EP2723720A1

EP2723720A1 - Method for producing pyrazolylcarboxanilides

Info

Publication number: EP2723720A1
Application number: EP12728549.2A
Authority: EP
Inventors: Wahed Ahmed Moradi; Norbert Lui; Michael Dockner
Original assignee: Bayer Intellectual Property GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2011-06-21
Filing date: 2012-06-19
Publication date: 2014-04-30
Also published as: US20140128617A1; WO2012175511A1; KR20140036240A; BR112013032988A2; JP2014523425A; MX2013014312A; CN103619822A

Abstract

The invention relates to a simplified method for producing pyrazolylcarboxanilides by reacting pyrazolyl carboxylic acid esters with anilines in the presence of a base and removing at least one reaction product.

Description

Process for the preparation of pyrazolylcarboxanilides

The present invention relates to a process for the preparation of pyrazolylcarboxanilides by reacting pyrazolylcarboxylic esters with anilines in the presence of a base.

It is known that 3- (difluoromethyl) -1-methyl-N-phenyl-1H-pyrazole-4-carboxanilides have fungicidal properties (cf., for example, WO 2003/070705).

Numerous methods for the synthesis of pyrazolylcarboxanilides are known from the literature (see WO 2006/024388, US 2011/0054183, US 2010/0174094). In the currently most widely practiced processes, corresponding pyrazolylcarboxylic acid derivatives, for example, pyrazolylcarboxylic acid halides (eg, pyrazolylcarboxylic acid chlorides), are reacted with aniline derivatives, for example, 3 ', 4'-dichloro-5-fluorobiphenyl-2-amine, optionally in the presence of a base. The disadvantage of the process described in the prior art is that the pyrazolylcarboxylic acid chloride used as the coupling partner has to be prepared in two stages from the pyrazolylcarboxylic acid ester. The design of technical processes, however, is strongly determined by economic and environmental considerations, with each additional stage associated with significant costs.

An economically interesting and easier access to carboxamides from Carbonsäureestern is the aminolysis of such esters (see. Eg, Jerry March, Advanced Organic Chemistry, 4 ^{th 'Edition,} pp. 421-424). However, the direct reaction of unactivated esters with anilines remains a difficult reaction and limited in their practical applicability. For example, the aminolysis of carboxylic acid esters often requires high temperatures (J. Am. Chem. Soc., 1949, 2215) and / or high pressures (Angew Chem, 1986, 98, 569-570). To be able to carry out the reaction on a laboratory scale under milder conditions, strongly alkaline, organometallic catalysts are used which, however, do not tolerate highly functionalized substrates and, moreover, are technically impracticable (J.A. Chem. Soc., 1955, 469-472, Tetrahedron Lett., 1971, 321-322, J. Org. Chem., 1963, 2915-2917; J. Org. Chem., 1992, 6101-6103). Among other catalysts such as cyanides (J. Org. Chem., 1987, 52, 2033-2036), and boron tribromides (Tetrahedron Lett., 1974, 3995), trimethylaluminum has been highlighted. Although this catalyst allows the synthesis of amides in good yields and under mild reaction conditions, but is highly corrosive, pyrophoric and reacts explosively with water and is therefore unsuitable for large-scale implementation. The object of this invention is to provide a process for the synthesis of pyrazolylcarboxanilides starting from pyrazolylcarboxylic acid esters and anilines, which is more economical compared to the processes known from the prior art. The process should be suitable for large-scale implementation and provide pyrazolylcarboxanilides in high yield and high purity. The object is achieved by a process for the preparation of fungicidally active pyrazolylcarboxanilides of the formula (III)

is hydrogen, fluorine or chlorine, is methyl, difluoromethyl or trifluoromethyl, is hydrogen, fluorine, chlorine, methyl, iso-propyl, methylthio or trifluoromethyl, for 1, 2, 3 or 4, preferably for 1 or 2, especially preferably represents 1, represents optionally mono- to trisubstituted, identically or differently substituted phenyl, where the substituents are selected from halogen, C 1 -C -alkyl, C 1 -C -alkoxy, C 1 -C 2 -haloalkyl or C 2 -C 4 -alkyl. Haloalkoxy having in each case 1 to 6 fluorine, chlorine and / or bromine atoms, hydroxyimino-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxyimino-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkoxyimino-C 1 -C 4 -alkyl, or in two adjacent substituents of difluoromethylenedioxy or tetrafluoroethylenedioxy; or represents in each case optionally monosubstituted to trisubstituted, identically or differently by C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and / or C 3 -C 10 -cycloalkyl-substituted C 3 -C 10 -cycloalkyl or C 3 -C 10 -cycloalkyl, or unsubstituted (linear or branched) Ci-C2o-alkyl or mono- or polysubstituted by identical or different fluorine, chlorine, bromine, iodine and / or C3-C6-cycloalkyl-substituted Ci- C2o-alkyl, wherein the cycloalkyl moiety in turn may be monounsaturated to four-fold, the same or different, by fluorine, chlorine, bromine, iodine, Ci-C4-alkyl and / or Ci-C4-haloalkyl may be substituted, or in each case optionally mono- or polysubstituted by identical or different fluorine, chlorine, bromine, iodine and / or C 3 -C 6 -cycloalkyl-substituted C 2 -C 20 -alkenyl or C 2 -C 20 -alkynyl, where the cycloalkyl part in turn is optionally monosubstituted to four-fold, identical or different, by halogen, C 1 -C 4 -alkyl and / or C 1 -C 4 -haloalkyl may be substituted or, together with the phenyl radical, for both syn isomers of N - [(1RS, 4SR, 9RS) -1,2,3,4-tetrahydro-9- (isopropyl) -l, 4-methanonaphthalene, or for both anti isomers of N- [(1RS, 4SR, 9SR) -1,2,3,4-tetrahydro-9-isopropyl-1,4-methanonaphthalene, or, together with the phenyl radical, for N - [(1RS, 4SR) - l, 2,3,4-tetrahydro-9- (dichloromethylene) - 1, 4-methanonaphthalene, or, together with the phenyl radical, for N- (l, 3-dihydro-l, l, 3-trimethyl-4 -isobenzofuranyl, by reaction of pyrazolylcarboxylic esters of the formula (I)

in which

R ¹ and R ^{2 are} as defined above and

R ^{5 is} C ₁ -C ₆ -alkyl, C ₁ -C ₆ -aryl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -thioalkyl, C ₁ -C ₆ -

Alkylthioalkyl, C ₆ alkylsulphonyl Ci-C ₆ alkyl, Ci-C ₆ cyanoalkyl, Ci-C ₆ haloalkyl, Ci-C ₆ - is nitroalkyl, C3-Cg-aryl or C3-Cg-cycloalkyl, with anilines of the formula (II)

in which

R, R and n are as defined above, wherein the reaction is carried out in the presence of a base and removing at least one of the products resulting from the reaction and optionally in an inert solvent. The pyrazolylcarboxylic acid esters used as starting materials are generally defined by the formula (I). According to a preferred embodiment of the present invention are used as starting materials Pyrazolylcarbonsäureester of formula (I), in which

R ^{5 is} methyl, ethyl or benzyl.

According to a particularly preferred embodiment of the present invention are used as starting materials Pyrazolylcarbonsäureester of formula (I), in which

R ^{5 is} ethyl or methyl.

The anilines used as starting materials are generally defined by the formula (II). According to a preferred embodiment of the present invention, the starting materials used are anilines of the formula (II) in which R ³ , R ⁴ and n are as defined above and the substituent R ^{3 is} in the 5-position.

According to a further preferred embodiment of the present invention, the starting materials used are anilines of the formula (II) in which

R ^{3 is} hydrogen, fluorine or chlorine, n is 1 or 2,

R ^{4 is} optionally two or three times, identically substituted phenyl, where the substituents are selected from fluorine or chlorine, or for C 2 -C 4 haloalkoxy with in each case 3 to 6 fluorine atoms and 0 to 1 chlorine atoms; or C3-bicycloalkyl optionally substituted once to four times, identically or differently by halogen and / or C 1 -C 4 -alkyl; or unsubstituted (linear or branched) C 2 -C 6 -alkyl; or, together with the phenyl radical, for both syn isomers of N - [(1RS, 4SR, 9RS) - 1, 2,3,4-tetrahydro-9- (isopropyl) -l, 4-methanonaphthalene, or for both anti isomers of N- [(1RS, 4SR, 9SR) -1,2,3,4-tetrahydro-9-isopropyl-1,4-methanonaphthalene; or, together with the phenyl radical, is N - [(lRS, 4SR) -1,2,3,4-tetrahydro-9- (dichloromethylene) -1,4-methanonaphthalene; or, together with the phenyl radical, is N- (1,3-dihydro-1,1,3-trimethyl-4-isobenzofuranyl. According to a particularly preferred embodiment of the present invention are used as starting materials anilines of the formula (II), in which

R ^{3 is} 5-fluoro, n is 1 and R ^{4 is} 3, 4-dichlorophenyl; or

R ^{3 is} hydrogen, n is 1 and

R ^{4 is} 3,4,5-trifluorophenyl; or

R ^{3 is} hydrogen, n is 1 and

R ^{4 is} 2- (l, l, 2,2-tetrafluoroethoxy), 2- (l, l, 2,3,3,3-hexafluoropropoxy) or 2- (3-Cl-l, l, 2-trifluoroethoxy) ; or

R ^{3 is} hydrogen, n is 1 and R ^{4 is} 2- (1, 1'-bicyclopropyl); or

R ^{3 is} hydrogen, n is 1 and

R ^{4 is} 2- (1,3-dimethylbutyl); or

R ^{3 is} hydrogen, n is 1 and

R ⁴ together with the phenyl radical for both syn isomers of N - [(1RS, 4SR, 9RS) - 1, 2,3,4-tetrahydro-9- (isopropyl) -l, 4-methanonaphthalene, or for both anti isomers of N - [(1RS, 4SR, 9SR) -1, 2,3,4-tetrahydro-9-isopropyl-1,4-methanonaphthalene; or

R ^{3 is} hydrogen, n is 1 and R together with the phenyl radical for N- [9- (dichloromethylene) -l, 2,3,4-tetrahydro-1, 4-methanonaphthalen-5-yl], for N - [(1S, 4R) -9- ( Dichloromethylene) -l, 2,3,4-tetrahydro-1, 4-methanonaphthalene-5-yl] - or N - [(1R, 4S) -9- (dichloromethylene) -1,3,3,4-tetrahydro -l, 4-methanonaphthalen-5-yl] -; or R ^{3 is} hydrogen, n is 1, and

R ⁴ together with the phenyl radical is N- (1,3-dihydro-1,1,3-trimethyl-4-isobenzofuranyl.

The anilines of the formula (II) to be used as starting materials in carrying out the process according to the invention can also be prepared in situ from the corresponding anilides, for example N-acetanilides.

According to a preferred embodiment of the present invention, the fungicidally active pyrazolylcarboxanilides of the formula (III) are selected from the group consisting of bixafen, fluxapyroxad, sedaxanes, isopyrazam, N- [9- (dichloromethylene) -1,3,3,4-tetrahydro- l, 4-methanonaphthalene-5-yl] -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide, N - [(1S, 4R) -9- (dichloromethylene) -1,3,2 , 4-tetrahydro-1,4-methanonaphthalen-5-yl] -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-c arb ox amide, N- [(1R, 4S) -9 - (dichloromethylene) - 1, 2,3, 4-tetrahydro-1,4-methanonaphthalene-5-yl] -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide, furametpyr, penflufen, 3 - (Difluoromethyl) -1-methyl-N- [2- (1,1,2,2-tetrafluoroethoxy) phenyl] -1H-pyrazole-4-carboxamide, 3- (difluoromethyl) -N- [4-fluoro-2 - (1, 1, 2,3,3,3-hexafluoropropoxy) phenyl] -1-methyl-1H-pyrazole-4-carboxamide, 3- (difluoromethyl) -1-methyl-N- [2- (l, 1,2,3,3,3-hexafluoropropoxy) phenyl] -1-methyl-1H-pyrazole-4-carboxamide and 3- (difluoromethane ethyl) -1-methyl-N- [2- (3-Cl-1, 1, 2-trifluoroethoxy) phenyl] -1 H -pyrazole-4-carboxamide.

Bixafen with the chemical name N- (3 ', 4'-dichloro-5-fluoro-1, -biphenyl-2-yl) -3- (difluoro-methyl) -1-methyl-1H-pyrazole-4-carboxamide and its production process starting from known and commercially available components are described in the document WO 2003/070705 A. F lux ap yrax ad with the same description of 3- (difluoromethyl) -1-methyl-N- (3 ', 4', 5'-trifluorobiphenyl-2-yl) -1H-pyrazole-4 -carboxamide and its production process starting from known and commercially available components is described in the document WO 2006/087343 A.

Sedaxane, which is a mixture of two cis isomers 2 '- [(lRS, 2RS) -l, 1'-bicycloprop-2-yl] -3- (difluoromethyl) -1-methylpyrazole-4-carboxanilide and two trans isomers are 2'- [(lRS, 2SR) -l, 1'-bicycloprop-2-yl] -3- (difluoromethyl) -1-methylpyrazole-4-carboxanilide and its production process starting from known and commercially available components are described in the publications WO 2003/074491 A, WO 2006/015865 A and WO 2006/015866 A.

Isopyrazam, which is a mixture of 2 syn isomers of 3- (difluoromethyl) -1-methyl-N - [(IRS, 4SR, 9RS) -1,2,3,4-tetrahydro-9-isopropyl-1 , 4-methanonaphthalene-5-yl] pyrazole-4-carboxamide and 2 anti-isomers of 3- (difluoromethyl) -l-methyl-N - [(lRS, 4SR, 9SR) -l, 2,3,4-tetrahydro- 9-isopropyl-l, 4-methanonaphthalen-5-yl] pyrazole-4-carboxamide and its production process starting from known and commercially available components are described in the document WO 2004/035589 A.

N- [9- (dichloromethylene) -l, 2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl] -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide, N - [(1S, 4R) -9- (dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalene-5-yl] -3- (difluoromethyl) -l-methyl-1H-pyrazole 4-C arb ox amide and N - [(IR, 4 S) -9- (dichloromethylene) -1,3,3,4-tetrahydro-1,4-methanonaphthalene-5-yl] -3- (difluoromethyl) - 1-methyl-1 H-pyrazole-4-carboxamide and their production processes starting from known and commercially available components are described in the document WO 2007/048556 A furametpyr with the chemical name 5-chloro-N- (l, 3-dihydro -l, l, 3-trimethyl-4-isobenzofuranyl) -1,3-dimethyl-lH-pyrazole-4-carboxamide is described in the document EP 03 15502.

Penflufen with the chemical name N- [2- (l, 3-dimethylbutyl) phenyl] -5-fluoro-l, 3-dimethyl-lH-pyrazole-4-carboxamide and its production process starting from known and commercially available components are in the Publication WO 2003/010149 A described.

3- (Difluoromethyl) -1-methyl-N- [2- (1,1,2,2-tetrafluoroethoxy) phenyl] -1H-pyrazole-4-carboxamide, 3- (difluoromethyl) -N- [4-fluoro 2- (1,1,3,3,3,3-hexafluoropropoxy) phenyl] -1-methyl-1H-pyrazole-4-carboxamide, 3- (difluoromethyl) -1-methyl-N- [2- (1 , 1, 2,3,3,3-hexafluoropropoxy) phenyl] -1-methyl-1H-pyrazole-4-carboxamide and 3- (difluoromethyl) -1-methyl-N- [2- (3-Cl-1 , 1, 2-trifluoroethoxy) phenyl] - 1 H-pyrazole-4-carboxamide are described in WO 2007/017450.

According to a particularly preferred embodiment of the present invention, the fungicidally active pyrazolylcarboxanilides of the formula (III) are selected from the group consisting of bixafen, fluxapyroxad and isopyrazam.

According to a very particularly preferred embodiment of the present invention, the fungicidally active pyrazolylcarboxanilide of the formula (III) is bixafen.

It has surprisingly been found that Pyrazolylcarbonsäureester of formula (I) with anilines of the formula (II) in the presence of a base, such as sodium, in organic Solvents, such as toluene or NMP or mixtures thereof in good yields to the corresponding fungicidally effective Pyrazolylcarboxaniliden of formula (III) can be implemented. The equilibrium of the reaction is shifted out of this reaction mixture to the desired pyrazolylcarboxanilides by removing at least one of the products present in equilibrium in the reaction mixture. For economic reasons, it is preferable to remove at least one alcohol resulting from the reaction from the reaction mixture.

Furthermore, it was surprisingly found that under the basic reaction conditions, the acidic difluoromethyl group of the pyrazole is not decomposed.

In a preferred embodiment of the present invention, the at least one reaction product that is removed is at least one alcohol. According to a particularly preferred embodiment of the present invention, the at least one alcohol is removed by distillation.

According to another embodiment of the present invention, the methanol and ethanol formed in the reaction are removed. The general or preferred radical definitions or explanations given above can also be combined as desired between each other, ie between the respective ranges and the preferred ranges. They apply accordingly to the end products as well as to the precursors and intermediates. In addition, individual definitions can be omitted.

If, for example, 3 ', 4'-dichloro-5-fluorobiphenyl-2-amine and ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylate are used as starting materials, and a base is formed and the product formed in the reaction Alcohol removed from the reaction mixture, the course of the process according to the invention by the following scheme (I) can be illustrated:

(Ii)

Scheme (I)

The pyrazolylcarboxylic esters of the formula (I) required as starting materials for carrying out the process according to the invention are known and / or can be prepared by known processes (cf., for example, WO 2009/106230, WO 2008/022777).

The anilines of the formula (II) furthermore required for carrying out the process according to the invention as starting materials are likewise known and / or can be prepared by known processes, for example by hydrogenation of the corresponding nitroaromatics (R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH, 2 ^nd edition 1999, 821 ff). According to the present invention, suitable bases are, for example, organic bases such. B. all amidine or guanidine bases, such as DBU, DBN, pentamethyl or Pentaisopropylguanidin, which must not contain reactive NH groups, and phosphine-imine bases (Schwesinger bases) as the tert-butyliminotris (dimethylamino) -phosphorane and the 1 tert-butyl-4,4,4-tris (dimethylamino) -2,2-bis- [tris (dimethylamino) -phosphoranylideneamino] -2λ ⁵ , 4λ ⁵ -catenadi (phosphazene). Trialkylamines which may be alicyclic or open-chain; Alkali and alkaline earth salts of aliphatic and / or aromatic carboxylic acids, such as acetates, propionates or benzoates; Alkali and alkaline earth carbonates, bicarbonates, phosphates, hydrogen phosphates and / or hydroxides; and metal alkoxides, in particular alkali metal or alkaline earth metal alkoxides, such as, for example, sodium methoxide, potassium methoxide, sodium ethanolate, magnesium methoxide, calcium ethoxide, sodium tert. Butoxide, potassium tert-butoxide or alkali isoamylate. Preferably, the base is an alkali alkoxide selected from the group consisting of sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert. butoxide, potassium tert-butoxide and alkali isoamylate. Particularly preferred are sodium methylate and sodium ethylate. The use of sodium methylate and sodium ethylate is particularly preferred for reasons of economy. The necessary amount of base present in the reaction step based on aniline can be determined by the skilled person simply by routine experimentation. The molar ratio of aniline to used base is 0.01 to 10, preferably 0.9 to 2, particularly preferably 1 to 1, 1. The use of larger amounts of base is possible in principle, but is disadvantageous for economic reasons.

The process according to the invention is optionally carried out in an inert solvent. Suitable solvents for carrying out the process according to the invention are all organic solvents which are inert under the reaction conditions.

Examples include ethers, such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl glycol diphenyl ether, dipropyl ether, diisopropyl ether, D-n-butyl ether , Diisobutyl ether, D ii so amyl ether, ethylene glycol dimethyl ether, diglyme, triglyme, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, 2-ethoxyethyl ether, isopropyl ethyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, methylcyclopentyl ether, tert-amyl methyl ether (TAME) Dichloroethyl ether and polyethers of ethylene oxide and / or propylene oxide; Acetonitrile, butyronitrile, aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and technical hydrocarbons which may be substituted by fluorine and chlorine atoms, such as dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; For example, so-called white spirits with components having boiling points in the range, for example, from 40 ° C to 250 ° C, cymene, gasoline fractions within a boiling interval of 70 ° C to 190 ° C, cyclohexane, methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene, xylene , Mesitylene, ethylbenzene, cumene, chlorobenzene, bromobenzene, benzotrifluoride, nitrobenzene; Dibutyl or ethylene carbonate, dialkyl sulfoxides, Ν, Ν-dialkylamides of aliphatic carboxylic acids or alkylated lactams. Preference is given to solvents which are selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dioxane, methylcyclopentyl ether, tert-amyl methyl ether (TAME), diglyme, toluene, xylene, mesitylene, cumene, N, N-dimethylacetamide, Ν, Ν Dimethylformamide, N-methylpyrrolidone and mixtures of these. Very particular preference is given to mixtures of NMP and toluene, xylene or cumene. Preference is given to a mixing ratio of toluene: NMP of 10: 1, more preferably of 5: 1.

Solvents are advantageously used in such an amount that the reaction mixture remains easy to stir throughout the process.

According to another embodiment of the present invention, the process according to the invention is carried out without a solvent.

The reaction is carried out at a temperature of 20 to 200 ° C, preferably from 50 to 100 ° C, more preferably from 50 to 80 ° C, and at a pressure between 1 mbar and 100 bar, preferably at a pressure between 100 mbar and 600 mbar performed. The following examples serve to illustrate the process according to the invention, without limiting it to:

Production Example 1

1. Synthesis of N- (3 ', 4'-dichloro-5-fluorobiphenyl-2-yl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide to remove methanol and ethanol

25.20 g [97.39 mmol, 99% GC purity] of 3 ', 4'-dichloro-5-fluorobiphenyl-2-amine and 20.50 g [99.40 mmol, 99% GC purity] of ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylate was dissolved in 70 g of toluene and 15 g of NMP. 18.26 g of sodium methylate (30% by weight in methanol) at 70 ° C. and 500 mbar of vacuum were metered into this solution while stirring in one hour. Methanol and ethanol were removed from the reaction mixture as an azeotrope with toluene. After completion of the addition of sodium methylate, the reaction mixture was stirred at 500 mbar and 70 ° C for 15 minutes. The vacuum was then reduced to 400 mbar for 15 minutes and to 200 mbar for another hour. The internal temperature dropped to approx. 60 ° C. After completion of the reaction, 200 g of water and 100 g of toluene were added to the still stirrable reaction mixture at 45 ° C. First, a sticky mass formed, from which the product crystallized. The pH of the suspension was adjusted to 7 with an HCl solution, cooled to about 5 ° C, the solid was filtered off, washed with 50 g of water and 50 g of toluene and dried. This gave 36.9 g [83.91 mmol] of N- (3 ', 4'-dichloro-5-fluorobiphenyl-2-yl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide white solid with a purity of 94.2% (86.1% yield). 'H-NMR (de-DMSO) δ: 9.74 (s, 1H), 8.21 (s, 1H), 7.68 (m, 1H), 7.64 (m, 1H), 7.48-7.46 (m, 1H), 7.40- 7.38 (m, 1H), 7.34-7.27 (m, 2H), 7.18 (t, 1H, J = 54 Hz), 3.92 (s, 3H).

2. Comparative Example Synthesis of N- (3 ', 4'-dichloro-5-fluorobiphenyl-2-yl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide without removal of methanol and ethanol

6.15 g [24 mmol, 99% GC purity] of 3 ', 4'-dichloro-5-fluorobiphenyl-2-amine and 5.0 g [24.49 mmol, 99% GC purity] of ethyl 3- (Difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylate was dissolved in 17 g of toluene and 3.6 g of NMP. 4.5 g of sodium methylate (30% by weight) in methanol) at 80 ° C. were metered into this solution while stirring in 15 minutes. Upon completion of the addition of sodium methylate, the Reaction mixture stirred at 80 ° C for 7 hours. The reaction was monitored by GC analysis. After about 7 hours, N- (3 ', 4'-dichloro-5-fluorobiphenyl-2-yl) -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide having a GC purity of 66 was obtained , 4%.

Preparation Example 2: Synthesis of 3- (difluoromethyl) -1-methyl-N- (3 ', 4', 5'-trifluorobiphenyl-2-yl) -1H-pyrazole-4-carboxamide

10 g [44.27 mmol, 98.9% GC purity] of 3 ', 4', 5'-trifluorobiphenyl-2-amine and 9.04 g [44.27 mmol, 99% GC purity] of ethyl-3 - (Difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylate were dissolved in 35 g of toluene and 7.5 g of NMP. 8.37 g of sodium methylate (30% by weight in methanol) at 70 ° C. and 500 mbar of vacuum were metered into this solution while stirring in 20 minutes. Methanol and ethanol were removed from the reaction mixture as an azeotrope with toluene. After completion of the addition of sodium methylate, the reaction mixture was stirred at 500 mbar and 70 ° C for 15 minutes. Subsequently, the vacuum was reduced to 300 mbar for 2 hours and to 200 mbar for a further hour. The reaction was monitored by GC-MS analysis. There was obtained 3- (difluoromethyl) -1-methyl-N- (3 ', 4', 5'-trifluorobiphenyl-2-yl) -1H-pyrazole-4-carboxamide having a GC-MS purity of 39%.

Production Example 3

S ynths s e v o n 3- (difluoromethyl) -N- (9-isopropyl-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl) -1-methyl-1H-pyrazole-4-carboxamide

9.86 g [48.98 mmol] of 9-isopropyl-l, 2,3,4-tetrahydro-l, 4-methanonaphthalene-5-amine (isomer mixture) and 10 g [48.98 mmol] of ethyl 3- ( difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylate were dissolved in 35 g of toluene and 7.5 g of NMP. To this solution was metered in 45 with stirring Minutes 9.08 g of sodium methylate (30 wt.% In methanol) at 70 ° C and 500 mbar vacuum. Methanol and ethanol were removed from the reaction mixture as an azeotrope with toluene. After completion of the addition of sodium methylate, the reaction mixture was stirred at 500 mbar and 70 ° C for 15 minutes. The vacuum was then reduced to 400 mbar for 15 minutes and to 200 mbar for 1.5 hours. After completion of the reaction, 100 g of water and 50 g of toluene were added to the reaction mixture at 45 ° C. After separation of the organic phase, the aqueous phase was extracted three times with 50 g of toluene, the combined organic phases were dried with Na2SÜ4 and then the solvent was removed in vacuo. 18.2 g of 3- (difluoromethyl) -N- (9-isopropyl-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl) -1-methyl-1H-pyrazole-4 were obtained -carboxamide as an isomer mixture with a GC-MS purity of 71.3%.

Claims

claims

1. Process for the preparation of fungicidally active pyrazolylcarboxanilides of the formula (III)

is hydrogen, fluorine or chlorine, is methyl, difluoromethyl or trifluoromethyl, is hydrogen, fluorine, chlorine, methyl, iso-propyl, methylthio or trifluoromethyl, for 1, 2, 3 or 4, preferably for 1 or 2, especially preferably represents 1, represents optionally mono- to trisubstituted, identically or differently substituted phenyl, where the substituents are selected from halogen, C 1 -C -alkyl, C 1 -C -alkoxy, C 1 -C 2 -haloalkyl or C 2 -C 4 -alkyl. Halogenoalkoxy having in each case 1 to 6 fluorine, chlorine and / or bromine atoms, hydroxyimino-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxyimino-C 1 -C 4 -alkyl, C 1 -C 4 -halogenoalkoxyimino-C 1 -C 4 -alkyl, or in the case of two adjacent substituents of difluoromethylenedioxy or tetrafluoroethylenedioxy; or represents in each case optionally monosubstituted to trisubstituted, identically or differently by C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and / or C 3 -C 10 -cycloalkyl-substituted C 3 -C 10 -cycloalkyl or C 3 -C 10 -cycloalkyl, or unsubstituted (linear or branched) Ci-C2o-alkyl or mono- or polysubstituted by identical or different fluorine, chlorine, bromine, iodine and / or C3-C6-cycloalkyl-substituted Ci-C2o-alkyl, wherein the cycloalkyl moiety in turn, optionally mono- to four-fold, the same or different, by fluorine, chlorine, bromine, iodine, Ci-C4-alkyl and / or Ci-C4-haloalkyl may be substituted, or in each case optionally mono- or polysubstituted by identical or different fluorine, chlorine, bromine, iodine and / or C 3 -C 6 -cycloalkyl-substituted C 2 -C 20 -alkenyl or C 2 -C 20 -alkynyl, where the cycloalkyl part in turn is optionally monosubstituted to four-fold, identical or may be differently substituted by halogen, Ci-C i-alkyl and / or Ci-C i-haloalkyl, or, together with the phenyl radical, for both syn isomers of N - [(1RS, 4SR, 9RS) -1,2 , 3,4-tetrahydro-9- (isopropyl) -l, 4-methanonaphthalene, or for both anti-isomers of N- [(1RS, 4SR, 9SR) -1,2,3,4-tetrahydro-9-isopropyl - 1, 4-methanonaphthalene, or, which together with the phenyl radical, represents N - [(1RS, 4SR) -1,3,3,4-tetrahydro-9- (dichloromethylene) -1,4-methanonaphthalene, or, together with the phenyl radical, represents N- (1,3-dihydro-1,1,3-trimethyl-4-isobenzofuranyl, by reaction of pyrazolylcarboxylic acid esters of the formula (I)

in which

R ¹ and R ^{2 are} as defined above and

R ^{5 is} C ₁ -C ₆ -alkyl, C ₁ -C ₆ -aryl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -thioalkyl, C ₁ -C ₆ -alkylthioalkyl, C ₁ -C 4 -alkyl C ₆ -alkylsulfonyl-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C 4 -nitroalkyl, C ₃ -C ₅ -aryl or C ₃ -C ₈ -cycloalkyl is aniline of the formula (II )

in which

R ³ , R ⁴ and n are as defined above, characterized in that the reaction is carried out in the presence of a base and removing at least one reaction product and optionally in an inert solvent.

2. The method according to claim 1, characterized in that pyrazolylcarboxylic esters of the formula (I) are used as starting materials, in which

R ^{5 is} methyl, ethyl or benzyl.

3. The method according to any one of claims 1 or 2, characterized in that one uses as starting materials anilines of the formula (II), in which

R ^{3 is} hydrogen, fluorine or chlorine, n is 1 or 2,

R ^{4 is} optionally double or triple, identically substituted phenyl, wherein the substituents are selected from fluorine or chlorine, or for C 2 -C 4 haloalkoxy having in each case 3 to 6 fluorine atoms and 0 to 1 chlorine atoms; or C3-bicycloalkyl optionally substituted once to four times, identically or differently by halogen and / or C 1 -C -alkyl; or unsubstituted (linear or branched) C 2 -C 6 -alkyl; or, together with the phenyl radical, for both syn isomers of N - [(1RS, 4SR, 9RS) - 1, 2,3,4-tetrahydro-9- (isopropyl) -l, 4-methanonaphthalene, or for both anti isomers of N- [(1RS, 4SR, 9SR) -1,2,3,4-tetrahydro-9-isopropyl-1,4-methanonaphthalene; or, together with the phenyl radical, is N - [(lRS, 4SR) -1,2,3,4-tetrahydro-9- (dichloromethylene) -1,4-methanonaphthalene; or, together with the phenyl radical, is N- (1,3-dihydro-1,1,3-trimethyl-4-isobenzofuranyl.

4. The method according to any one of claims 1 to 3, characterized in that one uses as starting materials anilines of the formula (II), in which

R ^{3 is} 5-fluoro, n is 1 and

R is 3,4'-dichlorophenyl; or R is hydrogen, n is 1 and

R ^{4 is} 3,4,5-trifluorophenyl; or is 2- (l, l, 2,2-tetrafluoroethoxy), 2- (l, l, 2,3,3,3-hexafluoropropoxy) or 2- (3-Cl-l, l, 2-trifluoroethoxy) ; or is 2- (1, 1'-bicyclopropyl); or is 2- (1,3-dimethylbutyl); or together with the phenyl radical for both syn isomers of N - [(1RS, 4SR, 9RS) -1,2,3,4-tetrahydro-9- (isopropyl) -l, 4-methanonaphthalene, or for both anti isomers of N - [(1RS, 4SR, 9SR) -1,2,3,4-tetrahydro-9-isopropyl-1,4-methanonaphthalene; or together with the phenyl radical for N- [9- (dichloromethylene) -l, 2,3,4-tetrahydro-1, 4-methanonaphthalen-5-yl], for N - [(1S, 4R) -9- ( Dichloromethylene) -l, 2,3,4-tetrahydro-1, 4-methanonaphthalene-5-yl] - or N - [(1R, 4S) -9- (dichloromethylene) -1,3,3,4-tetrahydro -l, 4-methanonaphthalen-5-yl] -; or together with the phenyl radical is N- (1,3-dihydro-1,1,3-trimethyl-4-isobenzofuranyl.

A method according to any one of claims 1 to 4, characterized in that the compound of formula (III) is selected from the group consisting of bixafen, Fluxapyroxad, Sedaxane, isopyrazam, N- [9- (dichloromethylene) -l, 2,3, 4-tetrahydro-1,4-methanonaphthalene-5-yl] -3- (difluoromethyl) -l-methyl-1H-pyrazole-4-carboxamide, N - [(1S, 4R) -9- (dichloromethylene) -l , 2,3,4-tetrahydro-1,4-methanonaphthalene-5-yl] -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide, N- [(1R, 4S) -9 (Dichloromethylene) -1,3,3,4-tetrahydro-1,4-methanonaphthalene-5-yl] -3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide, furametpyr, penflufen, 3 - (Difluoromethyl) -1-methyl-N- [2- (1,1,2,2-tetrafluoroethoxy) phenyl] -1 H -pyrazole-4-carboxamide, 3- (difluoromethyl) -N- [4-fluoro-2 - (l, l, 2,3,3, 3-hexafluoropropoxy) phenyl] -1-methyl-1H-pyrazole-4-carboxamide, 3- (difluoromethyl) -1-methyl-N- [2- (1, l , 2,3,3,3-hexafluoropropoxy) phenyl] -1-methyl-1H-pyrazole-4-carboxamide and 3- (difluoromethyl) -1-methyl-N- [2- (3-Cl-1, 1 , 2-trifluoroethoxy) phenyl] -1 H -pyrazole-4-carboxamide.

A method according to any one of claims 1 to 5, characterized in that the compound of formula (III) is selected from the group consisting of bixafen, Fluxapyroxad and isopyrazam.

7. The method according to any one of claims 1 to 6, characterized in that the compound of formula (III) is bixafen.

A process according to any one of claims 1 to 7, characterized in that the at least one reaction product which is removed is at least one alcohol.

9. The method according to claim 8, characterized in that the at least one alcohol is removed by distillation.

10. The method according to any one of claims 1 to 9, characterized in that the base is selected from the group consisting of sodium, potassium, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and alkali isoamylate.

11. The method according to claim 10, characterized in that the base is selected from the group consisting of sodium methoxide and sodium ethoxide.

12. The method according to any one of claims 1 to 11, characterized in that the inert solvent is selected from tetrahydrofuran, methyl-tetrahydrofuran, dioxane, methylcyclopentyl ether, tert-amyl methyl ether, diglyme, toluene, xylene, mesitylene, cumene, N, N - Dimethylacetamide, Ν, Ν-dimethylformamide, N-methylpyrrolidone and mixtures of these.

13. The method according to any one of claims 1 to 12, characterized in that the reaction is carried out without a solvent.

14. The method according to any one of claims 1 to 13, characterized in that the molar ratio of aniline to base is 0.01 to 10.

15. The method according to any one of claims 1 to 14, characterized in that the reaction takes place at a temperature of 20 to 200 ° C.