Preparation of aromatic carboxamides by palladium catalyzed carbonylation

Abstract

The present invention relates to a process for the preparation of aromatic carboxamides of formula I, which are obtainable by a palladium catalysed carbonylation reaction of aromatic chlorides of formula II, amines of formula III and carbon monoxide in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene. The present invention further relates to a process for the preparation of aryl-5-trifluoromethyl-1,2,4-oxadiazoles, which are known for the control of phytopathogenic fungi.

Description

[0001] This invention relates to a method for preparing an aromatic carboxylamide of formula I, which can be obtained by palladium-catalyzed carbonylation reaction of an aromatic chloride of formula II, an amine of formula III, and carbon monoxide in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). This invention further relates to a method for preparing aryl-5-trifluoromethyl-1,2,4- Methods involving diazoles, as described, for example, in WO 2015 / 185485 or WO 2017 / 211649, are known for controlling plant pathogenic fungi.

[0002]

[0003] Carbonylation reactions for the preparation of aromatic carboxamides of formula I are known in the art. These transformations are transition metal-catalyzed processes that produce carboxamides from aryl halides, carbon monoxide, and amines in a single step. This procedure enables the rapid acquisition of diverse structural units. In these reactions, a base must be added to neutralize the hydrogen halides released during the reaction.

[0004] Heck et al. first reported this type of palladium-catalyzed procedure in the Journal of Organic Chemistry 1974, 39, 3318 (and patents US 3988358 and US 4128554). Since then, many variations of this reaction type have been described in the literature.

[0005] The economic benefits are primarily focused on the use of aromatic chlorides, as they are both inexpensive and generally readily available. However, their relative chemical inertness makes them more challenging substrates in palladium-catalyzed carbonylation reactions, which is arguably the main reason why most reported reactions use more reactive aromatic bromides, iodides, or trifluoromethanesulfonates. Batch reactions with aromatic chlorides typically require the presence of 2 mol% or more catalyst to achieve complete conversion of the aromatic chloride. However, at such high catalyst loadings, scaling up to industrial-scale applications is economically prohibitive in many cases. High catalyst concentrations can also lead to unwanted catalyst precipitation under reaction conditions.

[0006] Perry et al. reported an increase in the conversion of aromatic chlorides in amino carbonylation reactions (at constant catalyst concentration) by adding halides, particularly sodium iodide (Journal of Organic Chemistry 1996, 61, 7482-7485 and US 5672750). The reaction of aromatic chlorides, carbon monoxide (5 psig or 0.34 bar (34 kPa)), 3 mol% palladium catalyst, 6 mol% bidentate phosphine ligand, 1.2 equivalents of 1,8-diazabicyclo-[5.4.0]undecyl-7-ene (DBU), and at least 1 equivalent of sodium iodide at 115 °C provided carboxamides in good yields compared to the same reaction without sodium iodide, which produced only small amounts of carboxamides. The disadvantages of this method are that the use of halides incurs additional costs, complicates post-processing procedures, and often leads to reactor corrosion.

[0007] Buchwald et al. (Angew. Chem. Int. Ed. 2007, 46, 8460-8463) described the effect of base on the palladium-catalyzed amino carbonylation of aromatic chlorides at atmospheric pressure. The procedure was performed at 120 °C using 2 mol% palladium catalyst, bidentate phosphine ligand, and 2 equivalents of base. Optimal yields were obtained using sodium phenoxide as the base. The use of DBU resulted in relatively low conversion of aromatic chlorides and poor yields of carboxamides.

[0008] WO 2009 / 144197 A1 discloses a method for producing aromatic and heteroaromatic carboxylic acids, carboxylic acid esters, and carboxylic acid amides (carboxamides). Carboxamides are prepared from aniline and aromatic chlorides at 130-150 °C and 15 bar (1500 kPa) in the presence of a palladium catalyst and 1.5 equivalents of base, such as DBU, triethylamine, and potassium carbonate (Operating Examples 6-1 to 6-3). Carboxamides are obtained in low to moderate yields.

[0009] Diangpeng Chen et al. (Org. Chem. Front. 2019, 6, 1403-1408; see also CN109867284) reported a palladium-catalyzed (amino)carbonylation reaction using N-formyl-TBD, which can be generated in situ from formate and TBD. The authors demonstrated that N-formyl-TBD is a common source of non-gaseous carbon monoxide in carbonylation reactions using aromatic iodides or aromatic bromides.

[0010] However, the prior art has not reported the use of TBD in palladium-catalyzed amino carbonylation reactions involving aromatic chlorides.

[0011] 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (referred to as “TBD” in this paper, CAS 5807-14-7) is a strong Brønsted base that has been widely used in organic synthesis (Review: Synlett 2014, 25, 894-895).

[0012]

[0013] One object of the present invention is to overcome the drawbacks of known aminocarbonylation processes and to provide an improved, more economical, and plant-friendly method for the industrial-scale preparation of aromatic carboxamides, focusing on low-pressure reactions (less than 20 bar (2000 kPa)), wherein the catalyst is sufficiently efficient to allow operation at low catalyst concentrations (i.e., <0.5 mol% catalyst loading based on the amount of aromatic chloride), and wherein the catalyst turnover is sufficiently stable to achieve complete conversion within a reasonable time. It is known that improved catalyst stability implies lower catalyst loading, which is required for the efficient conversion of aromatic chlorides.

[0014] The inventors unexpectedly discovered that the method of the present invention provides a solution to these problems. The method of the present invention is cost-effective because it allows the use of significantly lower amounts of palladium catalyst than previously reported procedures. Furthermore, the method of the present invention does not require excessively high carbon monoxide pressure.

[0015] Accordingly, the present invention relates to a method for preparing compounds of formula I.

[0016]

[0017] in

[0018] Aryl is a phenyl or 5- or 6-membered aromatic heterocycle; wherein the ring member atoms of the aromatic heterocycle, in addition to the carbon atom, include 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms, provided that the heterocycle cannot contain 2 adjacent atoms selected from O and S; wherein Aryl is further unsubstituted or further constituted by n other identical or different groups R A Replace; among them

[0019] n is 0, 1, 2, 3 or 4;

[0020] R A Independently selected from fluorine, chlorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, -S(=O)2-CH3, -OC≡N, -SC≡N, -N=C=O, -N=C=S, di-C1-C6-alkylamino, -C(=O)-C1-C6-alkyl, -C(=O)-O-C1-C6-alkyl, and -CH2OH; R1 It is C1-C6-alkyl, C1-C6-alkoxy, C3-C 11 -Cycloalkyl, C3-C8-cycloalkenyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxyimino-C1-C4-alkyl, C2-C6-enoxyimino-C1-C4-alkyl, C2-C6-alkynoxyimino-C1-C4-alkyl, C1-C6-alkylamino, di-C1-C6-alkylamino, -C(=O)-C1-C6-alkyl, -C(=O)-O-C1-C6-alkyl, C(=O)-N(C1-C6-alkyl)2, phenyl-C1-C4-alkyl, phenyl-C1-C4-alkenyl, phenyl-C1-C4-alkynyl, heteroaryl-C1-C4-alkyl, phenyl, naphthyl or 3 to 10 saturated, part The heterocyclic or aromatic monocyclic or bicyclic rings are defined as follows: The ring member atoms of the monocyclic or bicyclic heterocycle, in addition to carbon atoms, further include 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms, provided that the heterocycle cannot contain two adjacent atoms selected from O and S; wherein the heteroaryl group in the heteroaryl-C1-C4-alkyl group is a 5- or 6-membered aromatic heterocycle, wherein the ring member atoms of the heterocycle, in addition to carbon atoms, further include 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms, provided that the heterocycle cannot contain two adjacent atoms selected from O and S; wherein any of the above-mentioned aliphatic or cyclic groups are not substituted or surrounded by 1, 2, 3, or up to the maximum possible number of identical or different groups R. 1a Replace; or R 1 and R 2 Together with the nitrogen atoms they are attached to, they form 3 to 10-membered heterocycles of monocyclic or bicyclic nature, which are saturated or partially unsaturated, wherein the heterocycle contains no other heteroatoms besides one nitrogen atom and one or more carbon atoms, or includes one, two, or three other heteroatoms independently selected from N, O, and S as ring member atoms, provided that the heterocycle does not contain two adjacent atoms selected from O and S; wherein the heterocycle is not substituted or is occupied by one, two, three, four, or up to the maximum possible number of the same or different groups R. 1a Replace; among them

[0021] R 1aIt is a halogen, oxo, cyano, NO2, OH, SH, NH2, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, C3-C8-cycloalkyl, -NHSO2-C1-C4-alkyl, -(C=O)-C1-C4-alkyl, -C(=O)-O-C1-C4-alkyl, C1-C6-alkyl alkylsulfonyl, hydroxyC1-C4-alkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4-alkyl), C1-C4-alkylthio-C1-C4-alkyl, aminoC1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, di-C1-C4-alkylamino-C1-C4-alkyl, aminocarbonyl-C1-C4-alkyl, or C1-C4-alkoxy-C1-C4-alkyl;

[0022] R 2 It is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C3-C 11 -cycloalkyl, -C(=O)-C1-C6-alkyl, -C(=O)-C3-C 11 -cycloalkyl or -C(=O)-O-C1-C6-alkyl; wherein R 2 Any aliphatic or cyclic group is not substituted or is surrounded by one, two, three, or up to the maximum possible number of groups selected from halogens, hydroxyl groups, oxo groups, cyano groups, C1-C6-alkyl groups, C1-C6-alkoxy groups, and C3-C6-alkyl groups. 11 - Substitution of the same or different groups of cycloalkyl groups;

[0023] The method includes reacting an aromatic chloride of formula II with carbon monoxide and an amine compound of formula III.

[0024] Aryl-Cl II

[0025] Aryl is defined above for compounds of formula I.

[0026]

[0027] Where R 1 and R 2 As defined above for compounds of formula I; wherein the reaction is carried out in the presence of a palladium-based catalyst, a solvent and a base; wherein the method is characterized in that the base is 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0028] The carbonylation reaction of the present invention is carried out in the presence of a palladium-based catalyst selected from at least one Pd(II) compound or Pd(0) compound, or a complex obtained by complexing a Pd(II) compound or Pd(0) compound with a ligand, particularly a phosphine ligand. The palladium-based catalyst can be used as a pre-formulated complex or can be combined in situ by combining the palladium compound and the ligand or its salt.

[0029] Suitable palladium compounds or complexes are, for example, palladium(II) acetate, palladium(II) chloride, palladium(II) bromide, palladium(II) nitrate, palladium(II) acetylacetone, palladium(O)-dibenzylacetone complex, palladium(O)-tetra(triphenylphosphine), palladium(O)-bis(tri-o-tolylphosphine), palladium(O)(DPEphos)dicarbonyl, palladium(II)-(bis(diphenylphosphine)ferrocene)dichloride, palladium(II) propionate, palladium(II)-bis(triphenylphosphine)dichloride, palladium(II) nitrate, palladium(II)-bis(acetonitrile)dichloride, palladium(II)-bis(benzylnitrile)dichloride, palladium(II) hydroxide, [palladium(allyl)Cl]2, palladium(O), palladium(O)carbon (Pd / C), and palladium(II)-bis(benzylnitrile)-dichloride.

[0030] The carbonylation reaction is preferably carried out in the presence of a suitable Pd(II) compound or Pd(0) compound complexed with a ligand, especially a monodentate or bidentate phosphine ligand.

[0031] Preferred examples of monodentate phosphines are trialkylphosphine, triarylphosphine, dialkylarylphosphine, alkyldiarylphosphine, cycloalkyldiarylphosphine, dicycloalkylarylphosphine, and tricycloalkylphosphine. Other preferred examples of phosphines are triheterocyclic phosphines and triheteroarylphosphines. Preferred examples of trialkylphosphines are triethylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, triisopropylphosphine, and tribenzylphosphine. Preferred examples of tricycloalkylphosphines are tri(cyclopentyl)phosphine and tri(cyclohexyl)phosphine. Preferred examples of triarylphosphines are triphenylphosphine, tri(p-tolyl)phosphine, tri(m-tolyl)phosphine, tri(o-tolyl)phosphine, tri(p-methoxyphenyl)phosphine, tri(p-dimethylaminophenyl)phosphine, tri(sodium-m-sulfonic acid phenyl)phosphine, diphenyl(2-sulfonic acid phenyl)phosphine, tri(1-naphthyl)phosphine, and diphenyl-2-pyridylphosphine. Preferred examples of dialkylarylphosphines are dimethylphenylphosphine and di-tert-butylphenylphosphine.

[0032] Preferred examples of alkyl diarylphosphines are ethyl diphenylphosphine and isopropyl diphenylphosphine. One example of a preferred cycloalkyl diarylphosphine is cyclohexyl diphenylphosphine. Another example of a preferred dicycloalkyl arylphosphine is dicyclohexylphenylphosphine. Further examples of preferred triarylphosphines are tris(o-methoxyphenyl)phosphine, tris(m-methoxyphenyl)phosphine, tris(p-fluorophenyl)phosphine, tris(m-fluorophenyl)phosphine, tris(o-fluorophenyl)phosphine, tris(p-chlorophenyl)phosphine, tris(m-chlorophenyl)phosphine, tris(pentafluorophenyl)phosphine, tris(p-trifluoromethylphenyl)phosphine, tris[3,5-bis(trifluoromethyl)phenyl]phosphine, diphenyl(o-methoxyphenyl)phosphine, diphenyl(o-methylphenyl)phosphine, tris(3,5-dimethylphenyl)phosphine, and tri-2-naphthylphosphine. One example of a preferred triheraylphosphine is tris(o-furanyl)phosphine. One example of a preferred trialkylphosphine is triisobutylphosphine. An example of a preferred triherocyclic phosphine is tris(1-pyrrolidinyl)phosphine. Particularly preferred are triphenylphosphine, di-tert-butylphenylphosphine, cyclohexyldiphenylphosphine, dicyclohexylphenylphosphine, tris(p-tolyl)phosphine, and tris(cyclohexyl)phosphine.

[0033] Suitable didentate phosphine ligands include 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthrene (Xanthrene). os), bis(2-diphenylphosphine)phenyl ether (DPEphos), 1,2-bis(di-tert-butylphosphine)benzene, 1,2-bis(di-tert-pentylphosphine)benzene, 1,2-bis(di-tert-butylphosphine)naphthalene, 2,2-dimethyl-1,3-bis(diphenylphosphine)propane, 1,3-bis(diisopropylphosphine)propane (DiPrPP), 1,3-bis(tert-butylphosphine)propane (DtBuP) P), 1,3-bis(n-butylphosphino)-propane (DnBuPP), 1,3-bis(diisopropylphosphino)-ethane (DCPE), 1,3-bis(dicyclohexylphosphino)-butane (DCPB), (1R)-1-[bis(1,1-dimethylethyl)phosphino]-2-[(1R)-1-[bis(2-methylphenyl)phosphino]ethyl]ferrocene, (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl]ethyl]ethyl]ferrocene (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene, (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene, 2-ethyl-2-butyl-1,3-bis(diphenylphosphino)-propane and 1,3-bis(dicyclohexylphosphino)-propane (DCPP).

[0034] In a preferred embodiment, the carbonylation reaction is carried out in the presence of a bidentate phosphine ligand, particularly DCPP.

[0035] Complexes with monodentate ligands of the type L2Pd(II)X2 or Pd(0)L4 (X = anionic ligand; L = electrically neutral phosphine ligand) are also suitable for the carbonylation reactions of the present invention, such as (tris(cyclohexyl)phosphine)2Pd(II)Cl2 or Pd(0)(triphenylphosphine)4. Complexes with bidentate ligands of the type LPd(II)X2, Pd(0)L2 or Pd(0)L2(CO)2 are also suitable, such as (DCPP)Pd(II)Cl2 or (DCPE)Pd(II)Cl2. Many ligands are also available as salts, which can be used in combination with palladium compounds in the present invention, such as P(tert-Bu)3*HBF4 or DCPP*2HBF4.

[0036] In one aspect, the carbonylation reaction is carried out in the presence of free phosphine, meaning that an excess of phosphine is used so that a portion of it is not bound in the palladium complex. The molar ratio of phosphine ligand to palladium is typically between 0.5:1 and 10:1, preferably between 0.5:1 and 5:1.

[0037] The palladium catalyst is used in an amount of less than 2 mol%, or less than 1 mol%, or less than 0.5 mol% based on the amount of the aromatic chloride of formula II, preferably between 0.001 and 0.3 mol%, more preferably between 0.001 and 0.2 mol%.

[0038] Under the reaction conditions of this invention, the Pd catalyst can undergo ligand exchange reactions to allow the anionic ligand X and / or the neutral ligand L to be replaced by other ligands present in the reaction mixture, such as CO, amines, or even a portion of the substrate molecule (which can form a large number of complexes or aryl halides after elementary reactions such as oxidative addition).

[0039] Palladium catalysts can be used as homogeneous solutions in the reaction medium, or they can be formed from heterogeneous catalyst precursors, such as colloidal Pd(0), Pd(0) applied to a support material, or Pd(II) compounds applied to a support material, such as Pd(0) or Pd(II) salts. Suitable support materials are, for example, inorganic metal oxides, silicates, and carbon.

[0040] Palladium catalysts can be removed from the reaction mixture using conventional post-treatment procedures known to those skilled in the art and can be reused in carbonylation reactions of the type described herein after separation.

[0041] After the reaction, the Pd catalyst can be reused. To achieve this, TBD*HCl can be removed from the resulting reaction mixture by filtration, followed by solvent removal by distillation, and then product separation by filtration or distillation. The remaining residue contains a large portion of the palladium catalyst, which can be reused in subsequent aminocarbonylation reactions. All operations must be carried out in a manner that does not affect catalyst performance, i.e., under an inert atmosphere.

[0042] The carbonylation reaction of this invention is carried out in the presence of carbon monoxide. This means that the reaction is carried out with pure carbon monoxide or with a mixture of carbon monoxide and an inert gas, such as nitrogen or a rare gas (helium, neon, argon). The carbonylation is typically carried out in a reaction vessel at atmospheric pressure or at elevated pressure. The term "elevated pressure" in this invention refers to a pressure above 1 bar (100 kPa). Suitable reaction vessels or reactors are those skilled in the art, for example, from "Ullmanns..." As known in "der technischen Chemie, Vol. 1, 3rd edition, 1951, p. 769 and thereafter".

[0043] According to the invention, the partial pressure of carbon monoxide in the carbonylation is less than 100 bar (10000 kPa), preferably less than 50 bar (5000 kPa), more preferably less than 20 bar (2000 kPa), and in a particularly preferred aspect, less than 15 bar (1500 kPa). In a further aspect of the invention, the partial pressure of carbon monoxide varies between 0.1 and 200 bar (100 to 20000 kPa), between 1 and 100 bar (100 to 10000 kPa), between 1 and 50 bar (100 to 5000 kPa), between 2 and 20 bar (200 to 2000 kPa), or between 5 and 15 bar (500 to 1500 kPa).

[0044] In one embodiment, the carbonylation reaction is carried out in the absence or in reduced amounts of oxygen or air.

[0045] When performed in batches, carbonylation requires batch times of 1 to 100 hours, 2 to 50 hours, or 5 to 20 hours to allow complete conversion of the aromatic chloride.

[0046] The temperature of the carbonylation reaction is suitably in the range of 20°C to 200°C; preferably in the range of 50°C to 180°C; more preferably in the range of 50°C to 150°C; and particularly in the range of 100°C to 140°C.

[0047] In one embodiment, the carbonylation is carried out at a temperature of 50 to 180°C and at a carbon monoxide partial pressure of 1 to 100 bar (100 to 5,000 kPa).

[0048] In one embodiment, the carbonylation reaction of the present invention is carried out at a temperature of 50°C to 150°C and at a carbon monoxide partial pressure of 2 to 20 bar (200 to 2,000 kPa).

[0049] In one embodiment, the carbonylation reaction of the present invention is carried out at a temperature of 100°C to 140°C and at a carbon monoxide partial pressure of 5 to 15 bar (500 to 1500 kPa).

[0050] The carbonylation reaction of this invention is carried out in the presence of an inert solvent. Suitable solvents are, for example, aliphatic, alicyclic, and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, dichloroethane, and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzyl nitrile), ethers (diethyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dioxane). Diethylene glycol monomethyl ether or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carboxylic acid esters and lactones (ethyl acetate and methyl acetate, valproic acid lactone), N-substituted lactams (N-methylpyrrolidone), carboxamides (N,N-dimethylformamide, N,N-dimethylacetamide), acyclic urea (dimethylimidazoline), nitriles (such as acetonitrile or propionitrile), and sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, sulfolane).

[0051] Preferred solvents are typically polar organic solvents, such as tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dioxane, 2-methyltetrahydrofuran, N,N-dimethylacetamide, toluene, and acetonitrile.

[0052] TBD is used in an amount of at least 30 mol%, at least 80 mol%, or at least 100 mol% based on the compound of formula II. In another aspect of the invention, TBD is used in an amount of from 30 mol% to 1000 mol% based on the compound of formula II. In a further aspect of the invention, TBD is used in an amount of from 50 mol% to 200 mol% based on the compound of formula II. In yet another aspect, TBD is used in an amount of from 80 mol% to 130 mol% based on the compound of formula II.

[0053] In addition to TBD, the carbonylation reaction of the present invention can also be carried out in the presence of an inorganic base b1. Preferred examples of inorganic base b1 are alkali metal and alkaline earth metal carbonates, hydroxides, and phosphates, which are advantageous because they are inexpensive, easy to handle, and can be easily removed by aqueous post-treatment after the carbonylation reaction. Preferred alkali metal carbonates are sodium carbonate and potassium carbonate, especially potassium carbonate. Preferred alkaline earth metal carbonates are magnesium carbonate and calcium carbonate. Preferred alkali metal phosphates are trisodium phosphate (Na3PO4) and disodium hydrogen phosphate (Na2HPO4).

[0054] The molar ratio of the compound of Formula III to the compound of Formula II is generally between 1:1 and 10:1, preferably between 1:1 and 5:1, and more preferably between 1:1 and 2:1.

[0055] In one embodiment of the invention, the aromatic chloride used in the carbonylation process is of formula II.a.

[0056]

[0057] Where n is 0 or 1; A 1 and A 2 Independently selected from nitrogen, CH or CR A ;where A 1 and A 2 No more than one of them is nitrogen; of which R A As defined or preferably defined herein, compounds of formula I are used to obtain aromatic carboxamides of formula Ia.

[0058]

[0059] Among them, variables n and R A A 1 and A 2 It has the meaning as defined for compound II.a, where the variable R 1 and R 2 It has the meaning as defined for compounds of formula I.

[0060] In one embodiment of the invention, the aromatic chloride used in the carbonylation process is of formula II.b.

[0061]

[0062] Where n is 0 or 1, R A As defined or preferably defined herein, compounds of formula I are used to obtain aromatic carboxamides of formula Ib.

[0063]

[0064] Where the variables n and R A It has the meaning as defined for compound II.b, where the variable R 1 and R 2 It has the meaning as defined or preferably defined herein for compounds of Formula I.

[0065] The compounds of formulas II.a and II.b are commercially available or can be prepared from readily available raw materials using standard procedures known to those skilled in the art.

[0066] In one aspect of the invention, variable A in the compound of formula I is phenyl.

[0067] In one embodiment of the invention, the group R in the compounds of formulas I, Ia, Ib, II, II.a and II.b A It is fluorine, chlorine, CN, methyl, ethyl, n-propyl, isopropyl, CF3, CHF2, CH2F, -S(=O)2-CH3, -C(=O)-O-ethyl, -C(=O)-O-methyl, -C(=O)-ethyl, -C(=O)-methyl.

[0068] In one embodiment of the invention, the group R in the compounds of formulas I, Ia, Ib, II, II.a and II.b A It is fluorine, chlorine, CN, methyl, ethyl, CF3, -S(=O)2-CH3, -C(=O)-O-ethyl, -C(=O)-O-methyl, -C(=O)-ethyl, -C(=O)-methyl.

[0069] In one respect, in the compounds of formulas I, Ia, Ib, II, II.a, and II.b, the variable n is 1 and R A It's fluorine.

[0070] In a preferred embodiment, in the compounds of formulas I, Ia, Ib, II, II.a and II.b, the variable n is 0.

[0071] Further embodiments involve the variable R in compounds of formulas I, III, Ia and Ib, IV, V and VI. 1 and R 2 The meaning of .

[0072] One embodiment relates to the preparation of compounds of formulas I, III, Ia and Ib, IV, V and VI, wherein R 1 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pent-1-yl, or phenyl; wherein the phenyl group is unsubstituted or substituted by 1, 2, 3, or up to the maximum possible number of the same or different groups selected from fluorine, chloro, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl; R 2 It is hydrogen, methyl, or ethyl.

[0073] Another embodiment relates to the preparation of compounds of formulas I, III, Ia and Ib, IV, V and VI, wherein R 1 It is methyl or phenyl, wherein the phenyl ring is unsubstituted or substituted by 1, 2, 3 or 4 identical or different groups selected from halogens; wherein R 2 It is hydrogen, methyl, or ethyl.

[0074] Further embodiments relate to the preparation of compounds of formulas I, III, Ia and Ib, IV, V and VI, wherein R 1 It is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pent-1-yl, 2-fluorophenyl, 4-fluorophenyl, or 2-difluoromethoxy-phenyl; R 2 It is hydrogen.

[0075] Another embodiment relates to the preparation of compounds of formulas I, III, Ia and Ib, IV, V and VI, wherein R 1 It is methyl, 2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl; especially methyl or 2-fluorophenyl; wherein R 2 It is hydrogen.

[0076] In a preferred embodiment of the invention (Embodiment E.1), the carbonylation reaction is carried out at a temperature of 100°C to 140°C and at a carbon monoxide partial pressure of 5 to 15 bar (500 to 1500 kPa).

[0077] Implementation Scheme E.2: Based on Implementation Scheme E.1, wherein the reaction is carried out in the presence of a palladium catalyst in an amount of less than 2 mol% based on the compound of Formula II; wherein at least one organic monodentate or bidentate phosphine ligand is used in the palladium catalyst, selected from triphenylphosphine, tri(tolyl)phosphine, tri-n-butylphosphine, tricyclohexylphosphine, triisopropylphosphine, tri-tert-butylphosphine, S-phos(2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), cyclohexyldiphenylphosphine, triisopropylphosphine, phenyldicyclohexylphosphine, butyldiadamantylphosphine, 1,2-bis(dimethylphosphino)ethane, 2,2'-bis(diphenyl)phosphine Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)-propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), bis(2-diphenylphosphino)phenyl ether (DPEphos), 1,2-bis(di-tert-butylphosphinomethyl)benzene, 1,2-bis(di-tert-pentylphosphinomethyl)benzene, 1,2-bis(di-tert-pentylphosphinomethyl)benzene, 1,2-bis(di-tert-butylphosphinomethyl)benzene, -tert-butylphosphinomethyl)naphthalene, 2,2-dimethyl-1,3-bis(diphenylphosphino)-propane, 1,3-bis(diisopropylphosphino)-propane (DiPrPP), 1,3-bis(tert-butylphosphino)-propane (DtBuPP), 1,3-bis(n-butylphosphino)-propane (DnBuPP), 1,3-bis(diisopropylphosphino)-ethane (DCPE), 1,3-bis(dicyclohexylphosphino)-butane (DCPB), (1R)-1-[bis(1,1-dimethylethyl)phosphino]-2-[(1R)-1-[bis(2-methylphenyl)phosphino]ethyl]di Ferrocene, (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene, (2R)-1-[(1R)-1-(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene, (1R)-1-(dicyclohexylphosphino)-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene, 2-ethyl-2-butyl-1,3-bis(diphenylphosphino)-propane and 1,3-bis(dicyclohexylphosphino)-propane (DCPP); wherein the molar ratio of phosphine ligand to palladium is between 0.5:1 and 5:1.

[0078] Implementation scheme E.3: Based on implementation scheme E.2, wherein the molar ratio of the compound of formula III to the compound of formula II is between 1:1 and 2:1.

[0079] Implementation scheme E.4: Based on implementation scheme E.3, wherein the solvent is tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dioxane, 2-methyltetrahydrofuran, N,N-dimethylacetamide, toluene, or acetonitrile.

[0080] Implementation scheme E.5: Based on implementation scheme E.4, wherein TBD is used in an amount of at least 80 mol% based on the amount of the compound of formula II.

[0081] Implementation scheme E.6: Based on implementation scheme E.4, wherein TBD is used in an amount of 80 mol% to 130 mol% based on the amount of the compound of formula II.

[0082] Implementation Scheme E.6: Based on Implementation Scheme E.5 or E.6, wherein the method relates to the preparation of compounds of formulas Ib, IV, V and VI, wherein R 1 It is methyl or 2-fluorophenyl; wherein R 2 It is hydrogen.

[0083] Compounds of formula Ib can be further transformed to obtain compounds of formula IV, wherein the variable R A n, R 1 and R 2 As defined or preferred herein. Compound IV is used for the synthesis of 3-aryl-5-trifluoromethyl-1,2,4- A valuable chemical intermediate for diazoles, 3-aryl-5-trifluoromethyl-1,2,4- Diazoles are known to be used to control plant pathogenic fungi.

[0084]

[0085] Accordingly, compounds of formula IV can be obtained by treating compounds of formula Ib with hydroxylamine or a salt thereof, such as hydrochloride, in the presence of a base, preferably triethylamine, sodium hydroxide, or sodium methoxide, in a suitable solvent such as methanol, ethanol, or water, or a mixture of these solvents, at a temperature of 0°C to 100°C. For relevant examples, see Kitamura, S. et al., Chem. Pharm. Bull. 2001, 49, 268, or any of the patent references cited above.

[0086] Typically, the antifungal 3-aryl-5-trifluoromethyl-1,2,4- The preparation of diazoles involves the reaction of a hydroxymidamine compound of formula IV with an activated derivative of trifluoroacetic acid to form... A diazole ring. Accordingly, in a further embodiment of the invention, a compound of formula IV is reacted with an activator of trifluoroacetic acid to obtain a compound of formula V, wherein the variable R... A n, R 1 and R2 As defined or preferred in this document.

[0087]

[0088] Used to form The procedures for diazoles are described in WO 2017 / 198852, WO 2017 / 207757, WO2017220485, WO 2018 / 065414, WO 2019 / 020451 and WO 2017 / 211652 A1.

[0089] Another embodiment of the invention relates to a method that further includes the step of reacting a compound of formula V to obtain a compound of formula VI, wherein the variable R A n, R 1 and R 2 As defined or preferred in this document.

[0090]

[0091] Compounds of Formula VI can be prepared from compounds of Formula V by treatment with Lawesson's reagent or phosphorus pentasulfide in an inert organic solvent such as non-halogenated aliphatic hydrocarbons, non-halogenated alicyclic hydrocarbons, haloalphatic hydrocarbons, haloaromatic hydrocarbons, amides, ethers, esters, ketones, nitriles; for example toluene, tetrahydrofuran, dioxane, or ethyl acetate; at a temperature of 0°C to 130°C, preferably 60°C to 80°C. See, for example, Eur. J. Med. Chem. 2011, 46(9), 3917-3925; Synthesis 2003, 13, 1929–1958, WO 2006 / 0123242, WO 2010 / 086820, WO 2014 / 0151863, WO 2019 / 020451, and WO 2017 / 211649. After the reaction is complete, the reaction mixture is post-treated in a common manner.

[0092] In particular, the present invention relates to the preparation of compounds Va, Vb and VI.a.

[0093]

[0094] In the definitions of variables given above, set terms that typically represent the substituents involved are used.

[0095] Term "C" n -C m "Indicates the possible number of carbon atoms in the substituent or substituent structural portion involved in each case."

[0096] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0097] The term "oxo" refers to an oxygen atom =O that bonds to a carbon or sulfur atom, thereby forming, for example, a ketone group -C(=O)- or a sulfinyl group -S(=O)-.

[0098] The term "formyl group" refers to the group C(=O)H.

[0099] The term “C1-C6-alkyl” refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.

[0100] The term "C2-C6-alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and a double bond at any position, such as vinyl, 1-propenyl, 2-propenyl (allyl), 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl.

[0101] The term "C2-C6-ynyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl.

[0102] The term "C1-C6-haloalkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as defined above), wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2 -Fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, CH2-C2F5, CF2-C2F5, CF(CF3)2, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl.

[0103] The term “C1-C6-alkoxy” refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms bonded via oxygen at any position in an alkyl group (as defined above), such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, or 1,1-dimethylethoxy.

[0104] The term "C1-C6-haloalkoxy" refers to a C1-C6-alkoxy group as defined above, in which some or all of the hydrogen atoms can be replaced by halogen atoms as mentioned above. Examples include OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2- ... ,2-trichloroethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2-C2F5, OCF2-C2F5, 1-(CH2F)-2-fluoroethoxy, 1-(CH2Cl)-2-chloroethoxy, 1-(CH2Br)-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

[0105] The term "phenyl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl group is replaced by a phenyl or heteroaryl group, respectively (as defined above).

[0106] The term "C1-C4-alkoxy-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl group is replaced by a C1-C4-alkoxy group (as defined above). Similarly, the term "C1-C4-alkylthio-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl group is replaced by a C1-C4-alkylthio group (as defined above).

[0107] As used herein, the term "C1-C6-alkylthio" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms bonded via a sulfur atom (as defined above). Correspondingly, as used herein, the term "C1-C6-haloalkylthio" refers to a straight-chain or branched haloalkyl group having 1 to 6 carbon atoms bonded via a sulfur atom at any position within the haloalkyl group (as defined above).

[0108] The term "C1-C4-alkoxyimino" refers to a divalent imino (C1-C4-alkyl-ON=) with a C1-C4-alkoxy group as a substituent, such as methylimino, ethylimino, propylimino, 1-methylethylimino, butylimino, 1-methylpropylimino, 2-methylpropylimino, 1,1-dimethylethylimino, etc.

[0109] The term “C1-C6-alkoxyimino-C1-C4-alkyl” refers to an alkyl group having 1 to 4 carbon atoms, in which two hydrogen atoms of one carbon atom of the alkyl group are replaced by a divalent C1-C6-alkoxyimino (C1-C6-alkyl-ON=) as defined above.

[0110] The term "C2-C6-enoxyimino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms in which two hydrogen atoms of one carbon atom of the alkyl group are replaced by a divalent C2-C6-enoxyimino (C2-C6-enyl-ON=).

[0111] The term "C2-C6-alkynoxyimino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, in which two hydrogen atoms of one carbon atom of the alkyl group are replaced by a divalent C2-C6-alkynoxyimino (C2-C6-alkynyl-ON=).

[0112] The term "hydroxy C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, in which one hydrogen atom of the alkyl group is replaced by an OH group.

[0113] The term "aminoC1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, in which one hydrogen atom of the alkyl group is replaced by an NH2 group.

[0114] The term "C1-C6-alkylamino" refers to an amino group substituted with one residue of a group independently selected from the definition of the term C1-C6-alkyl. Similarly, the term "di-C1-C6-alkylamino" refers to an amino group substituted with two residues of a group independently selected from the definition of the term C1-C6-alkyl.

[0115] The term "C1-C4-alkylamino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl group is replaced by a nitrogen-bonded C1-C4-alkyl-NH- group (as defined above). Similarly, the term "di-C1-C4-alkylamino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl group is replaced by a nitrogen-bonded (C1-C4-alkyl)2N- group (as defined above).

[0116] The term "aminocarbonyl-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, in which one hydrogen atom of the alkyl group is replaced by a –(C=O)-NH2 group.

[0117] The term "C2-C6-alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and a double bond at any position, such as vinyl, 1-propenyl, 2-propenyl (allyl), 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl.

[0118] The term "C2-C6-ynyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl.

[0119] The term "C3-C" 11 "-Cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic saturated monovalent hydrocarbon group with 3 to 11 carbon ring members connected via one of the ring carbon atoms by substituting a hydrogen atom, such as cyclopropyl (C3H5), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, norcaranyl (bicyclo[4.1.0]heptyl) and norbornyl (bicyclo[2.2.1]heptyl).

[0120] The term "C3-C" 11 "-cycloalkyl-C1-C6-alkyl" means that one hydrogen atom of the alkyl group is separated from the hydrogen atom of the alkyl group by a C3-C6 alkyl group as defined above. 11 - Cycloalkyl-substituted alkyl groups having 1 to 11 carbon atoms.

[0121] The term "C3-C" 11 "-cycloalkoxy" refers to a cyclic monovalent hydrocarbon group (as defined above) with 3 to 11 carbocyclic members bonded via oxygen at any position on a cycloalkyl group, such as cyclopropoxy.

[0122] The terms "-C(=O)-C1-C4-alkyl", "-C(=O)-O-C1-C4-alkyl", and "-C(=O)-C3-C" are used to describe the alkyl group of C1-C4-alkyl groups. 11 "-cycloalkyl" refers to a group that is attached to the rest of a compound via a carbon atom of a -C(=O)- group.

[0123] The term "aliphatic" refers to compounds or groups composed of carbon and hydrogen that are non-aromatic. "Alicyclic" compounds or groups are organic compounds that are both aliphatic and cyclic. They contain one or more fully carbon rings, which may be saturated or unsaturated but do not possess aromatic properties.

[0124] The term "cyclic moiety" or "cyclic group" refers to a group that is an alicyclic or aromatic ring, such as a phenyl or heteroaryl group.

[0125] The term "wherein any aliphatic or cyclic group is unsubstituted or substituted" refers to an aliphatic group, a cyclic group, and a group containing both an aliphatic and a cyclic moiety in one group, such as in, for example, C3-C8-cycloalkyl-C1-C4-alkyl; thus, a group containing both an aliphatic and a cyclic moiety—which may be substituted or unsubstituted independently of each other.

[0126] The term "phenyl" refers to an aromatic ring system consisting of six carbon atoms (commonly known as a benzene ring).

[0127] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic system that includes 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, in addition to a carbon atom.

[0128] The term "saturated 3- to 7-membered carbon ring" is understood to refer to a monocyclic saturated carbon ring with 3, 4, or 5 carbon ring members. Examples include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0129] The term "3 to 10-membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic heterocycles, wherein the ring member atoms of the monocyclic or bicyclic heterocycle further include 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms in addition to carbon atoms" is understood to refer to aromatic monocyclic and bicyclic heteroaromatic ring systems, as well as saturated and partially unsaturated heterocycles, for example:

[0130] 3- or 4-membered saturated heterocycles containing one or two heteroatoms selected from N, O and S as ring members, such as ethylene oxide, aziridine propane, thioheteropropane, oxetane, aziridine, thiethane, [1,2]dioxetane, [1,2]dithioheterobutane, and [1,2]diazatane.

[0131] And 5- or 6-membered saturated or partially unsaturated heterocycles containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, such as 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-iso azolealkyl, 4-iso azolealkyl, 5-iso Alzolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazoleyl, 4-pyrazoleyl, 5-pyrazoleyl, 2- azolealkyl, 4- azolealkyl, 5- Alzolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4- diazolidin-3-yl, 1,2,4- Diazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4- Diazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl, 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,4-dihydrothiophen-2-yl, 2,4-dihydrothiophen-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-iso Azoline-3-yl, 3-iso Azoline-3-yl, 4-iso Azoline-3-yl, 2-iso Azoline-4-yl, 3-iso Azoline-4-yl, 4-iso Azoline-4-yl, 2-iso Azoline-5-yl, 3-iso Azoline-5-yl, 4-iso Azoline-5-yl, 2-isothiazoline-3-yl, 3-isothiazoline-3-yl, 4-isothiazoline-3-yl, 2-isothiazoline-4-yl, 3-isothiazoline-4-yl, 4-isothiazoline-4-yl, 2-isothiazoline-5-yl, 3-isothiazoline-5-yl, 4-isothiazoline-5-yl, 2,3-dihydropyrazole-1-yl, 2,3-dihydropyrazole-2-yl, 2,3-dihydropyrazole -3-yl, 2,3-dihydropyrazole-4-yl, 2,3-dihydropyrazole-5-yl, 3,4-dihydropyrazole-1-yl, 3,4-dihydropyrazole-3-yl, 3,4-dihydropyrazole-4-yl, 3,4-dihydropyrazole-5-yl, 4,5-dihydropyrazole-1-yl, 4,5-dihydropyrazole-3-yl, 4,5-dihydropyrazole-4-yl, 4,5-dihydropyrazole-5-yl, 2,3-dihydro 2-Azazole, 2,3-dihydro Azol-3-yl, 2,3-dihydro Azol-4-yl, 2,3-dihydro Azol-5-yl, 3,4-dihydro Azol-2-yl, 3,4-dihydro 3-Azazole, 3,4-dihydro Azol-4-yl, 3,4-dihydro Azol-5-yl, 3,4-dihydro Azol-2-yl, 3,4-dihydro 3-Azazole, 3,4-dihydro Azoxy-4-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxane-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothiophenyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperidinyl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl and their corresponding - subunits; and 7-membered saturated or partially unsaturated heterocycles, such as tetrahydro- and hexahydroaza- radicals, such as 2,3,4,5-tetrahydro[1H]aza -1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro[2H]aza -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]aza -1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]aza -1-, -2-, -3-, -4-, -5-, -6- or -7-yl, hexahydrozaza -1-, -2-, -3-, or -4-yl groups, tetrahydro- and hexahydroxyheptatrienyl groups, such as 2,3,4,5-tetrahydro[1H]oxetane-2-, -3-, -4-, -5-, -6-, or -7-yl groups, 2,3,4,7-tetrahydro[1H]oxetane-2-, -3-, -4-, -5-, -6-, or -7-yl groups, 2,3,6,7-tetrahydro[1H]oxetane-2-, -3-, -4-, -5-, -6-, or -7-yl groups, and hexahydroxyheptatrienyl groups. -1-, -2-, -3- or -4-yl, tetrahydro- and hexahydro-1,3-diaza 1,4-diazine, tetrahydro- and hexahydro-1,4-diaza alkyl, tetrahydro- and hexahydro-1,3-oxazine oxazepinyl, tetrahydro- and hexahydro-1,4-oxazepinyl dioxepinyl, tetrahydro- and hexahydro-1,3-dioxepinyl, tetrahydro- and hexahydro-1,4-dioxepinyl and the corresponding - subunits.

[0132] The terms "5- or 6-membered heteroaryl" or "5- or 6-membered aromatic heterocycle" refer to aromatic ring systems that include 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, in addition to a carbon atom. Examples of 5-membered heteroaryl rings include pyrrolo-1-yl, pyrrolo-2-yl, pyrrolo-3-yl, thiophenolo-2-yl, thiophenolo-3-yl, furanolo-2-yl, furanolo-3-yl, pyrazololo-1-yl, pyrazololo-3-yl, pyrazololo-4-yl, pyrazololo-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, and imidazole-5-yl. 2-Azolium azole-4-yl, Azol-5-yl, isozonol Azol-3-yl, isozonol Azol-4-yl, isozonol 5-yl thiazolyl, 2-yl thiazolyl, 4-yl thiazolyl, 5-yl thiazolyl, 3-yl isothiazol-3, 4-yl isothiazol-4, 5-yl isothiazol-5, 1,2,4-triazol-1-yl, 3-yl 1,2,4-triazol-3, 5-yl 1,2,4-triazol-5, 1,2,4- diazol-3-yl, 1,2,4- Diazol-5-yl and 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl; or

[0133] Six-membered heteroaryl groups, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and 1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl.

[0134] Operational Examples

[0135] The invention is further illustrated by the following operational examples.

[0136] Example 1) Preparation of 4-cyano-N-(2-fluorophenyl)-benzamide

[0137] Palladium(II) chloride (4.1 mg, 0.023 mmol), 1,3-bis(dicyclohexylphosphino)propanebis(tetrafluoroborate) (12.5 mg, 0.020 mmol), TBD (1.1 g, 8.0 mmol), and 4-chlorobenzyl nitrile (1.09 g, 8.0 mmol) were maintained under argon atmosphere in an autoclave. 2-fluoroaniline (1.67 g, 15 mmol) and tetrahydrofuran (10 mL) were added under argon atmosphere, and carbon monoxide was introduced into the reaction vessel at 10 bar (1000 kPa). The reaction mixture was stirred at 130 °C for 20 h (stirring rate 1000 rpm). The reaction mixture was then cooled to room temperature, followed by pressure release. GC conversion*: 96%; selectivity for carboxamide: 99%.

[0138] *Analytical GC method: VF-23 column (60 m x 0.25 mm / 0.25 μm; temperature: 50 °C for 2 min, then 10 °C / min to 100 °C; then 15 °C / min to 200 °C; 200 °C for 5 min; then 20 °C / min to 250 °C; flow rate: 2.0 mL / min; hydrogen as carrier gas). R (2-Fluoroaniline) = 10.9 min; t R (4-Chlorobenzenenitrile) = 12.5 min; t R (Carboxylamide) = 34.3 min.

[0139] Table 1 provides the experimental results for variations in the reaction conditions of Example 1 described above. [Commentary on the results]

[0140] Unless otherwise stated, Examples 1, 1.1, 1.2, and 1.6 in Table 1 each represent variations according to the invention, since the reaction is carried out using various Pd sources with TBD as the base.

[0141] Examples 1.3 to 1.5 in Table 1 represent comparative examples, showing that under the selected conditions (with a low catalyst loading of 0.25 mol% Pd), the reaction using TBD proceeds much faster after 20 hours compared to the case where TBD is replaced by an equimolar amount of another base.

[0142] Table 1:

[0143]

[0144] a) Same as in Example 1 above;

[0145] b) The embodiments representing the present invention are the same as those in Embodiment 1, except as otherwise mentioned in Table 1;

[0146] c)The comparative examples not based on the present invention are the same as in Example 1, except as otherwise mentioned in Table 1.

[0147] Example 2) Preparation of N,N-diethyl-3,5-dimethylbenzamide

[0148] Palladium(II) chloride (57 mg, 0.32 mmol, 4 mol%), 1,3-bis(dicyclohexylphosphino)propanebis(tetrafluoroborate) (197 mg, 0.32 mmol, 4 mol%), TBD (1.1 g, 8.0 mmol), and 5-chloro-m-xylene (1.13 g, 8.0 mmol) were maintained under argon atmosphere in an autoclave. Diethylamine (2.93 g, 40 mmol) and N-methylpyrrolidine (15 mL) were added under argon atmosphere, and carbon monoxide was introduced into the reaction vessel at 10 bar (1000 kPa). The reaction mixture was stirred at 130 °C for 20 h (stirring rate 1000 rpm). The reaction mixture was then cooled to room temperature, followed by pressure release. GC conversion*: 73%; selectivity for carboxamide: 87%.

[0149] Table 2 provides experimental results for variations of the reaction conditions in Example 2 above. Example 2 in Table 2 represents the reaction conditions according to the invention (using a different aryl halide / amine combination compared to Table 1) because the reaction uses TBD as a base. Example 2.1 is not a comparative example of the invention. In this case, the reaction using TBD also proceeded faster after 20 hours compared to the case where TBD was replaced by an equimolar amount of potassium carbonate.

[0150] Table 2:

[0151]

[0152] a) The embodiments representing the present invention are the same as those in Embodiment 2, except as otherwise mentioned in Table 2;

[0153] b) Comparative examples not based on the present invention; as in Example 2, potassium carbonate was used instead of TBD.

[0154] Example 3) Preparation of methyl 4-((2-fluorophenyl)carbamoyl)benzoate

[0155] Palladium(II) chloride (7.8 mg, 0.044 mmol), 1,3-bis(dicyclohexylphosphino)propanebis(tetrafluoroborate) (25 mg, 0.041 mmol), TBD (1.1 g, 8.0 mmol), and methyl 4-chlorobenzoate (1.41 g, 8.27 mmol) were transferred to a glass autoclave under an argon atmosphere. 2-fluoroaniline (1.69 g, 15 mmol) and tetrahydrofuran (15 mL) were added under a constant argon flow. The autoclave was pressurized with carbon monoxide at 10 bar (1000 kPa). The reaction mixture was stirred at 130 °C for 20 hours (stirring rate 1000 rpm). The reaction mixture was then cooled to room temperature, followed by pressure release. GC conversion*: 84%; selectivity for carboxamide: 52%.

[0156] Table 3 provides experimental results for variations of the reaction conditions in Example 3 described above.

[0157] Example 3 in Table 3 represents the reaction conditions according to the invention (using a different aryl halide / amine combination compared to Table 1) because the reaction uses TBD as a base. Example 3.1 is not a comparative example of the invention. As in other examples, in this case, the reaction using TBD proceeds much faster after 20 hours compared to the case where TBD is replaced by an equimolar amount of potassium carbonate.

[0158] Table 3:

[0159]

[0160] a) Same as in Example 3 above;

[0161] b) Comparative examples not based on the present invention; potassium carbonate is used instead of TBD.

Claims

1. A process for the preparation of an aromatic carboxamide of formula I, ###0001### wherein n is 0, 1, 2, 3 or 4; the process comprising reacting an aromatic chloride of formula II with carbon monoxide and an amine compound of formula III ###0002### Aryl-CI II ###0003### wherein Aryl is as defined above for the compound of formula I, ###0004### wherein the reaction is carried out in the presence of a palladium-based catalyst, a solvent and a base; wherein the process is characterized in that the base is 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

2. The process according to claim 1, wherein the aromatic chloride is of formula II.b, ###0005### Aryl is phenyl; wherein Aryl is further unsubstituted or further substituted by n identical or different groups R A substituted; wherein 3. The process according to claim 1, wherein n is 0. R A independently selected from the group consisting of fluorine, chlorine, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, -S(=O)2-CH3, -O-CºN, -S-CºN, -N=C=O, -N=C=S, di-C1-C6-alkylamino, -C(=O)-C1-C6-alkyl, -C(=O)-O-C1-C6-alkyl and -CH2OH; R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[l. l. l]pentan- 1 -yl or phenyl; wherein phenyl is unsubstituted or substituted by 1, 2, 3 or up to the maximum possible number of identical or different groups selected from fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl; R 2 is hydrogen, methyl or ethyl; 4. The process according to claim 2, wherein n is 0.

7. The process according to any one of claims 1 to 4, wherein the process is carried out at a temperature of from 70 °C to 140 °C.

8. The process according to any one of claims 1 to 4, wherein the process is carried out at a pressure of from 300 to 2000 kPa. wherein R 1 and R 2 are as defined above for the compounds of formula I; 9. The process according to any one of claims 1 to 4, wherein 1,5,7-triazabicyclo[4.4.0]dec-5-ene is used in an amount of at least 80 mol% based on the amount of the compound of formula II.

10. The process according to any one of claims 1 to 4, wherein the palladium-based catalyst is prepared from a Pd(II) compound or a Pd(0) compound by complexation with a monodentate or bidentate phosphine ligand. wherein n is 0 or 1, R A as defined in claim 1 for a compound of formula I to obtain an aromatic carboxamide of formula I.b, wherein the variables n and R A having the meanings as defined for compound II.b, wherein the variables R 1 and R 2 have the meanings as defined for compounds of the formula I. ​ ​ 5. The method according to any one of claims 1 to 4, wherein in the compounds of the formulae I and III R 1 is methyl or phenyl, wherein phenyl is unsubstituted or substituted by 1, 2, 3 or 4 identical or different radicals selected from halogen; wherein R 2 is hydrogen, methyl or ethyl.

6. The method according to any one of claims 1 to 4, wherein in the compounds of formulae I and III, R 1 is methyl or 2-fluorophenyl; wherein R 2 is hydrogen. ​ ​ ​ ​ 11. The process according to any one of claims 1 to 4, wherein the palladium-based catalyst is prepared from a Pd(ll) compound or a Pd(O) compound by complexation with a monodentate or bidentate phosphine ligand selected from the group consisting of triphenylphosphine, tri(tolyl)phosphine, tri(n-butyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, cyclohexyldiphenylphosphine, triisopropylphosphine, phenyldicyclohexylphosphine, butyldigadialkyphosphine, 1,2-bis(dimethylphosphino)ethane, 2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)-propane, 1,4-bis(diphenylphosphino)butane, 1,1 '-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis[(2-diphenylphosphino)phenyl]ether, 1,2-bis(di-tert-butylphosphinomethyl)benzene, 1,2-bis(di-tert-amylphosphinomethyl)benzene, 1,2-bis(di-tert-butylphosphinomethyl)naphthalene, 2,2-dimethyl-1,3-bis(diphenylphosphino)-propane, 1,3-bis(diisopropylphosphino)-propane, 1,3-bis(tert-butylphosphino)-propane, 1,3-bis(n-butylphosphino)-propane, 1,2-bis(diisopropylphosphino)-ethane, 1,3-bis(dicyclohexylphosphino)-butane, (1 R)-1 -[bis(1,1 -dimethylethyl)phosphino]-2-[(1 R)-1 -[bis(2-methylphenyl)phosphino]ethyl]ferrocene, (2R)-1 -[(1 R)-1 -[bis(1,1 -dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene, (2R)-1 -[(1 R)-1 -(dicyclohexylphosphino)ethyl]-2-(diphenylphosphino)ferrocene, (1 R)-1 -(dicyclohexylphosphino)-2-[(1 R)-1 -(dicyclohexylphosphino)ethyl]ferrocene, 2-ethyl-2-butyl-1,3-bis(diphenylphosphino)-propane and 1,3-bis(dicyclohexylphosphino)-propane; wherein the molar ratio of phosphine ligand to palladium is between 0.5:1 and 5:

1.

12. The process according to claim 2, which is further used for the step of reacting the compound of formula I.b with hydroxylamine or a salt thereof to obtain a compound of formula IV 13. The process according to claim 12, which is further used for the step of reacting the compound of formula IV with an activated derivative of trifluoroacetic acid to obtain a compound of formula V 14. The process according to claim 13, which is further used for the step of reacting the compound of formula V with Lawesson's reagent or phosphorus pentasulfide to obtain a compound of formula VI

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