed first with dilute hydrochloric acid and then with water, dried over sodium sulfate and concentrated in vacuo. 1.14 g of the title compound are obtained.

LC / MS: m / e = 219 (MH ⁺ ).

GC / MS (silver): m / e = 362 (M ⁺ , 2 x sil., 10%), 347 (M ⁺ -15, 2 x sil., 45%). Example 2

N- (2-bromo-4-cyano-6-methylphenyl) -1- (3-chloropyridin-2-yl) -3 - {[5- (trifluoromethyl) -2H-tetrazol-2-yl] methyl} -H pyrazole-5-carboxami

To a solution of 3.74 g of 1- (3-chloro-2-yl) -3- {[5- (trifluoromethyl) -2H-tetrazol-2-yl] methyl} -1H-pyrazole-5-carboxylic acid in 20 ml of acetonitrile are added 1.86 g of 3-methylpyridine. Then at 0 ° C 1, 37 g of methanesulfonyl chloride are added dropwise. After 30 minutes at 0 ° C, the red solution thus obtained is slowly added dropwise to a solution of 2.11 g of 4-amino-3-bromo-5-methylbenzonitrile and 1, 12 g of 3-methylpyridine in 20 ml of acetonitrile. The mixture is stirred for one hour at room temperature and for 1 hour at 40 ° C, cooled to room temperature, the reaction mixture is mixed with water and methylene chloride, the organic phase is separated off, washed with dilute hydrochloric acid, dried and concentrated. The crude product thus obtained is purified by chromatography on silica gel (cyclohexane / ethyl acetate). This gives 1.30 g of the title compound as a light beige solid.

LC / MS: m / e = 566 (MH ⁺ with ⁷⁹ Br and ³⁵ C1). Example 3

Methyl 2 - ({[1- (3-chloropyridin-2-yl) -3 - {[5- (trifluoromethyl) -2H-tetrazol-2-yl] methyl] -1H-pyrazol-5-yl] carbonyl} amino) -5-cyano-3-methylbenzoate

In a 30 ml autoclave under nitrogen as protective gas 0.567 g of N- (2-bromo-4-cyano-6-methylphenyl) -1- (3-chloro-2-yl) -3- {[5- ( trifluoromethyl) -2H-tetrazol-2-yl] methyl} -1H-pyrazole-5-carboxamide, 0.463 g of tri-n-butylamine, 0.066 g of triphenylphosphine, 0.035 g of bis (triphenylphosphine) palladium (II) chloride and 10 ml of methanol combined. After sealing, the autoclave is purged with carbon monoxide, heated to 1 10 ° C and maintained a carbon monoxide pressure of 10 bar. After 18 hours, allow to cool to room temperature, relax the autoclave, stir Reaction mixture with methylene chloride, filtered through diatomaceous earth, the filtrate is washed first with dilute hydrochloric acid and then with water, dried over sodium sulfate and concentrated in vacuo. 0.49 g of the title compound are obtained.

LC / MS: m / e = 546 (MH ⁺ with ³⁵ C1).

Example 4 1- (3-Chloropyridin-2-yl) -N- [4-cyano-2- (dimethylcarbamoyl) -6-methylphenyl] -3 - {[5- (trifluoromethyl) -2H-tetrazol-2-yl] methyl} -LH-pyrazole-5-carboxamide

In a 30 ml autoclave under nitrogen as protective gas 0.567 g of N- (2-bromo-4-cyano-6-methylphenyl) -1- (3-chloropyridin-2-yl) -3 - {[5- (trifluoromethyl) -2H-tetrazol-2-yl] methyl} -1 H -pyrazole-5-carboxamide, 0.463 g of tri-n-butylamine, 0.066 g of triphenylphosphine, 0.035 g of bis (triphenylphosphine) -palladium (II) chloride and 2 ml of dimethylamine , After sealing, the autoclave is purged with carbon monoxide, heated to 110 ° C and maintained a carbon monoxide pressure of 10 bar. After 18 hours, allowed to cool to room temperature, the autoclave, the reaction mixture is stirred with methylene chloride, filtered through diatomaceous earth, the filtrate washed first with dilute hydrochloric acid and then with water, dried over sodium sulfate and concentrated in vacuo. 0.475 g of the title compound are obtained.

LC / MS: m / e = 559 (MH ⁺ with ³⁵ C1).

Claims

claims represents optionally mono- or polysubstituted by identical or different, fluorine-substituted or chlorine-substituted O-C6-alkyl, or C6-Cio-aryl, or represents a hetaryl radical of the general formula (II),

in which

^R8 is Ci-Ce-alkyl, C ₃ -C ₆ cycloalkyl, Ci-C ₄ alkoxy, Ci-C ₄ alkylthio, Ci-C ₄ -Alkylsulfmyl, G, C ₄ alkylsulfonyl, group, which is optionally monosubstituted or multiply, the same or different, may be substituted by chlorine or fluorine, or is fluorine, chlorine, cyano, alkylamino, dialkylamino, cycloalkylaniino or C3-C6-trialkylsilyl,

Z is CH or N, and

Y represents hydrogen, fluorine, chlorine, optionally mono- or polysubstituted, identically or differently, chlorine-substituted or fluorine-substituted C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl or represents cyano, alkylamino, dialkylamino, cycloalkylaniino, C 3 -C 6 -trialkylsilyl or a radical of the general formula (III)

stands,

in which

is Ci-Cs-alkyl, which may optionally be mono- or polysubstituted, identically or differently, by halogen, is a radical OR ⁵ or NR ⁶ R ⁷ , wherein

R ⁵ , R ⁶ and R ⁷ independently of one another represent hydrogen, G-Ce-alkyl, or Ce-Cio-aryl,

R ^{3 is} hydrogen, optionally mono- or polysubstituted, identically or differently by fluorine or chlorine-substituted Ci-C6-alkyl, G-C6-alkoxy or C3-C6-cycloalkyl,

R ^{4 is} hydrogen, fluorine, chlorine, cyano, optionally mono- or melirfach, identically or differently, by fluorine or chlorine-substituted Ci-C4-alkyl, GC ₄ -alkoxy, GC ₄ - alkylthio, Ci-C ₄ alkylsulfmyl, Ci -C ₄ alkylsulfonyl, Ci-C ₄ alkylamino, di- (GC - alkyl) amino, C3-C6-cycloalkylamino, (Ci-C ₄ alkoxy) imino, (Ci-C ₄ alkyl) (Ci-C ₄ -alkoxy) imino, SF5 or C3-C6-trialkylsilyl, characterized in that substituted antoanilic acid amide derivatives of the formula (IV)

in which the radicals R ¹ , R ^J and R ^{4 have} the abovementioned meaning

and X is chlorine, bromine or iodine, in the presence of a palladium catalyst and optionally a phosphine ligand simultaneously with carbon monoxide and a compound of the general formula (V)

R ⁵ -OH (V), in which R ^{5 has} the meanings given above, or a compound of general formula (VI)

2. The method according to claim 1, characterized in that the compounds of general formula (IV) are prepared by

Compounds of the general

in which X, R and R have the meanings given above,

with acids of the general formula (VIII)

R'COOH (VIII) in which R ^{1 has} the meanings given above, is reacted.

Process according to claim 2, characterized in that the compounds of general formula (IV) are prepared in the presence of a condensing agent and a base.

Process according to one of Claims 1 to 3, characterized in that palladium (II) salts or Pd (0) species are used as the palladium catalyst.

Process according to Claim 4, characterized in that the palladium catalyst used is bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, palladium chloride, palladium bromide or palladium acetate.

A process according to any one of claims 1 to 5, characterized in that as phosphine ligands compounds of general formula (X) p _R lü _R ll _R 12 where R ¹⁰ , R ¹¹ and R ¹² independently of one another are hydrogen, linear or branched G-Cs-alkyl, vinyl, aryl or heteroaryl selected from pyridine, pyrimidine, pyrrole, thiophene or furan, which in turn with further substituents from the series linear or branched Ci-Cs-alkyl or C6-Cio-aryl, linear or branched G-Cs-alkyloxy or Ci-Cio-aryloxy, halogenated linear or branched Ci-Cs-alkyl or halogenated C6-Cio-aryl, Ce-Cio-aryloxycarbonyl, linear or branched Ci-Cs-alkylamino, linear or branched G Cs-dialkylamino, Cis-Cs-arylamino, G-Cs-diarylamino, hydroxy, carboxyl, cyano, or halogen, or chelating biphosphines can be substituted.

7. The method according to claim 6, wherein the chelating biphosphines are selected from 1, 2-bis (diphenylphosphino) ethane, 1, 2-bis (diphenylphosphino) propane, 1, 2-bis (diphenylphosphino) butane, 2, 2 ' Bis (diphenylphosphino) -1,1'-binaphthyl and 1,1'-bis (diphenylphosphino) ferrocene.

8. The method according to claim 6, wherein is used as the phosphine ligand triphenylphosphine.

9. The method according to any one of claims 6 to 8, characterized in that 1 -20 molar equivalents of phosphine are used based on the amount of palladium catalyst.

10. Compounds of the general

where the radicals R ¹ , R ³ , R ⁴ and X have the meanings given above.

1 1. Compounds of general formula (IV) according to claim 10, wherein

R ^{1 is} optionally mono- or polysubstituted, identically or differently, fluorine-substituted or chlorine-substituted G-C 6 -alkyl, or C 10 -alk-aryl, or is a hetaryl radical of the general formula (II),

in which

R ^{8 is} optionally mono- or polysubstituted, identical or different, by fluorine or chlorine substituted G-Ce alkyl, C ₃ -C ₆ cycloalkyl, Ci-C ₄ alkoxy, Ci-C ₄ alkylthio, GC ₄ - alkylsulfinyl, Ci-C4-alkylsulfonyl,, or represents fluorine, chlorine, cyano, Alkylamino, dialkylamino, cycloalkylamino or C3-C6-trialkylsilyl,

Z is CH or N, and

Y represents hydrogen, fluorine, chlorine, G-Ce alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -fluoro- or chloroalkyl, Ci-C6-fluoro- or Chlorcycloalkyl, Ci-C4-alkoxy, Ci-C4 -fluoro- or chloroalkoxy, C ₁ -C4- alkylthio, Ci-C ₄ -Alkylsulfmyl, Ci-C ₄ alkylsulfonyl, Ci-C ₄ -fluoro- or Chloralkylthio, GC ₄ -fluoro- or Chloralkylsulfinyl, GC ₄ - Fluoro or chloroalkylsulfonyl, cyano, alkylamino, dialkylamino, cycloalkylamino, C3-C6-trialkylsilyl or a radical of the general formula (III)

in which

R ^{9 is} G-Ci-alkyl, which may be monosubstituted or polysubstituted, identically or differently, by halogen,

R ^{3 is} methyl,

R ^{3 is} also chlorine,

R ^{4 is} chlorine or cyano, and

X is bromine or iodine. 12. Compounds of general formula (IV) according to any one of claims 10 or 1 1, wherein R ^{1 is} a hetaryl radical of all the formula (II),

in which

R ^{8 is} fluorine or chlorine, Z stands for N, and

Y is hydrogen, fluorine, chlorine or a radical of the general formula (III)

stands

in which

R ^{9 is} CF ₃ or C ₂ F ₅ ,

R ^{3 is} methyl,

R ^{4 is} chlorine or cyano, and

X stands for bromine.