EP3810585A1 - Process for preparing tricyclic compounds - Google Patents

Abstract

The present invention relates to a process for preparing compounds of the formula (I), starting from compounds of the formula (II), wherein X, R1, R2, R3, R4, U, A1, A2, A3 and A4 are defined as described above. The invention further relates to compounds of formulae (III) and (IV), wherein all variables are defined as above.

Description

 Manufacturing process for tricyclic compounds

The present invention relates to a process for the preparation of tricyclic compounds of the formula (I)

starting from compounds of the formula (II)

wherein X, R ¹ , R ² , R ³ , R ⁴ , U, Ai, A, A and A are defined as described below.

The preparation of compounds according to formula (I) is e.g. B. from W02018 / 104214, WO2015 / 067646, WO2015 / 067647 or WO2016 / 174052 known. The preparation is carried out by means of a palladium-catalyzed Suzuki coupling using pyrazole-boronic acid derivatives or the corresponding arylboronic acid derivatives. The disadvantage of this process is the use of costly, high catalyst loads of between 5 and 10 mol% palladium as well as the technically complex preparation and necessary isolation of the boron acid derivatives, some of which are not very stable.

Because of the importance of tricyclic compounds of the general formula (I) as novel agrochemical active substances or precursors therefor, the object of the present invention is to provide a process for the preparation of compounds of the general formula (I) which can be used on an industrial scale and at low cost can and bypasses the disadvantages described above, in particular the high catalyst loading and the difficult isolation of the boronic acid derivatives. It is also desirable to obtain the special / V-arylpyrazole derivatives with high yield and high purity, so that the target compound preferably does not have to be subjected to any further, possibly complex, purification.

This object was achieved according to the invention by a process for the preparation of compounds of the formula (I) wherein

R ^{1 represents} hydrogen, cyano, halogen, C ₁ -C ₄ -alkyl optionally substituted with halogen or CN or represents Ci-C _t -alkoxy optionally substituted with halogen, R ^{2 represents} halogen, trifluoromethylsulfonyl, trifluoromethylsulfinyl, trifluoromethylsulfanyl, optionally with halogen substituted Ci-C _t -alkyl or represents optionally substituted with halogen Ci-C _t -alkoxy and

R ³ is hydrogen cyano, halogen, optionally substituted with halogen or CN C ₁ -C ₄ - alkyl or optionally substituted with halogen Ci-C ₄ -alkoxy, R ⁴ represents hydrogen, optionally substituted with halogen or CN-substituted Ci-Cs Alkyl or C ₃ -C ₆ cycloalkyl optionally substituted with halogen or CN,

U represents oxygen or a group N (R ⁵ ), where

R ^{5 represents} hydrogen, optionally substituted with halogen or CN (YCe-alkyl or optionally C ₃ -C ₆ -cycloalkyl substituted with halogen or CN, Ai stands for ('-Re,

A _{2 stands} for CR ₇ ,

A _{3 represents} C-Rs or N,

A _{4 stands} for CR ₉ ,

R _Ö , R ₇ , Re and R ₉ each independently represent hydrogen, C 1 -C ₄ -alkyl or halogen optionally substituted by halogen or CN, starting from compounds of the formula (II) wherein R ¹ , R ² and R ^{3 are} as defined above and X is iodine or bromine, comprising the steps

(1): Reaction of the compounds of the formula (II) with a magnesium- or lithium-based metalating reagent to give compounds of the formula (III)

where R ¹ , R ² , R ³ are defined as above, Y stands for chlorine, bromine or iodine, n stands for 0 or 1 and M stands for magnesium (if n = 1) or lithium (if n = 0),

(2): Reaction of the compounds of the formula (III) with an inorganic zinc compound to give compounds of the formula (IV)

wherein R ¹ , R ² , R ³ and Y are as defined above and m is 1 or 2, and

(3): Reaction of compounds of the formula (IV) with compounds of the formula (V)

wherein Ai, A2, A3, A4, R ⁴ , U and R ^{5 are} as defined above and Z represents bromine or iodine, in the presence of at least one Pd (0) or Pd (II) compound and at least one monodentate or bidentate Ligands, to compounds of formula (I). The process according to the invention has the advantage over the process described above that, on the one hand, isolation of the reactive species and thus an additional reaction step can be dispensed with, the catalyst loading and thus the environmental and cost impact are significantly reduced and the target compounds of the general form (I) can be obtained in good yields and high purities without an expensive purification step.

The preferred embodiments described below relate, if applicable, to all formulas described herein.

In a preferred embodiment of the invention, Re, R7, Rs and R9 each independently represent hydrogen, methyl or halogen.

In a further preferred embodiment of the invention, at most two, particularly preferably at most one of the radicals Re, R7, Rs and R9 are not hydrogen. Re, R7 and Rg are particularly preferably hydrogen and R _{9 is} Cj-C _t -alkyl or halogen which is optionally substituted by halogen or CN.

In a very particularly preferred embodiment, R ₉ stands for halogen, in particular for CI, F, I or Br and emphasized for CI.

In a further preferred embodiment, A _{3 is} N.

In a further preferred embodiment, Ai is C-H,

A ₂ for CH,

A ₃ for CH or N and A ₄ for CR ₉ , where R ₉ is defined as above.

In a further particularly preferred embodiment, Ai is C-H,

A ₂ for CH,

A ₃ for N and

A ₄ for C-halogen, preferably for C-Cl, CF, CI, C-Br, more preferably for C-Cl. In the event that U stands for O, the following preferred configurations for R ⁴ apply:

In a particularly preferred embodiment, R4 is hydrogen or (YCe-alkyl, very particularly preferably methyl or ethyl.

In the event that U stands for N (R ⁵ ), the following preferred configurations for R ⁴ and R ⁵ apply:

In a preferred embodiment of the invention, at most one of the radicals R ⁴ or R ^{5 is} hydrogen.

In a further preferred embodiment, R4 stands for C3-C6-cycloalkyl optionally substituted with CI, Br, I, F or CN, very particularly preferably for cyclopropyl or 1-CN-cyclopropyl.

In a particularly preferred embodiment

R4 for C3-C6-cycloalkyl optionally substituted with CI, Br, I, F or CN and R5 for hydrogen or Ci-C _t -alkyl optionally substituted with CI, Br, I, F or CN.

Is very particularly preferred

R4 for cyclopropyl or 1-CN-cyclopropyl and

R5 represents hydrogen or Ci-C _t alkyl, especially methyl or ethyl.

In a preferred embodiment of the invention, U stands for a group N (R ⁵ ).

In a preferred embodiment of the invention

R ² for halogen-substituted Ci-C _t -alkyl or halogen-substituted Ci-C _t -alkoxy, such as difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2nd , 2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, l-chloro-1,2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1st , 1- difluoroethyl, pentafluoroethyl, pentafluoro-tert-butyl, heptafluoro-n-propyl, heptafluoro-isopropyl, nonafluoro-n-butyl, nonafluoro-sec-butyl, fluoromethoxy, difluoromethoxy, chloro-difluoromethoxy, dichlorofluoromethoxy, trifluoromethoxy, trifluoromethoxy , 2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy or pentafluoroethoxy.

Is particularly preferred

R ² for Ci-C _t -alkyl substituted with fluorine or Ci-C _t -alkoxy substituted with fluorine.

Is very particularly preferred R ² for perfluoro-Ci-C ₃ alkyl (CF ₃ , C ₂ F ₅ or C ₃ F ₇ (n- or iso-propyl)) or perfluoro-C ₁ -C ₃ alkoxy (OCF ₃ , OC ₂ F ₅ or OC ₃ F ₇ (n- or iso-propoxy)).

It is particularly preferred

R ² for perfluoro-Ci-C ₃ alkyl, such as trifluoromethyl, pentafluoroethyl, heptafluoro-iso-propyl or heptafluoro-n-propyl, in particular for heptafluoro-iso-propyl.

In a further preferred embodiment, R ¹ and R ³ each independently represent a substituent selected from hydrogen, CI, Br, F, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkyl substituted by halogen, C ₁ -C ₃ -alkoxy or Ci-C ₃ alkoxy substituted with halogen.

In a further preferred embodiment, R ¹ and R ^{3 are} the substituents described herein, but R ¹ and R ^{3 are} not simultaneously in a compound for hydrogen. In other words, when R ¹ in a compound is hydrogen, R ^{3 is} one of the other substituents described herein and vice versa.

In a particularly preferred embodiment, R ¹ and R ³ each independently represent CI, Br, C ₁ -C ₃ -alkyl, or C ₁ -C ₃ -alkyl substituted with fluorine, C ₁ -C ₃ -alkoxy or Ci-C substituted by fluorine ₃ -alkoxy, especially for CI, Br, methyl, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

In a very particularly preferred embodiment, R ¹ and R ³ independently of one another are CI, Br or F, in particular CI or Br. In a particularly advantageous embodiment of the invention, R ¹ and R ^{3 are the} same halogen, in particular chlorine.

In a preferred embodiment of the invention, at least one of the radicals R ¹ , R ² , R ^{3 stands} for Ci-C _t -alkyl substituted with halogen or for Ci-C _t -alkoxy substituted with halogen, particularly preferably for Ci-C substituted with fluorine ₃ alkyl or for fluorine substituted Ci-C ₃ alkoxy.

In a further particularly advantageous embodiment of the invention

R ¹ for halogen or Ci-C ₃ -alkyl, in particular for Br, CI or methyl,

R ² is fluorine-substituted Ci-C _t alkyl or fluorine-substituted Ci-C _t -alkoxy, in particular heptafluoro-iso-propyl and

R ³ represents halogen, Ci-C ₃ alkyl substituted with fluorine or Ci-C ₃ alkyl, Ci-C ₃ alkoxy or fluoro substituted Ci-C ₃ alkoxy, in particular Cl, methyl, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

In a further preferred embodiment of the invention R ¹ for halogen or Ci-C3-alkyl, in particular for Br, CI or methyl,

R ² is fluorine-substituted Ci-C _t alkyl or fluorine-substituted Ci-C _t -alkoxy, in particular heptafluoro-iso-propyl,

R ^{3 represents} halogen, Ci-C3-alkyl or Ci-C3-alkyl, Ci-C3-alkoxy or fluorine-substituted Ci-C3-alkoxy or fluorine-substituted Ci-C3-alkoxy, in particular CI, methyl, trifluoromethyl, trifluoromethoxy or difluoromethoxy,

R ⁴ for hydrogen, Ci-C _ö alkyl or optionally substituted with CI, Br, I, F or CN substituted C3-C6-cycloalkyl, in particular for methyl, ethyl, cyclopropyl and 1-CN-cyclopropyl

U for oxygen or a group N (R ⁵ ), where

R ^{5 is} hydrogen or Ci-C _t alkyl, in particular methyl or ethyl,

Ai for C-H,

A ₂ for CH,

A3 for C-H or N, especially for N and

A4 for CR ₉ being

R9 stands for halogen, in particular for CI.

In a preferred embodiment of the invention, X stands for iodine.

Compounds of the formula (II) can be obtained by halogenation of the corresponding pyrazole derivatives. The production is already described in W02018 / 104214, WO2015 / 067646, WO2015 / 067647 or WO2016 / 174052.

Preferred halopyrazoles of the formula (II) are

4-bromo-1 - [4- (1, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) -2,6-dimethylphenyl] - 1 H-pyrazole

4-bromo-1 - [2,6-dichloro-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) phenyl] -1 H-pyrazole

4-bromo-1 - [2-chloro-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] -1 H-pyrazole

4-bromo-1 - [2-chloro-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) phenyl] -1 H-pyrazole

4-bromo-l- [2-chloro-6- (difluoromethoxy) -4- (l, l, l, 2,3,3,3-heptafluoropropane-2-yl) phenyl] -lH-pyrazole

4-bromo-1 - [4- (1, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) -2-methyl-6- (trifluoromethyl) phenyl] -1 H-pyrazole 4-bromo-1 - [2-bromo-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] -1 H-pyrazole

4-bromo-1 - [2-bromo-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) phenyl] - 1 H-pyrazole 1 - [ 4- (1, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) -2,6-dimethylphenyl] -4-iodo-1H-pyrazole

1 - [2,6-dichloro-4- (1, 1,1, 2,3,3,3-heptafluoropropan-2-yl) phenyl] -4-iodo-1 H-pyrazole

1 - [2-chloro-4- (1, 1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] -4-iodo-1 H-pyrazole l- [ 2-chloro-4- (l, l, l, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) phenyl] -4-iodo-lH-pyrazole 1 - [2-chloro 6- (difluoromethoxy) -4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) phenyl] -4-iodo-lH-pyrazole l- [4- (l, l, l , 2,3,3,3-heptafluoropropan-2-yl) -2-methyl-6- (trifluoromethyl) phenyl] -4-iodo-1H-pyrazole 1 - [2-bromo-4- (1,1,1 , 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] -4-iodo-1 H-pyrazole 1 - [2-bromo-4- (1,1,1, 2, 3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) phenyl] -4-iodo-1H-pyrazole

The following compounds are particularly preferred:

 4-bromo-1 - [2,6-dichloro-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) phenyl] -1 H-pyrazole

4-bromo-1 - [2-chloro-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] -1 H-pyrazole 4-bromo - 1 - [2-chloro-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) phenyl] - 1 H-pyrazole 4-bromo-l- [2-chloro-6- (difluoromethoxy) -4- (l, l, l, 2,3,3,3-heptafluoropropan-2-yl) phenyl] -lH-pyrazole 4-bromo-1 - [4- ( 1, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) -2-methyl-6- (trifluoromethyl) phenyl] - 1 H-pyrazole 4-bromo-1 - [2-bromo-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] - 1 H-pyrazole 4-bromo-1 - [2-bromo-4- (1, 1,1,3,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) phenyl] -1 H-pyrazole 1 - [2,6-dichloro-4- (1,1,1,2 , 3,3,3-heptafluoropropan-2-yl) phenyl] -4-iodo-1 H-pyrazole

1 - [2-chloro-4- (1, 1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] -4-iodo-1 H-pyrazole l- [ 2-chloro-4- (l, l, l, 2,3,3,3-heptafluoropropane-2-yl) -6- (trifluoromethoxy) phenyl] -4-iodo-lH-pyrazol

1 - [2-Chloro-6- (difluoromethoxy) -4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) phenyl] -4-iodo-1H-pyrazole l- [4 - (l, l, l, 2,3,3,3-heptafluoropropane-2-yl) -2-methyl-6- (trifluoromethyl) phenyl] -4-iodo-lH-pyrazol 1 - [2-bromo-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) phenyl] -4-iodo-1 H-pyrazole

1- [2-bromo-4- (l, l, l, 2,3,3,3-heptafluoropropane-2-yl) -6- (trifluoromethoxy) phenyl] -4-iodo-lH-pyrazol

Compounds of the formula (V) are obtainable by esterification or amidation of the corresponding halogenated aryl or A icroroarylcarhonic acid derivatives in analogy to the methods generally known to the person skilled in the art and their preparation is described, for example, in WO2018 / 104214, WO2014 / 186398 or WO2013 / 042035.

Preferred compounds of formula (V) are:

Methyl 2-chloro-5-iodo-pyridin-3-carboxylate

Methyl-5-bromo-2-chloro-pyridine-3-carboxylate

Ethyl 2-chloro-5-iodo-pyridin-3-carboxylate

Ethyl 5-bromo-2-chloro-pyridine-3-carboxylate n-propyl-2-chloro-5-iodo-pyridine-3-carboxylate n-propyl-5-bromo-2-chloro-pyridine-3-carboxylate

Isopropyl 2-chloro-5-iodo-pyridin-3-carboxylate

Isopropyl 5-bromo-2-chloro-pyridine-3-carboxylate tert-butyl-2-chloro-5-iodo-pyridine-3-carboxylate tert-butyl-5-bromo-2-chloro-pyridine-3-carboxylate

5-Bromo-2-chloro- / V, / V-dimethyl-pyridine-3-carboxamide

2-chloro-5-iodo / V, / V-dimethyl-pyridine-3-carboxamide 2-chloro / V-cyclopropyl-5-iodo / V-methyl-pyridine-3-carboxamide 5-bromo-2- chloro- / V-cyclopropyl- / V-methyl-pyridine-3-carboxamide 2-chloro-5-iodo / V-isopropyl- / V-methyl-pyridine-3-carboxamide 5-bromo-2-chloro- / V -isopropyl- / V-methyl-pyridine-3-carboxamide

The following are particularly preferred:

Methyl 2-chloro-5-iodo-pyridin-3-carboxylate Methyl 5-bromo-2-chloro-pyridine-3-carboxylate ethyl 2-chloro-5-iodo-pyridine-3-carboxylate ethyl 5-bromo-2-chloro-pyridine-3-carboxylate n-propyl-2-chloro -5-iodo-pyridine-3-carboxylate n-propyl 5-bromo-2-chloro-pyridine-3-carboxylate

2-chloro- / V-cyclopropyl-5-iodo- / V-methyl-pyridine-3-carboxamide

5-Bromo-2-chloro- / V-cyclopropyl-/ V-methyl-pyridine-3-carboxamide

The following compounds of the formula (I) are preferably prepared by the process described herein:

Unless otherwise defined elsewhere, the term “alkyl”, according to the invention, either alone or in combination with other terms, such as haloalkyl, for the purposes of the present invention, preferably a residue of a saturated, aliphatic hydrocarbon group having 1 to 12 1 to 6 and particularly preferably 1 to 4 carbon atoms understood, which can be branched or unbranched. Examples of C1-C12 alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, tert-pentyl , 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.

The term “alkoxy”, either alone or in combination with other terms, such as, for example, haloalkoxy, is understood here to mean an O-alkyl radical, the term “alkyl” having the meaning given above. Unless otherwise defined elsewhere, the term “aryl” is understood according to the invention to mean an aromatic radical having 6 to 14 carbon atoms, preferably phenyl, naphthyl, anthryl or phenanthrenyl, particularly preferably phenyl.

Unless otherwise defined elsewhere, the term “cycloalkyl”, either alone or in combination with other terms, is understood according to the invention to mean a C3-C8 cycloalkyl radical, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl ,

Halogen substituted residues e.g. Haloalkyl (= haloalkyl), are halogenated once or several times to the maximum possible number of substituents. In the case of multiple halogenation, the halogen atoms can be the same or different. Unless otherwise stated, optionally substituted radicals can be mono- or polysubstituted, in the case of multiple substitutions the substituents can be the same or different.

The general or priority areas listed above apply accordingly to the overall process. These definitions can be combined with one another, i.e. between the respective preferred areas.

Processes are preferably used according to the invention in which there is a combination of the meanings and ranges listed above as preferred.

Processes in which a combination of the meanings and ranges listed above as particularly preferred are particularly preferably used according to the invention.

Processes in which a combination of the meanings and ranges listed above as very particularly preferred are used very particularly preferably according to the invention.

According to the invention, methods are used in particular in which there is a combination of the meanings and ranges specified above as particularly.

Processes in which a combination of the meanings and ranges listed above as emphasized are used according to the invention.

Process description

Step 1):

According to the invention, the compounds of the formula (II) are reacted in a first step with a magnesium- or lithium-based metalating reagent to give compounds of the formula (III) where R ¹ , R ² and R ^{3 are} as defined above, Y is chlorine, bromine or iodine, preferably chlorine or bromine, n is 0 or 1 and M is magnesium (when n = 1) or lithium ( at n = 0).

M is furthermore preferably magnesium and n is 1.

Suitable magnesium or lithium-based metalation reagents are, in particular, alkyl lithium compounds LiR, where R stands for Ci-Ce alkyl, and alkyl magnesium halide compounds RMgHal, where R stands for (VCe alkyl and shark for halogen, preferably for chlorine, bromine or iodine. Preferred n-butyllithium, sec-butyllithium, tert-butyllithium, n-hexyllithium, methyl magnesium chloride, bromide or iodide, ethyl magnesium chloride, bromide or iodide or (n- or iso) propyl magnesium chloride, bromide or iodide are particularly preferred n-Butyllithium, n-Hexyllithium, methyl magnesium chloride or bromide, ethyl magnesium chloride or bromide or isopropyl magnesium chloride or bromide and very particularly preferably methyl magnesium bromide or chloride, ethyl magnesium bromide or chloride or isopropyl magnesium chloride or bromide can be used become.

If appropriate, the reactivity of the metalation reagent can be increased by the addition of lithium chloride; the metalation of compounds of the general formula (II) to compounds of the formula (III) is preferably carried out according to the invention without the addition of activating agents.

Amounts between 0.8 and 2.0 equivalents, particularly preferably between 0.9 and 1.5 equivalents, very particularly preferably between 1.0 and 1.2 equivalents, are preferred, based on the total amount of substances of the compounds of the formula ( II), the magnesium or lithium based metalation reagents used.

The metalating reagent is preferred in its commercially available form, in the case of lithium reagents as a solution in a non-polar solvent such as hydrocarbons (for example n-pentane, n-hexane, n-heptane, cyclohexane) or aromatic solvents (for example toluene or trifluoromethylbenzene) and in the case of magnesium reagents as Solution in ethereal solvents (e.g. diethyl ether, tert-butyl methyl ether, tetrahydrofuran (THF) or methyl THF), used without further dilution. The metalation reagent is preferred in concentrations between 0.2 mol / L to 5.0 mol / L, particularly preferably in concentrations between 0.2 mol / L to 3.0 mol / L, very particularly preferably in concentrations between 0.5 mol / L L to 3.0 mol / L used. The metalating reagent according to the invention is preferably metered as a solution in the diluent or solvent defined above as preferred to a solution of the compound of the formula (II) in a diluent or solvent according to the invention, as defined below for step (1). Inverse dosing is also possible, but less preferred for technical reasons.

The reaction time of the metalation is preferably in the range of the metering time of the metalation reagent. The implementation is instant. Experts can easily estimate the dosing time based on their experience. However, the dosage is preferably between 0.5 to 6 hours, particularly preferably from 1 to 4 hours. Longer dosing times are also possible from a technical point of view, but are not sensible from an economic point of view.

The reaction can be carried out over a wide temperature range. It is usually carried out in a temperature range from -78 to 200 ° C., preferably at temperatures between -20 to 100 ° C., particularly preferably at temperatures between -10 to 50 ° C.

The reaction can be carried out under elevated or reduced pressure. However, it is preferably carried out under normal pressure, e.g. in the range of 1013 hPa + 300 hPa, or in the range of 1013 hPa + 100 hPa, or in the range of 1013 hPa + 50 hPa.

Step (1) is preferably carried out in a suitable diluent or solvent. Suitable solvents are in principle all organic solvents which are inert under the specific reaction conditions, such as, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane and industrial hydrocarbons, cyclohexane, methylcyclohexane, petroleum ether, ligroin, benzene, toluene, Trifluoromethylbenzene, xylene, mesitylene), aliphatic, cycloaliphatic or aromatic ethers (e.g. 1,2-dimethoxyethane (DME), diglyme, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, methyl tert-butyl ether, anisole ) or mixtures of the solvents mentioned.

Preferred solvents are hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, trifluoromethylbenzene, xylene, mesitylene, anisole, THF, 2-methyl-THF or methyl tert-butyl ether, toluene, trifluoromethylbenzene, xylene, anisole, THF or are particularly preferred Methyl tert-butyl ether.

Step 2):

In the process according to the invention, step (1) transmetallates the compounds of the formula (III) with an inorganic zinc compound to give compounds of the formula (IV),

where R ¹ , R ² , R ³ and Y are as defined above and n is 1 or 2.

 This is particularly advantageous since the zinc reagents formed have improved stability and selectivity and the compounds of the general formula (I) can thus be obtained with higher yields and purities.

Inorganic zinc compounds suitable for the transmetallation are, in particular, zinc halides and zinc acetate. Zinc chloride, zinc bromide, zinc iodide and zinc acetate are preferred, zinc chloride and zinc bromide are particularly preferred and zinc chloride is very particularly preferred. Mixtures of the reagents mentioned can also be used.

Amounts of between 0.4 and 2.0 equivalents, particularly preferably between 0.45 and 1.5 equivalents, very particularly preferably between 0.5 and 1.2 equivalents, based on the total amount of substances of the compounds of the formula ( III), the inorganic zinc compound used.

The zinc-based transmetallation reagent is preferably used in pure form or as a solution in a suitable ethereal solvent (for example THE, 2-methyl-THL or methyl tert-butyl ether) in concentrations between 0.05 mol / L to 3.0 mol / L , particularly preferably in pure form or as an ethereal solution in concentrations between 0.2 mol / L to 2.5 mol / L and very particularly preferably in pure form or as an ethereal solution in concentrations between 0.5 mol / L to 1.5 mol / L used.

According to the invention, the transmetallation can preferably be carried out by adding a solution of the inorganic zinc salt to a solution of the compounds of the general Lormel (III) in one of the solvents mentioned under step (1) or by inverse metering.

The duration of the dosage can range from 0.1 to 4 hours, particularly preferably from 0.2 to 2 hours. Longer dosing times are also possible from a technical point of view, but are not sensible from an economic point of view.

The reaction can be carried out over a wide temperature range. It is usually carried out in a temperature range from -78 to 200 ° C., preferably at temperatures between -20 to 100 ° C., particularly preferably at temperatures between -10 to 50 ° C.

The reaction can be carried out under elevated or reduced pressure. However, it is preferably carried out under normal pressure, for example in the range from 1013 hPa + 300 hPa, or in the range from 1013 hPa + 100 hPa, or in the range from 1013 hPa + 50 hPa. Step (2) is preferably carried out in a suitable diluent or solvent. Suitable solvents are in principle all organic solvents which are inert under the specific reaction conditions, such as, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane and industrial hydrocarbons, cyclohexane, methylcyclohexane, petroleum ether, ligroin, benzene, toluene, Trifluoromethylbenzene, xylene, mesitylene), aliphatic, cycloaliphatic or aromatic ethers (e.g. 1,2-dimethoxyethane (DME), diglyme, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, methyl tert-butyl ether, anisole ) or mixtures of the solvents mentioned.

Step (2) is preferably carried out in the same diluent or solvent as step (1).

Step 3):

Preparation of compounds of formula (I)

The process according to the invention further comprises the reaction of the compounds of the formula (IV) with compounds of the formula (V),

where Ai, A ₂ , A ₃ , A ₄ , R ₄ , R ⁵ , U and Z are defined as above,

in the presence of at least one Pd (0) or Pd (II) compound and at least one monodentate or bidentate ligand, to give compounds of the formula (I).

Suitable Pd (0) or Pd (II) compounds are in particular palladium (II) halides (preferably chloride, bromide, iodide), Pd (OAc) 2, palladium (II) pivalate, allyl palladium (II) chloride dimer, Pd ( acac) 2 (acac = acetylacetonate), Pd (N (),> ₂ , Pd (dba) 2 (dba = dibenzylidene acetone), Pd2 (dba) 3, dichloro-bis (triphenylphosphine) palladium (II), Pd (dppf) Ch (dppf = bis (diphenylphosphino) ferrocene), Pd (MeCN) ₂ Cl2, and tetrakis (triphenylphosphine) palladium (0) .PdCL, Pd (OAc) ₂ , allyl palladium (II) chloride dimer, Pd (acac ) 2, Pd2 (dba) 3, dichloro-bis (triphenylphosphine) palladium (II), Pd (dppf) Cl2 and Pd (MeCN) ₂ Cl2, Pd (OAc) ₂ , palladium (II) pivalate, allyl palladium (particularly preferred is II) chloride dimer, Pd2 (dba) 3, Pd (dppf) Cl2 and Pd (MeCN) 2Cl2 and very particularly preferably Pd (OAc) 2. Mixtures of the compounds mentioned can also be used.

Amounts of the Pd (0) or Pd (II) compound, based on the total amount of substance of the compounds of the formula (IV) used, are preferably between 0.0001 and 0.05 equivalents, particularly preferably between 0.0003 and 0.025 equivalents, very particularly preferably between 0.0004 and 0.01 equivalents.

Suitable monodentates or bidentate ligands are, for example, optionally mono- or polysubstituted triarylphosphines (in particular triphenylphosphine (PPlh), tris- (o-toluoyl) phosphine (P (o-tol) 3), tris- (p-toluoyl) phosphine (P ( p-tol) 3), diarylalkylphosphines, dialkylarylphosphines (especially RuPhos (2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl), CPhos (2- (2-dicyclohexylphosphanylphenyl) -N 1, Nl, N3, N3-tetramethyl-tetramethyl 1,3-diamine), APhos (4- (/ V, / V-dimethylamino) phenyl) di-ieri-butylphosphine), DavePhos (2-dicyclohexylphosphino-2 '- (/ V, / V-dimethylamino) biphenyl), Phenyl-DavePhos), trialkylphosphines (especially tris (tert-butyl) phosphine P (t-Bu) 3, tricyclohexylphosphine (P (Cy) 3)), diaryl- (dialkylamino) phosphines, aryl bis (dialkylamino) phosphines, diarylcycloalkylphosphines , BINAP (2,2'-bis (diphenylphosphino) -l, l'-binaph thalin), bis (diphenylphosphino) ferrocene (dppf), DPEPhos (oxydi-2,1-phenylene) bis (diphenylphosphine), XantPhos (4th , 5-bis (diphenylphosphino) -9,9-dimethy lxanthene), tert-butyl-XantPhos or N-XantPhos. Triphenylphosphine (PPh,), tris (o-toluoyl) phosphine (P (o-tol) ₃ ), tris (cyclohexyl) phosphine (PCy3), tris (tert-butyl) phosphine (P (t-Bu ) ₃ ), dppf, DPEPhos, XantPhos, tert-butyl-XantPhos or N-XantPhos, particularly preferably tris (cyclohexyl) phosphine (PCy3), dppf, DPEPhos, XantPhos, tert-butyl-XantPhos or N-Xantphos and very particularly XantPhos, tert-butyl-XantPhos or N-XantPhos is preferably used. Mixtures of the compounds mentioned can also be used.

The molar ratio between metal and ligand can be varied widely; amounts of the ligands, based on the total amount of palladium used, of from 1.0 to 6.0 equivalents are used, particularly preferably from 1.0 to 4.0 equivalents.

According to the invention, the palladium compounds and the ligands can be in pure form, as a separate solution in a suitable diluent or solvent, as an isolated, preformed palladium-ligand complex, in pure form or as a solution in a suitable diluent or solvent, or as a mixture with a molar ratio according to the invention can be used in a suitable diluent or solvent. The palladium compounds and the ligands are each preferably used as a separate solution in a suitable diluent or solvent according to the invention, preferably in concentrations between 0.05 and 2.0% by weight, particularly preferably in concentrations between 0.1 and 1.5% by weight .%.

Suitable diluents or solvents are those defined below for step (3), preferably the same diluent or solvent used for step (3).

The compound of the general formula (V) is preferred according to the invention in amounts, based on the total amount of substance used of the compounds of the general formula (IV), between 0.8 and 2.0 equivalents, particularly preferably between 0.85 and 1.5 equivalents, very particularly preferably between 0.9 and 1.2 equivalents.

The compound of general formula (V) can be used as a solid or as a solution in an organic solvent according to the invention in concentrations of 5-40% by weight, preferably as a solid or as a solution in an organic solvent according to the invention in concentrations of 10-30% by weight .%, very particularly preferably as a solid or as a solution in an organic solvent according to the invention in concentrations of 15-30% by weight.

The coupling step (3) according to the invention can preferably be carried out by adding the solution from step (2) to a solution of the compounds of the general formula (V) in one of the suitable solvents mentioned for step (3) or by inverse metering.

The reaction can be carried out over a wide temperature range. It is usually carried out in a temperature range from -78 to 200 ° C., preferably at temperatures between -10 to 150 ° C., particularly preferably between 15 to 120 ° C.

The reaction can be carried out under elevated or reduced pressure. However, it is preferably carried out under normal pressure, e.g. in the range of 1013 hPa + 300 hPa, or in the range of 1013 hPa + 100 hPa, or in the range of 1013 hPa + 50 hPa.

Step (3) is preferably carried out in a suitable diluent or solvent. Suitable solvents are in principle all organic solvents which are inert under the specific reaction conditions, such as, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane and industrial hydrocarbons, cyclohexane, methylcyclohexane, petroleum ether, ligroin, benzene, toluene, Trifluoromethylbenzene, xylene, mesitylene), aliphatic, cycloaliphatic or aromatic ethers (e.g. 1,2-dimethoxyethane (DME), diglyme, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, methyl tert-butyl ether, anisole ) or mixtures of the solvents mentioned.

Step (3) is preferably carried out in the same diluent or solvent as step (1) and step (2).

The work-up and isolation of the compounds (I) can, after complete reaction, take place, for. B. by a partial or no removal of part of the solvent, washing with water or an aqueous acid and separation of the organic phase and removal of the solvent under reduced pressure. The crude product can possibly also be recrystallized from a suitable solvent known to the person skilled in the art or can be precipitated by adding a further second solvent which is known to the person skilled in the art. Compounds of the formula (I) with U = oxygen can be defined in an optional step (4), according to the customary methods known to the person skilled in the art, in compounds of the formula (I) with U = N (R ⁵ ) (where R ^{5 is} as defined above is) to be converted.

The amide formation can either be carried out directly by reaction with compounds of the formula H2NR ⁴ or via the preparation of compounds of the general formula (I) with U = oxygen and R ⁴ = H in the presence of at least one base (see scheme 1).

The amide formation can, for example, be analogous to that described in WO2009 / 150230, WO2015 / 067646 or Org. Lett. 2011, 13, 5048. methods described. Scheme 1:

Step 1 :

Scheme 1 gives an overall schematic representation of the method according to the invention with all the steps. Reaction conditions and reactants are selected in accordance with the preferred and preferred embodiments of the invention described above. All variables in formulas (I), (G), (P), (III), (IV), and (V) are defined as described above. In a preferred embodiment of the method according to the invention, this comprises steps (1), (2), (3) and optionally (4) or consists thereof.

In a further preferred embodiment of the method according to the invention, steps (1), (2) and (3) take place in the same solvent or diluent.

In a particularly preferred embodiment of the method according to the invention, there is no isolation and / or purification of the intermediate stages (III) and (IV) between steps (1) and (2) and between (2) and (3).

In the event that the process according to the invention comprises step (4), isolation and optionally purification of the compounds of the formula (I) with U = oxygen is preferably carried out between step (3) and step (4).

Advantageously, the entire solvent or diluent is never removed during the entire process according to the invention, so that the intermediate compounds of the formulas (III) and (IV) are always in solution. Preference is given to less than 50% by volume (volume percent based on the volume of solvent used), more preferably less than 30% by volume, very particularly preferably less than 10% by volume and particularly preferably at most 5% by volume of the solvent (e.g. B. by evaporation, z. B. at a reaction temperature of around 40 ° C, or active removal z. B. by distillation and / or reduced pressure based on 1013 hPa). Emphasized, no solvent or diluent is removed during the entire process according to the invention.

A preferred embodiment of the method according to the invention is as follows:

The compounds of general formula (II) are in a suitable organic solvent with a metalating reagent according to the invention, e.g. Ethylmagnesiumbromid, at preferably -20 ° C to 100 ° C, particularly preferably at -10 ° C to 50 ° C. After the addition is complete, an inorganic zinc compound, e.g. Zinc chloride, for example dissolved in a suitable ethereal solvent, preferably metered in over 0.1 to 4 hours, particularly preferably over 0.2 to 2 hours. (Steps (1) and (2)). The compounds of the formula (IV) are preferably used directly in step (3) without further workup or isolation.

The compounds of the formula (IV) are then preferably in an organic solvent according to the invention, preferably in the same solvent as step (1) and (2), at preferably -10 ° C. to 150 ° C., particularly preferably at 15 ° C. to 120 ° ° C with compounds of formula (V) in the presence of a palladium source according to the invention, for example Palladium acetate, as well as a ligand according to the invention, e.g. Xantphos, implemented. (Step (3)) The resulting compounds of formula (I) can then be isolated and purified by the methods described above.

A particularly preferred embodiment of the method according to the invention is the following: The compounds of general formula (II) are placed in toluene or trifluoromethylbenzene and mixed with isopropylmagnesium or ethylmagnesium chloride or bromide at -10 ° C to 50 ° C. After the addition is complete, zinc chloride, for example as a solution in tetrahydrofuran, is metered into the reaction mixture over 0.2 to 2 hours. (Steps (1) and (2)). The compounds of the formula (IV) are preferably used directly in step (3) without further workup or isolation.

The compounds of the formula (IV) are then preferably reacted in toluene or trifluoromethylbenzene at 15 ° C. to 120 ° C. with compounds of the formula (V) in the presence of palladium acetate and xantphos. (Step (3)) The resulting compounds of formula (I) can then be isolated and purified by the methods described above.

The present invention also relates to the intermediate compounds of the formulas (III) and (IV).

The invention relates to compounds of the formula (III)

where R ¹ , R ² and R ^{3 are} as defined above and where at most one of the radicals R ¹ and R ^{3 is} methyl, Y is chlorine, bromine or iodine, preferably chlorine or bromine, n is 0 or 1 and M represents magnesium (when n = 1) or lithium (when n = 0).

M is furthermore preferably magnesium and n is 1.

The invention further relates to compounds of the formula (IV)

wherein R ¹ , R ² and R ^{3 are} as defined above, Y is chlorine, bromine or iodine, preferably chlorine or bromine and m is 1 or 2. Furthermore, the compounds of the formula (G) which are not the subject of the present invention are described herein.

(P where R ^{1 is} halogen or Ci-C ₃ alkyl,

R ^{2 represents} Ci-C _t -alkyl substituted by fluorine or Ci-C _t -alkoxy substituted by fluorine,

R ³ represents halogen, Ci-C ₃ alkyl substituted with fluorine or Ci-C ₃ alkyl, Ci-C ₃ alkoxy or fluoro substituted Ci-C ₃ alkoxy,

Ai for CH, A ₂ for CH,

A ₃ for CH or N and

A _{4 stands} for CR ₉ , where

R _{9 represents} halogen and

R ^{4 represents} hydrogen, C ₁ -C ₆ -alkyl optionally substituted by halogen or CN or C ₃ -C ₆ -cycloalkyl optionally substituted by halogen or CN, and where R ¹ and R ³ simultaneously represent methyl, A ₃ stands for N.

Preferred are

R ¹ for Br or CI,

R ² for heptafluoroisopropyl, R ³ for CI, methyl, trifluoromethyl, trifluoromethoxy or difluoromethoxy,

Ai for C-H,

A ₂ for CH,

A ₃ for N and A4 for C-Cl and

R ^{4 is} hydrogen or Ci-Cs-alkyl, especially hydrogen or (YCe-alkyl. Particular preference is given to the compounds of the formulas (Gl) to (G-4),

in which

R ^{4 represents} hydrogen, optionally substituted by halogen or CN Ci-Cs-alkyl or optionally substituted by halogen or CN C3-C6-cycloalkyl, preferably hydrogen or Ci-Ce-alkyl and particularly preferably methyl or ethyl.

Examples

The following examples explain the process according to the invention in more detail without restricting the invention to these.

methods:

The NMR data of the examples are listed in classic form (d values, multiplet splitting, number of H atoms).

The solvent and the frequency at which the NMR spectrum was recorded are given in each case. ^a) HPLC (High Performance Liquid Chromatography) on a phase reversal column (C18). Agilent 1100 LC system; Phenomex Prodigy 100 x 4mm ODS3; Eluent A: acetonitrile (0.25mL / L); Eluent B: water (0.25mL TFA / L); linear gradient from 5% acetonitrile to 95% acetonitrile in 7.00 min, then 95% acetonitrile for a further 1.00 min; Oven temperature 40 ° C; Flow: 2.0 mL / min.

Preparation of the compounds of the general formula (I)

Example 1) 2-Chloro / V-cyclopropyl-5- [l- [2,6-dichloro-4- [l, 2,2,2-tctrafluoro-l- (trii'luoromcthyl) - cthyl | phcnyl | pyrazole -4-yl | - / V-methyl-pyridine-3-carboxamide (1-1)

50.0 g (97.6 mmol, 1.0 eq) 1- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenyl] -4-iodine 1H pyrazole were placed in 200 ml of toluene, and 102.5 ml (IM in THF, 102.5 mmol, 1.05 eq) of ethyl magnesium bromide were added at 0-5 ° C. over 45 min. 72.5 mL (0.7 M in THF, 50.7 mmol 0.5 eq) zinc chloride, diluted with a further 150 mL tetrahydrofuran, were then metered in at this temperature over 75 min. After complete metering, the mixture was warmed to room temperature and stirred at this temperature for 10 min. The organozinc reagent thus prepared was then added to a solution of 28.8 g (97.6 mmol, 1.0 eq) of 5-bromo-2-chloro-N-cyclopropyl-N-methyl-pyridine-3-carboxamide, 11, 0 mg (0.05 mmol, 0.0005 eq) Pd (OAc) 2 and 56.5 mg (0.1 mmol, 0.001 eq) XantPhos in 50 mL toluene and 50 mL tetrahydrofuran were dosed at 70 ° C for 80 min. The mixture was stirred at this temperature for 2 h and after adding 250 ml of toluene, tetrahydrofuran was removed by distillation. The organic phase was washed with 400 mL 10% by weight HCl and the aqueous phase extracted once with 150 mL toluene. The combined organic phases were treated once with 16 g of N-acetylcysteine, dissolved in 500 ml of water, and then washed with 500 ml of water. After removal of the solvent under reduced pressure, suspension of the residue in 200 ml of n-heptane for 1 h at 60 ° C., cooling to room temperature and filtration and drying in vacuo at 40 ° C., the product was obtained as a beige solid: yield 46.0 g (79% of theory). Ή NMR (CDCls, 400 MHz) d (ppm) = 8.63 (d, J = 2.5 Hz, 1H), 8.13 (br s, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.80 (br s , 1H), 7.75 (s, 2H), 3.16 (s, 3H), 2.80-2.95 (m, 1H), 0.55-1.00 (m, 4H).

Example 2) 2-Chloro / V-cyclopropyl-5- [l- [2,6-dichloro-4- [1,2,2,2-tctrai'luoro-l- (trii'luoromcthyl) ethyl] phenyl ] pyrazol-4-yl] - V-methyl-pyridine-3-carboxamide (I-1)

2.5 g (4.73 mmol, 1.0 eq) 1- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenyl] -4-iodine - IH-pyrazole were placed in 10 mL trifluorotoluene and 4.97 mL (IM in THF, 4.97 mmol, 1.05 eq) ethyl magnesium bromide were added at 0-5 ° C for 15 min. Then 3.55 mL (0.7 M in THF, 2.48 mmol 0.53 eq) zinc chloride were metered in at this temperature over 15 min. After complete metering, the mixture was warmed to room temperature and stirred at this temperature for 10 min. The organozinc reagent thus prepared was then converted into a solution of 1.6 g (4.7 mmol, 1.0 eq) of 5-bromo-2-chloro-N-cyclopropyl-N-methyl-pyridine-3-carboxamide, 0, 4 mg (1.89 pmol, 0.0004 eq) Pd (OAc) 2 and 2.2 mg (3.78 pmol, 0.0008 eq) XantPhos in 2.5 mL trifluorotoluene and 2.5 mL tetrahydrofuran over 30 min dosed at 70 ° C. The mixture was stirred at this temperature for 2 h and after adding 50 ml of toluene, tetrahydrofuran was removed by distillation. The organic phase was washed with 100 mL 10% by weight HCl and the aqueous phase extracted once with 100 mL toluene. The combined organic phases were washed twice with 100 mL water. After removal of the solvent under reduced pressure, suspension of the residue in 20 ml of n-heptane for 1 h at RT and filtration and drying in vacuo at 40 ° C., the product was obtained as a beige solid: yield 2.1 g (72% of theory) Theory).

Ή NMR (CDCL, 400 MHz) d (ppm) = 8.63 (d, J = 2.5 Hz, 1H), 8.13 (br s, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.80 (br s , 1H), 7.75 (s, 2H), 3.16 (s, 3H), 2.80-2.95 (m, 1H), 0.55-1.00 (m, 4H).

Example 3) 2-Chloro-N-cyclopropyl-5- [l- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl] pyrazole-4- yl] pyridine-3-carboxamide (1-2)

0.2 g (0.37 mmol, 1.0 eq) 2-chloro-5- [l- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl ] phenyl] pyrazol-4-yl] pyridine-3-carboxylic acid and 27 mg (0.37 mmol, 1.0 eq) N, N-dimethylformamide were placed in 5.0 mL toluene and at 50 ° C with 133 mg (1, 11 mmol, 3.0 eq) thionyl chloride were added. After 1 h at 50 ° C., the volatile constituents were removed in vacuo and the residue was taken up in 5.0 ml of acetonitrile and 23 mg (0.41 mmol, 1.1 eq) of cyclopropylamine were added. 42 mg (0.41 mmol, 1.1 eq) of triethylamine were added at 0 ° C. and the reaction was warmed to 21 ° C. over 1 h. 45 mg (0.55 mmol, 1.5 eq) 50% by weight of NaOH were then slowly added dropwise, the volatile constituents were removed in vacuo and the residue was stirred with 20 ml of dichloromethane. The organic phase was separated off, the solvent was removed in vacuo and the product was obtained as a yellow oil: yield 160 mg (75% of theory). Ή NMR (CDCL, 400 MHz) d (ppm) = 8.65 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.16 (d, 0.7 Hz, 1H), 7.95 ( d, J = 0.7 Hz, 1H), 7.75 (s, 2H), 6.68 (br s, 1H), 2.95-2.99 (m, 1H), 0.93-0.95 (m, 2H), 0.69-0.71 (m, 2H ).

Example 4) 2-Chloro-N- (l-cyanocyclopropyl) -5- [l- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl] pyrazole -4-yl] pyridine-3-carboxamide (1-3)

0.2 g (0.37 mmol, 1.0 eq) 2-chloro-5- [l- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl ] phenyl] pyrazol-4-yl] pyridine-3-carboxylic acid and 27 mg (0.37 mmol, 1.0 eq) N, N-dimethylformamide were placed in 5.0 mL toluene and at 50 ° C with 133 mg (1, 11 mmol, 3.0 eq) thionyl chloride were added. After 1 h at 50 ° C., the volatile constituents were removed in vacuo and the residue was taken up in 5.0 ml of acetonitrile and 53 mg (0.44 mmol, 1.2 eq) of 1-aminocyclopropanecarbonitrile hydrochloride were added. At 0 ° C 94 mg (0.93 mmol, 2.5 eq) triethylamine were added and the reaction was warmed to 21 ° C over 1 h. 45 mg (0.55 mmol, 1.5 eq) 50% by weight of NaOH were then slowly added dropwise, the volatile constituents were removed in vacuo and the residue was stirred with 20 ml of dichloromethane. The organic phase was separated off, the solvent was removed in vacuo and the product was obtained as a yellow oil: yield 160 mg (72% of theory).

^ -NMR (CDCL, 400 MHz) d (ppm) = 8.70 (d, / = 2.5 Hz, 1H), 8.39 (d, / = 2.5 Hz, 1H), 8.18 (d, / =

0.8 Hz, 1H), 7.97 (d, / = 0.8 Hz, 1H), 7.75 (s, 2H), 1.71-1.74 (m, 2H), 1.42-1.46 (m, 2H).

Example 5) Methyl-2-chloro-5- [1- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenyl] pyrazol-4-yl] pyridine -3-carboxylate (1-4)

9.0 g (17.6 mmol, 1.0 eq) 1- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenyl] -4-iodine - IH-pyrazole were placed in 40 ml of toluene and 19.3 ml (IM in THF, 19.3 mmol, 1.05 eq) of ethyl magnesium bromide were added at 0-5 ° C over 40 min. 13.6 mL (0.7 M in THF, 9.1 mmol 0.5 eq) zinc chloride, diluted with a further 20 mL tetrahydrofuran, were then metered in at this temperature over 25 min. After complete dosing, the mixture was warmed to room temperature. The organozinc reagent thus prepared was then added to a solution of 4.6 g (17.6 mmol, 1.0 eq) of methyl 5-bromo-2-chloropyridine-3-carboxylate, 39.5 mg (0.2 mmol, 0.01 eq) Pd (OAc) 2 and 203 mg (0.4 mmol, 0.02 eq) XantPhos in 10 mL toluene and 10 mL tetrahydrofuran dosed at 70 ° C for 30 min. The mixture was stirred at this temperature for 4 h. After adding 50 ml of toluene, the organic phase was washed with 100 ml of 10% by weight HCl and twice with 100 ml of water each time. After drying over sodium sulfate and removal of the solvent, the residue was treated with 80 ml of n-heptane and, after filtration and drying in vacuo at 40 ° C., the product was obtained as a beige solid: yield 6.5 g (65% of theory). Ή NMR (CDCL, 400 MHz) d (ppm) = 8.72 (d, J = 2.5 Hz, 1H), 8.31 (br s, 1H), 8.17 (d, J = 2.5 Hz, 1H), 7.96 (br s , 1H), 7.75 (s, 1H), 4.00 (s, 3H).

Example 6) 2-Chloro-5- [l- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl] -pyrazol-4-yl] pyridine- 3-carboxylic acid (1-5)

1.1 g (1.8 mmol, 1.0 eq) of methyl 2-chloro-5- [l- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl ) ethyl] phenyl] pyrazol-4-yl] pyridine-3-carboxylate were dissolved in a mixture of 10 mL THF and 10 mL methanol and at 21 ° C with 0.07 g (2.75 mmol, 1.5 eq) LiOH added. The mixture was stirred for 12 h at room temperature and after addition of 50 ml of 20% by weight HCl, the product was obtained as a colorless solid after filtration: yield 0.9 g (90% of theory).

Ή NMR (CDCL, 400 MHz) d (ppm) = 8.78 (d, J = 2.5 Hz, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.19 (d, J = 0.7 Hz, 1H), 7.99 (d, J = 0.7 Hz, 1H), 7.75 (s, 2H).

Comparative examples Suzuki coupling analogous to WO2016 / 174052:

2-Chloro-N-cyclopropyl-5- [l- [2,6-dichloro-4- [l, 2,2,2-tetrafluoro-

1- (trifluoromethyl) ethyl] phenyl] pyrazol-4-yl] pyridine-3-carboxamide (1-2)

4.0 g (7.7 mmol, 1.0 eq) 1- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenyl] -4-iodine - 1H-pyrazole, 2.23 g (9.27 mmol, 1.2 eq) 6-chloro-5- (cyclopropylcarbamoyl) -3-pyridyl] boronic acid were placed under argon in 35 mL ethanol and 90 mL toluene and mixed with a Solution of 4.0 g (28.9 mmol, 3.75 eq) potassium carbonate in 25 mL degassed water. The reaction mixture was stirred at RT for 1 h, 379 mg (0.46 mmol, 0.06 eq) of PdCl2 (dppf) * CH ₂ Cl2 were added and the mixture was then stirred at 50 ° C. After 3 h at this temperature, complete conversion to the desired product was detected by HPLC ^a) . After cooling to RT, the phases were separated, the aqueous phase extracted with toluene and the combined organic phases once with a solution of 3.8 g of N-acetylcysteine in 100 ml of water, then with 100 ml of 10% by weight NaOH and finally with 100 ml saturated NaCL solution. After drying over sodium sulfate, distillation of the solvent in vacuo, the product could be obtained as a beige-brown solid: yield 3.77 g (75% of theory).

2-chloro-N-cyclopropyl-5- [l- [2,6-dichloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl] pyrazol-4-yl] pyridine- 3-carboxainide (1-2)

4.0 g (7.7 mmol, 1.0 eq) 1- [2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] phenyl] -4-iodine - 1H-pyrazole, 2.23 g (9.27 mmol, 1.2 eq) 6-chloro-5- (cyclopropylcarbamoyl) -3-pyridyl] boronic acid were placed under argon in 35 mL ethanol and 90 mL toluene and mixed with a Solution of 4.0 g (28.9 mmol, 3.75 eq) potassium carbonate in 25 mL degassed water. The reaction mixture was stirred at RT for 1 h, 63 mg (0.7 mmol, 0.01 eq) of PdCl2 (dppf) * CH ₂ Cl2 were added and then stirred at 50 ° C. After 10 h at this temperature, only an incomplete conversion to the desired product of 56% could be detected by HPLC ^a) . The product was not isolated.

The following tricyclic compounds of the general formula (I) could be prepared analogously to Examples (1), (3), (5) and (6):

Ethyl-2-chloro-5- [l- [2,6-dichloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] phenyl] pyrazol-4-yl] pyridine-3- carboxylate (1-6)

Ή NMR (CDC1 ₃ , 400 MHz) d (ppm) = 8.71 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.52 (s, 2H), 4.48 (q, J = 7.2 Hz, 1H), 1.43 (t, J = 7.2 Hz, 1H).

2-Chloro-5- [l- [2-chloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) phenyl] pyrazol-4-yl] -N -cyclopropyl-N-methyl-pyridine-3-carboxamide (1-7)

Ή NMR (CDC1 ₃ , 400 MHz) d (ppm) = 8.62 (d, J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.77 ( d, J = 2.5 Hz, 1H), 7.63 (s, 1H), 3.16 (s, 3H), 2.82-2.86 (m, 1H), 1.24-12.6 (m, 2H), 0.62 (br s,

2H).

2-Chloro-5- [l- [2-chloro-4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) phenyl] pyrazol-4-yl] -N -cyclopropyl-pyridine-3-carboxainide (1-8)

Ή NMR (CDCI3, 400 MHz) d (ppm) = 8.65 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.15 (s, 1H), 8.04 (br s, 1H), 7.99 (br s, 1H), 7.94 (s, 1H), 6.68 (br s, 1H), 3.00-2.92 (m, 1H), 0.96-0.91 (m, 2H), 0.71- 0.69 (m, 2H).

5- [l- [2-Bromo-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6-

(trifluoromethoxy) phenyl] pyrazol-4-yl] -2-chloro-N-cyclopropyl-N-methyl-pyridine-3-carboxainide d-9)

Ή NMR (CDCI3, 400 MHz) d (ppm) = 8.61 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.76 (d, J = 2.4 Hz, 1H) ), 7.57 (br s, 1H), 7.53 (s, 1H), 6.68 (br s, 1H), 3.17 (s, 3H), 3.00-2.92 (m, 1H), 0.96-0.91 (m, 2H), 0.65-0.56 (m, 2H).

Ethyl-2-chloro-5- [l- [2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) phenyl] pyrazol-4-yl] pyridine-3-carboxylate (1-10)

Ή NMR (CDCI3, 400 MHz) d (ppm) = 8.70 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 8.16 (s, 1H), 8.04 (br s, 1H), 7.99 (br s, 1H), 7.96 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). Ethyl-2-chloro-5- [l- [2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) phenyl] pyrazol-4-yl] pyridine-3-carboxylate (1-11)

Ή NMR (DMSO-d ₆ , 400 MHz) d (ppm) = 8.96 (d, J = 2.5 Hz, 1H), 8.93 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 4.39 (q, J = ΊL Hz, 2H), 1.36 (t, / = 7.1 Hz, 3H).

Methyl-2-chloro-5- [l- [2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) phenyl] pyrazol-4-yl] pyridine-3-carboxylate (1-12)

^ -NMR (DMSO-de, 400 MHz) d (ppm) = 8.95 (d, J = 2.5 Hz, 2H), 8.89 (s, 1H), 8.57 (s, 1H), 8.52 (d, J = 2.5 Hz , 2H), 3.92 (s, 3H).

2-chloro-5- [l- [2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) phenyl] pyrazol-4-yl] pyridine- 3-carboxylic acid (1-13)

^ -NMR (DMSO-de, 400 MHz) d (ppm) = 13.90 (br s, 1H), 8.92 (s, 1H), 8.91 (s, 1H), 8.58 (s, 1H), 8.48 (d, 7 = 2.5 Hz, 1H), 8.24 (d, / = 1.8 Hz, 1H), 7.96 (br s, 1H).

Methyl-2-chloro-5- [l- [2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) phenyl] pyrazol-4-yl] pyridine-3-carboxylate (1-14)

^ -NMR (DMSO-de, 400 MHz) d (ppm) = 8.97 (d, J = 2.4 Hz, 1H), 8.93 (s, 1H), 8.58 (s, 1H), 8.53 (d, J = 2.4 Hz , 1H), 8.23 (brs, 1H), 7.96 (br s, 1H), 3.89 (s, 3H).

Ethyl 5- [l- [2-bromo-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) phenyl] pyrazol-4-yl] -2-chloro -pyridine-3-carboxylate (1-15)

^ -NMR (CDC1 ₃ , 400 MHz) d (ppm) = 8.70 (d, J = 2.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.57 (br s, 1H), 7.53 (br s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).

2-chloro-5- [l- [2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) phenyl] pyrazol-4-yl] pyridine- 3-carboxylic acid (1-16)

^ -NMR (DMSO-de, 400 MHz) d (ppm) = 13.89 (br s, 1H), 8.93 (d, J = 2.5 Hz, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 7.51 (br s, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.10 (br s, 1H).

Methyl-5- [1- [2-bromo-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) phenyl] pyrazol-4-yl] -2-chloro -pyridine-3-carboxylate (1-17)

^ -NMR (CDCI3, 400 MHz) d (ppm) = 8.70 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.13 (s, 1H), 7.93 (s, 1H ), 7.57 (s, 1H), 7.53 (s, 1H), 3.65 (s, 3H). 5- [1-- [2-Bromo-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) phenyl] pyrazol-4-yl] -2-chloropyridine -3-carboxylic acid (1-18)

Ή NMR (DMSO-d ₆ , 400 MHz) d (ppm) = 8.91 (d, J = 2.4 Hz, 1H), 8.85 (s, 1H), 8.53 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.93 (s, 1H), 7.72 (s, 1H). 5- [l- [2-Bromo-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6-

(trifluoromethoxy) phenyl] pyrazol-4-yl] -2-chloro-N-cyclopropyl-pyridine-3-carboxamide (1-19)

Ή NMR (CDCls, 400 MHz) d (ppm) = 8.64 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.92 (s, 1H ), 7.57 (s, 1H), 7.53 (s, 1H), 6.69 (br s, 1H), 3.00-2.93 (m, 1H), 0.93-0.90 (m, 2H), 0.72-0-68 (m, 1H). 2-Chloro-5- [l- [2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6-

(trifluoromethoxy) phenyl] pyrazol-4-yl] -N-cyclopropyl-pyridine-3-carboxamide (1-20)

Ή NMR (DMSO-de, 400 MHz) d (ppm) = 8.88 (s, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.70 (d, J = 4.2 Hz, 1H), 8.57 (s , 1H), 8.23 (s, 1H), 8.20 (d, J = 2.4 H _z , IH), 7.97 (br s, 1H), 2.90-280 (m, 1H) 0.78-0.70 (m, 2H), 0.58 -0.53 (m, 2H).

Claims

Claims: Process for the preparation of compounds of formula (I) wherein R1 is hydrogen, cyano, halogen, optionally substituted with halogen or CN Ci-C t-alkyl or optionally substituted with halogen Ci-C t-alkoxy, R2 for halogen , Trifluoromethylsulfonyl, trifluoromethylsulfinyl, trifluoromethylsulfanyl, optionally substituted with halogen Ci-C t-alkyl or optionally substituted with halogen Ci-C t-alkoxy and R3 represents hydrogen, cyano, halogen, optionally substituted with halogen or CN Ci-C4-alkyl or represents Ci-C t-alkoxy optionally substituted with halogen, R4 represents hydrogen, Ci-Cs-alkyl optionally substituted by halogen or CN or C3-C6-cycloalkyl optionally substituted by halogen or CN, U represents oxygen or a group N. (R5), where R5 is hydrogen, Ci-Ce-alkyl optionally substituted with halogen or CN or optionally substituted with halogen or CN tes C3-C6-cycloalkyl, Ai stands for C-RÖ, A2 stands for C-R7, A3 stands for C-Rs or N, A4 stands for C-R9, RÖ, R7, Re and R9 each independently represent hydrogen , Ci-C4-alkyl or halogen optionally substituted with halogen or CN, starting from compounds of the formula (II) in which R1, R2 and R3 are as defined above and X is iodine or bromine, comprising the steps (1): Reaction of the compounds of the formula (II) with a magnesium- or lithium-based metalating reagent to give compounds of the formula (III) where R ¹ , R ² , R ³ are defined as above, Y stands for chlorine, bromine or iodine, n stands for 0 or 1 and M stands for magnesium (if n = 1) or lithium (if n = 0), (2): Reaction of the compounds of the formula (III) with an inorganic zinc compound to give compounds of the formula (IV) wherein R ¹ , R ² , R ³ and Y are as defined above and m is 1 or 2, and (3): Reaction of compounds of the formula (IV) with compounds of the formula (V) where Ai, A ₂ , A ₃ , A ₄ , R ⁴ , U and R ^{5 are} as defined above and Z is bromine or iodine, in the presence of at least one Pd (0) or Pd (II) compound and at least one monodentate or bidentate ligand, to give compounds of the formula (I). 2. The method according to claim 1, characterized in that Ai for C-H, Ai for C-H, A ₃ for CH or N and A4 stands for CR ₉  and R9 represents Ci-C4-alkyl or halogen optionally substituted with halogen or CN. 3. The method according to any one of claims 1 or 2, characterized in that A3 stands for N. 4. The method according to any one of claims 1 to 3, characterized in that at most one of the radicals R ⁴ or R ^{5 is} hydrogen. 5. The method according to any one of claims 1 to 4, characterized in that R ^{2 is} halogen-substituted Ci-C4-alkyl or halogen-substituted Ci-C4-alkoxy. 6. The method according to any one of claims 1 to 5, characterized in that R ¹ and R ^{3 are} each independently selected for a substituent selected from hydrogen, CI, Br, F, C ₁ -C ₃ alkyl, Ci-C3 substituted with halogen -Alkyl, Ci-C3-alkoxy or halogen-substituted Ci-C3-alkoxy. 7. The method according to any one of claims 1 to 6, characterized in that R ¹ and R ^{3 are} not simultaneously in a compound for hydrogen. 8. The method according to any one of claims 1 to 7, characterized in that R ^{1 is} halogen or Ci-C3-alkyl, R ² for Ci-C4-alkyl substituted with fluorine or Ci-C4-alkoxy substituted with fluorine and R ^{3 is} halogen, Ci-C3-alkyl or Ci-C3-alkyl, Ci-C3-alkoxy or fluorine-substituted Fluorine substituted Ci-C3-alkoxy. 9. The method according to any one of claims 1 to 8, characterized in that the magnesium or lithium-based metalating reagent in step (1) is selected from alkyl lithium compounds LiR, where R is (YCVAlkyl) and alkylmagnesium halide compounds RMgHal, where R is (YCVAlkyl and shark represents halogen. 10. The method according to any one of claims 1 to 9, characterized in that the amount of Pd (0) or Pd (II) compound in step (3), based on the total amount of substance used of the compounds of formula (IV), between 0 , 0001 and 0.05 equivalents. 11. The method according to any one of claims 1 to 10, characterized in that the inorganic zinc compound in step (2) is selected from zinc halides and zinc acetate. 12. The method according to any one of claims 1 to 11, characterized in that the Pd (0) or Pd (II) compound in step (3) is selected from palladium (II) halides, Pd (OAc) 2, palladium (II) pivalate, allyl palladium (II) chloride dimer, Pd (acac) 2 (acac = acetylacetonate) , Pd (NC> 3) 2, Pd (dba) ₂ (dba = dibenzylidene acetone), Pd ₂ (dba) ₃ , Dichloro-bis (triphenylphosphine) palladium (II), Pd (dppf) Cl2 (dppf = Bis (diphenylphosphino) ferrocene), Pd (MeCN) 2Cl2, and tetrakis (triphenylphosphine) palladium (0). 13. The method according to any one of claims 1 to 12, characterized in that the monodentate or bidentate ligands in step (3) are selected from optionally mono- or polysubstituted triarylphosphines, diarylalkylphosphines, dialkylarylphosphines, trialkylphosphines, diaryl- (dialkyklamino) phosins, aryl -bis (dialkylamino) phosphines, diarylcycloalkylphosphines, BINAP (2,2'-bis (diphenylphosphino) -l, l'-binaphthalene), bis (diphenylphosphino) ferrocene (dppf), DPEPhos (Oxydi-2, l-phenylene) bis (diphenylphosphine), XantPhos (4,5-bis (diphenylphosphino) -9,9-dimethylxanthene), tert-butyl-XantPhos or N-XantPhos. 14. The method according to claim 13, characterized in that the monodentate or bidentate ligands in step (3) are selected from triphenylphosphine (PPI13), tris- (o-toluoyl) phosphine (P (o-tol) ₃ ), tris- ( cyclohexyl) phosphine (PCy ₃ ), tris (tert-butyl) phosphine (P (t-Bu) ₃ ), dppf, DPEPhos, XantPhos, tert-butyl-XantPhos or N-XantPhos. 15. Compounds of the formula (III) wherein R ¹ , R ² and R ^{3 are} defined according to one of claims 1 or 5 to 8, wherein at most one of the radicals R ¹ and R ^{3 is} methyl, Y is chlorine, bromine or iodine, n is 0 or 1 and M represents magnesium (when n = 1) or lithium (when n = 0). 16. Compounds of the formula (IV) wherein R ¹ , R ² and R ^{3 are} defined according to one of claims 1 or 5 to 8, Y is chlorine, bromine or iodine and m is 1 or 2.