Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to a process for the preparation of tricyclic compounds of the formula (I)
• 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.
• 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.
• 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,
• 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 ⁇ , 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
• R 1 , R 2 , R 3 and Y are as defined above and m is 1 or 2, and
• 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.
• Re, R7, Rs and R9 each independently represent hydrogen, methyl or halogen.
• 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.
• R 9 stands for halogen, in particular for CI, F, I or Br and emphasized for CI.
• a 3 is N.
• Ai is C-H
• Ai is C-H
• a 4 for C-halogen preferably for C-Cl, CF, CI, C-Br, more preferably for C-Cl.
• U stands for O
• R 4 the following preferred configurations for R 4 apply:
• R4 is hydrogen or (YCe-alkyl, very particularly preferably methyl or ethyl.
• At most one of the radicals R 4 or R 5 is hydrogen.
• R4 stands for C3-C6-cycloalkyl optionally substituted with CI, Br, I, F or CN, very particularly preferably for cyclopropyl or 1-CN-cyclopropyl.
• 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.
• R5 represents hydrogen or Ci-C t alkyl, especially methyl or ethyl.
• U stands for a group N (R 5 ).
• 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-is
• 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)).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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
• R 5 is hydrogen or Ci-C t alkyl, in particular methyl or ethyl,
• R9 stands for halogen, in particular for CI.
• X stands for iodine.
• 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-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
• alkyl 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.
• 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.
• 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.
• 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.
• 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 ,
• Processes are preferably used according to the invention in which there is a combination of the meanings and ranges listed above as preferred.
• 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.
• 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.
• 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.
• 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.
• a non-polar solvent such as hydrocarbons (for example n-pentane, n-hexane, n-heptane, cyclohexane) or aromatic solvents (for example toluene or trifluoromethylbenzene)
• magnesium reagents as Solution in ethereal solvents (e
• 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.
• 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.
• DME 1,2-dimethoxyethane
• diglyme diglyme
• tetrahydrofuran THF
• 2-methyl-THF 1,4-dioxane
• methyl tert-butyl ether 1,4-dioxane
• anisole 1,4-dioxane
• 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 (1) transmetallates the compounds of the formula (III) with an inorganic zinc compound to give compounds of the formula (IV),
• R 1 , R 2 , R 3 and Y are as defined above and n is 1 or 2.
• 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.
• 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.
• a suitable ethereal solvent for example THE, 2-methyl-THL or methyl tert-butyl ether
• 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.
• Step (2) is preferably carried out in the same diluent or solvent as step (1).
• the process according to the invention further comprises the reaction of the compounds of the formula (IV) with compounds of the formula (V),
• 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-butylphosphin
• Triphenylphosphine Ph,
• 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.
• 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.
• DME 1,2-dimethoxyethane
• diglyme diglyme
• tetrahydrofuran THF
• 2-methyl-THF 1,4-dioxane
• methyl tert-butyl ether 1,4-dioxane
• anisole 1,4-dioxane
• 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.
• 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.
• steps (1), (2) and (3) take place in the same solvent or diluent.
• 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.
• Emphasized, no solvent or diluent is removed during the entire process according to the invention.
• 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.
• a metalating reagent e.g. Ethylmagnesiumbromid
• an inorganic zinc compound e.g. Zinc chloride
• a suitable ethereal solvent preferably metered in over 0.1 to 4 hours, particularly preferably over 0.2 to 2 hours.
• 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.
• a palladium source according to the invention for example Palladium acetate
• a ligand according to the invention e.g. Xantphos
• 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.
• zinc chloride for example as a solution in tetrahydrofuran, is metered into the reaction mixture over 0.2 to 2 hours.
• 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)
• M is furthermore preferably magnesium and n is 1.
• the invention further relates to compounds of the formula (IV)
• 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.
• 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,
• a 4 stands for CR 9 , where
• R 9 represents halogen
• 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.
• R 2 for heptafluoroisopropyl
• R 3 for CI, methyl, trifluoromethyl, trifluoromethoxy or difluoromethoxy
• 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),
• 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.
• 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).
• 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 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.

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