Preparation of 4-cyanobenzoyl chloride from alkali metal 4-carbamoyl-benzoate

Abstract

The invention relates to a method for producing 4-cyanobenzoyl chloride of formula (I) from an alkali metal 4-carbamoyl-benzoate of formula (II) with a chlorinating agent and a catalyst. # imgabs0 #

Description

[0001] The present invention relates to a process for preparing 4-cyanobenzoyl chloride of formula I from an alkali metal 4-carbamoyl-benzoate of formula II using a chlorinating agent and a catalyst.

[0002]

[0003] 4-Cyanobenzoyl chloride of formula I is a versatile and highly reactive synthetic intermediate which provides various strategic options for orthogonal synthesis concepts by exploiting the distinguishable reactivity of the nitrile and the chlorocarbonyl towards nucleophilic reactants. For example, the compounds of formula I can be used for the preparation of benzamide-type trifluoromethyl-1,2,4-oxadiazoles, such as the compounds disclosed in WO 2015 / 185485 A1 and WO 2017 / 211649 A1. These are effective agrochemicals for controlling phytopathogenic fungi.

[0004] The synthesis of 4-cyanobenzoyl chloride of formula I via 4-carbamoylbenzoic acid of type II is particularly attractive since it utilizes industrially available starting materials, such as terephthalic acid dichloride or the corresponding diesters, on a large scale and at low cost.

[0005] The reaction of carboxylic acids or their salts with suitable chlorinating agents to give the corresponding carboxylic acid chlorides is part of the common general knowledge in the field of synthetic chemistry. Similarly, it is well known that primary carboxamides undergo dehydration with the same type of chlorinating agents to give the corresponding nitriles. However, little is known about the selective conversion of compounds which are characterized by both of these functional groups in one molecule and the conversion of both functional groups in one step using one type of chlorinating agent without mutual interference.

[0006] This scarcity of reported procedures stems from the perception of the person skilled in the art that carboxylic acid halides are highly reactive electrophilic reagents which react non-selectively with nucleophilic substances, such as primary carboxamides or other intermediate substances which are prone to intermolecular reactions. Given these properties, when using a chlorinating agent with a bifunctional compound of formula II, the person skilled in the art would expect many side reactions, in particular including the unwanted formation of oligomers and / or polymers.

[0007] WO 2021 / 209377 A1 describes a process for preparing 4-cyanobenzoyl chloride by the reaction of 4-carbamoylbenzoic acid with various types of chlorinating agents, in particular phosphorus oxychloride.

[0008] To improve the overall synthesis efficiency in a multi-step process, it may be desirable to use an alkali metal benzoate of formula II instead of carbamoylbenzoic acid.

[0009] The inventors of the present invention have found that phosphorus trichloride does not produce 4-cyanobenzoyl chloride of formula I in the reaction with alkali metal benzoates of formula II (different from the reaction using free acids as shown in WO 2021 / 209377), but leads to the formation of a large amount of terephthaloyl dichloride together with other by-products (see Working Example 6 herein).

[0010] The inventors have further found that the use of thionyl chloride in these reactions has the same disadvantage of poor selectivity and provides 4-cyanobenzoyl chloride in low to medium yields (see Working Example 7 herein).

[0011] The inventors have surprisingly found that an almost quantitative yield of compound I can be obtained by reacting an alkali metal benzoate of formula II with a chlorinating agent selected from the group consisting of phosgene, diphosgene, and triphosgene; the method further includes the presence of a co-solvent and a carboxamide catalyst. This method is economically viable as it enables the efficient preparation of the compound of formula I in high yields on an industrial scale and substantially avoids the formation of unwanted by-products such as terephthaloyl dichloride.

[0012] Accordingly, the present invention relates to a method for preparing 4-cyanobenzoyl chloride of formula I,

[0013]

[0014] wherein

[0015] R is halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, or C1-C4-haloalkoxy;

[0016] n is 0, 1, or 2;

[0017] The method comprises reacting an alkali metal 4-carbamoylbenzoate of formula II with a chlorinating agent,

[0018]

[0019] wherein in the alkali metal benzoate of formula II, the variables n and R are as defined above for the compound of formula I, and wherein M + is an alkali metal cation,

[0020] The chlorinating agent is selected from the group consisting of phosgene, diphosgene, and triphosgene; the method further includes the presence of a co-solvent and a sub-stoichiometric amount, based on the amount of the alkali metal benzoate of formula II, of a carboxamide catalyst of formula C.

[0021]

[0022] Wherein

[0023] R C1 is hydrogen, methyl, or NR C4 R C5 ; wherein R C4 and R C5 are each independently selected from the group consisting of hydrogen and C1-C4-alkyl;

[0024] R C2 is C1-C4-alkyl;

[0025] Or

[0026] R C1 and R C2 together with the group -NR C3 -C(=O)- to form a saturated or partially unsaturated 5- or 6-membered heterocycle, wherein the heterocycle optionally further contains 1 or 2 heteroatoms independently selected from N, O, and S as ring member atoms in addition to one nitrogen atom, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and wherein one or two CH2 groups of the heterocycle can be replaced by one or two groups independently selected from C(=O) and C(=S);

[0027] R C3 is hydrogen or C1-C4-alkyl;

[0028] Or

[0029] R C2 and R C3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 5- or 6-membered heterocycle, wherein the heterocycle optionally further contains 1 or 2 heteroatoms independently selected from N, O, and S as ring member atoms in addition to one nitrogen atom, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and wherein one or two CH2 groups of the heterocycle can be replaced by one or two groups independently selected from C(=O) and C(=S).

[0030] In one aspect of the present invention, the alkali metal cation in the alkali metal benzoate having formula II is potassium or sodium, preferably potassium.

[0031] In a preferred embodiment, the chlorinating agent in the method of the present invention is phosgene.

[0032] Typically, the amount of the chlorinating agent in the method of the present invention is between 2 and 5 equivalents, preferably between 2 and 3 equivalents, based on the amount of compound II.

[0033] The method of the present invention is carried out in a co-solvent. The term "co-solvent" as used herein refers to an inert aprotic organic solvent which merely acts as a solvent and is not consumed during the reaction. To avoid doubt, the co-solvent is different from reactants such as compound II, the chlorinating agent or the catalyst.

[0034] Suitable co-solvents are, for example, aliphatic hydrocarbons, cycloaliphatic hydrocarbons and aromatic hydrocarbons (non-limiting examples are: pentane, hexane, heptane, octane, nonane, decane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons (non-limiting examples are: methylene chloride, chloroform, dichloroethane and tetrachloroethane), nitriles (non-limiting examples are: acetonitrile, propionitrile, benzonitrile), ethers (non-limiting examples are: diethyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dioxane, diethylene glycol monomethyl ether or monoethyl ether), and sulfoxides and sulfones (non-limiting examples are: dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone).

[0035] In one aspect of the present invention, the co-solvent is selected from the group consisting of: nitriles, ethers, sulfoxides, sulfones, aliphatic hydrocarbons, cycloaliphatic hydrocarbons and aromatic hydrocarbons having 1 to 10 carbon atoms (wherein these hydrocarbons are halogenated or non-halogenated); or mixtures thereof.

[0036] Preferred co-solvents are selected from the group consisting of: dioxane, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran, benzene, toluene, xylene, mesitylene, chlorobenzene, n-hexane, n-heptane, n-octane, n-nonane, n-decane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, dichloroethane; or mixtures thereof.

[0037] The method of the present invention requires the presence of a carboxamide catalyst of formula C in a sub-stoichiometric amount based on the amount of the alkali metal benzoate of formula II.

[0038] In one embodiment, the catalyst of formula C is used in a sub-stoichiometric amount based on the amount of the alkali metal benzoate of formula II

[0039]

[0040] wherein

[0041] R C1 is hydrogen or methyl;

[0042] R C2 is a C1-C4-alkyl;

[0043] R C3 is hydrogen or a C1-C4-alkyl.

[0044] In one aspect of the present invention, the method is carried out in the presence of the following sub-stoichiometric amounts based on the amount of Compound II: N,N-dimethylformamide, N,N-diethylformamide, N,N-di-n-propylformamide, N,N-diisopropylformamide, N,N-di-n-butylformamide, N,N-diisobutylformamide, N,N-di-tert-butylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-di-n-propylacetamide, N,N-diisopropylacetamide, N,N-di-n-butylacetamide, N,N-diisobutylacetamide, N,N-di-tert-butylacetamide, N-methylformamide, N-ethylformamide, N-n-propylformamide, N-isopropylformamide, N-n-butylformamide, N-isobutylformamide, N-tert-butylformamide, N-methylacetamide, N-ethylacetamide, N-n-propylacetamide, N-isopropylacetamide, N-n-butylacetamide, N-isobutylacetamide, N-tert-butylacetamide, N-acetylpyrrolidine, 1-acetyl-2-pyrrolidone, acetylpiperidine, 1-acetyl-2-piperidone, urea, N,N'-dimethylurea, tetramethylurea, 2-imidazolidinone, 1,3-dimethyl-2-imidazolidinone, tetrahydro-2(1H)-pyrimidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; preferably N,N-dimethylformamide and N,N-dimethylacetamide.

[0045] In one aspect, catalyst C is used in an amount up to 0.5 equivalent, up to 0.2 equivalent, or up to 0.1 equivalent based on the amount of Compound II.

[0046] In another aspect, catalyst C is used in an amount between 0.001 and 0.1 equivalent, or in the range of 0.01 and 0.1 equivalent based on the amount of Compound II.

[0047] In another aspect, N,N-dimethylformamide or N,N-dimethylacetamide, preferably N,N-dimethylformamide, is used in an amount up to 0.5 equivalent, up to 0.2 equivalent, or up to 0.1 equivalent based on the amount of Compound II. In another aspect, N,N-dimethylformamide or N,N-dimethylacetamide, preferably N,N-dimethylformamide, is used in an amount between 0.001 and 0.1 equivalent, or between 0.01 and 0.1 equivalent based on the amount of Compound II.

[0048] The inventors have found that the temperature in the process of the present invention can vary within a wide range. The reaction can be carried out at ambient temperature, or the reaction mixture can be heated to reflux. Theoretical considerations as well as experimental results show that lower temperatures result in lower conversion rates, i.e., longer reaction times. Correspondingly, the reaction proceeds faster at higher temperatures, but the inventors have also detected higher amounts of unwanted by-products formed at high temperatures, especially under reflux conditions. In one aspect, the process of the present invention is carried out at a temperature in the range of 20 °C to the reflux temperature, or at a temperature in the range of 20 °C to 90 °C, or at a temperature in the range of 20 °C to 70 °C; preferably at a temperature in the range of 40 °C to 90 °C, or in the range of 40 °C to 70 °C; most preferably in the range of 50 °C to 80 °C.

[0049] In a particularly preferred embodiment, the process of the present invention is carried out in benzene, toluene, xylene, mesitylene, chlorobenzene, n-hexane, n-heptane, n-octane, n-nonane, n-decane, cyclohexane or a mixture thereof, and the reaction mixture is heated in the range of 50 °C to 80 °C.

[0050] In another particularly preferred embodiment, the process of the present invention is carried out in toluene, and the reaction mixture is heated to a temperature in the range of 50 °C to 80 °C.

[0051] The reaction is carried out at a pressure in the range between 100 kPa (1 bar) and 500 kPa, preferably between 100 kPa and 300 kPa. Most preferably, the reaction is carried out at atmospheric pressure.

[0052] The reaction is generally carried out within 1 to 12 hours; preferably within 1 to 8 hours; more preferably within 1 to 6 hours.

[0053] In one aspect of the present invention, in the compounds of formula I or II, the variable n is 0 or 1 and R is fluorine.

[0054] In a preferred embodiment, in the compounds of formula I or II, the variable n is 0.

[0055] In a preferred embodiment of the present invention (Embodiment E.1), the alkali metal cation in the alkali metal benzoate of formula II is potassium or sodium.

[0056] Embodiment E.2: is based on Embodiment E.1, wherein the chlorinating agent is phosgene.

[0057] Example E.3: is based on Example E.2, wherein the auxiliary solvent is dioxane, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran, benzene, toluene, xylene, mesitylene, chlorobenzene, n-hexane, n-heptane, n-octane, n-nonane, n-decane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or a mixture thereof.

[0058] Example E.4: is based on Example E.3, wherein the reaction is carried out in the presence of N,N-dimethylformamide or N,N-dimethylacetamide in an amount up to 0.5 equivalent based on the amount of the alkali metal benzoate of formula II.

[0059] Example E.5: is based on Example E.4, wherein the reaction mixture is heated to a temperature in the range of 20 °C to the reflux temperature.

[0060] Example E.6: is based on Example E.4, wherein the reaction mixture is heated to a temperature in the range of 40 °C to 90 °C.

[0061] Example E.7: is based on Example E.4, wherein the reaction mixture is heated to a temperature in the range of 50 °C to 80 °C.

[0062] Example E.8: is based on Example E.5, wherein the pressure is in the range between 100 kPa and 500 kPa.

[0063] Example E.9: is based on Example E.6, wherein the pressure is in the range between 100 kPa and 500 kPa.

[0064] Example E.10: is based on Example E.7, wherein the pressure is in the range between 100 kPa and 500 kPa.

[0065] Example E.11: is based on Example E.5, wherein the reaction is carried out at atmospheric pressure.

[0066] Example E.12: is based on Example E.6, wherein the reaction is carried out at atmospheric pressure.

[0067] Example E.13: is based on Example E.7, wherein the reaction is carried out at atmospheric pressure.

[0068] Example E.14: is based on any one of Examples E.1 to E.13, wherein in the compound of formula I or II, n is 0 or 1 and R is fluorine.

[0069] Example E.15: is based on any one of Examples E.1 to E.13, wherein in the compound of formula I or II, n is 0.

[0070] Compounds of formula II can be obtained in a two-step process which involves the mono-saponification of a terephthalic acid diester of formula IIa

[0071]

[0072] (wherein R* is a C1-C8-alkyl, wherein the alkyl is unsubstituted or substituted by 1 or 2 hydroxyl groups) with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide (as described in Industrial Engineering Chemistry 1957, 49, 10, 1692) to produce a compound of formula IIb,

[0073]

[0074] wherein M + is the corresponding alkali metal cation. In a second step, the compound IIb is reacted with ammonia (such as as described in DE2313580) to produce a compound of formula II, and the variables n and R in compounds IIa and IIb are as defined herein for compounds of formula I and II. The diesters of formula IIa are commercially available or they can be prepared from commercially available starting materials using synthetic procedures well known to those skilled in the art.

[0075] In another embodiment, the present invention relates to a process which comprises the step of reacting a compound of formula I (wherein the variable n is 0) with an amine of formula III,

[0076] R 1 -NH-R 2 III

[0077] wherein

[0078] R 1 is a 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-alkenyloxyimino-C1-C4-alkyl, C2-C6-alkynyloxyimino-C1-C4-alkyl, C1-C6-alkylamino, di-C1-C6-alkylamino, -C(=O)-C1-C6-alkyl, -C(=O)-O-C1-C6-alkyl, phenyl-C1-C4-alkyl, phenyl-C1-C4-alkenyl, phenyl-C1-C4-alkynyl, heteroaryl-C1-C4-alkyl, phenyl, naphthyl, or a 3- to 10-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocycle, wherein the ring member atoms of the monocyclic or bicyclic heterocycle contain, in addition to carbon atoms, 1, 2, 3 or 4 further heteroatoms selected from N, O and S as ring member atoms, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and wherein the heteroaryl in the group heteroaryl-C1-C4-alkyl is a 5- or 6-membered aromatic heterocycle, wherein the ring member atoms of the heterocycle contain, in addition to carbon atoms, 1, 2, 3 or 4 heteroatoms selected from N, O, and S as ring member atoms, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and wherein any of the above-mentioned aliphatic or cyclic groups is unsubstituted or substituted by 1, 2, 3, or up to the maximum possible number of identical or different groups R 1a substituted; or

[0079] R 1 and R 2 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated monocyclic or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle does not contain additional heteroatoms other than one nitrogen atom and one or more carbon atoms or further contains 1, 2 or 3 additional heteroatoms independently selected from N, O, and S as ring member atoms, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4, or up to the maximum possible number of identical or different groups R 1a substituted; wherein

[0080] R 1ais 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)-C1-C4-alkyl, C1-C6-alkylsulfonyl, hydroxy-C1-C4-alkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4-alkyl), C1-C4-alkylthio-C1-C4-alkyl, amino-C1-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;

[0081] R 2 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C3-C 11 -cycloalkyl, -C(=O)H, -C(=O)-C1-C6-alkyl, -C(=O)-C3-C 11 -cycloalkyl, or -C(=O)-O-C1-C6-alkyl; and wherein any of the aliphatic or cyclic groups in R 2 is unsubstituted or substituted by 1, 2, 3, or up to the maximum possible number of identical or different groups selected from the group consisting of halogen, hydroxy, oxo, cyano, C1-C6-alkyl, C1-C6-alkoxy, and C3-C 11 -cycloalkyl;

[0082] to obtain a compound of formula IV

[0083]

[0084] Similar transformations are described in WO 2013 / 008162 A1, WO 2015 / 185485 A1, or WO 2017 / 211652 A1 and the references cited therein.

[0085] The amine of formula III is commercially available or can be prepared, for example, according to R.C. Larock, Comprehensive Organic Transformations, Wiley-VCH Verlag, 2nd Edition 1999, pages 1929 ff.

[0086] In another embodiment, the present invention relates to a method that includes the following steps: reacting a compound having formula IV with hydroxylamine or its hydrochloride salt 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 between 0 °C and 100 °C to obtain a compound having formula Va,

[0087]

[0088] reacting it further with an activated derivative of trifluoroacetic acid (such as ethyl trifluoroacetate, trifluoroacetic anhydride or trifluoroacetyl chloride) to obtain a compound having formula V

[0089]

[0090] For relevant examples, see Kitamura, S. et al., Chem. Pharm. Bull. [Chemical and Pharmaceutical Bulletin] 2001, 49, 268 or WO 2013 / 008162 A1 or WO 2015 / 185485 A1.

[0091] In another embodiment, reacting a compound having formula V with a suitable sulfenylating reagent to obtain a compound having formula VI,

[0092]

[0093] as described in WO 2019 / 020451 A1 and WO 2017 / 211649 A1 and the references cited therein.

[0094] In a preferred embodiment, in the compounds having formulae III, IV, V and VI, the variables R 1 and R 2 have the following meanings:

[0095] R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pent-1-yl, or phenyl; and wherein the phenyl is unsubstituted or substituted by 1, 2, 3 or up to the maximum possible number of the same or different groups selected from the group consisting of: fluorine, chlorine, cyano, OH, NH2, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl; and

[0096] R 2 is hydrogen, methyl, or ethyl.

[0097] In another preferred embodiment, in the compounds having formulae III, IV, V and VI, the variable R1 and R 2 has the following meanings:

[0098] R 1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pent-1-yl, 2-fluorophenyl, 4-fluorophenyl, or 2,4-difluorophenyl; especially methyl or 2-fluorophenyl; and

[0099] R 2 is hydrogen.

[0100] In the definitions of the variables given above, collective terms are used that generally represent the substituents under discussion.

[0101] The term "C n -C m " indicates the possible number of carbon atoms in the substituent or substituent moiety under discussion in each case.

[0102] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0103] The term "oxo group" means an oxygen atom =O, which is bonded to a carbon atom or a sulfur atom, thus forming, for example, a keto group -C(=O)- or a sulfinyl group -S(=O)- group.

[0104] The term "C1-C n -alkyl" means a straight-chain or branched-chain saturated hydrocarbon group having 1 to n carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl.

[0105] The term "C2-C6-alkenyl" means a straight-chain or branched-chain 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-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl.

[0106] The term "C2-C6-alkynyl" means a straight-chain or branched-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl.

[0107] The term "C1-C6-haloalkyl" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as defined above), where some or all of the hydrogen atoms in these groups can be replaced by halogen atoms as mentioned above, for example 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.

[0108] The term "C1-C6-alkoxy" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as defined above), which is bonded via oxygen at any position in the alkyl group, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

[0109] The term "C1-C6-haloalkoxy" means a C1-C6-alkoxy as defined above, where some or all of the hydrogen atoms can be replaced by halogen atoms as mentioned above, for example, 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-fluoroethoxy, 2,2,2-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.

[0110] The term "phenyl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl group is correspondingly replaced by a phenyl group or a heteroaryl group.

[0111] The term "C1-C4-alkoxy-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms (as defined above), 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 (as defined above), wherein one hydrogen atom of the alkyl group is replaced by a C1-C4-alkylthio group.

[0112] The term "C1-C6-alkylthio" as used herein refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms bonded via a sulfur atom (as defined above). Correspondingly, the term "C1-C6-haloalkylthio" as used herein refers to a straight-chain or branched-chain haloalkyl group having 1 to 6 carbon atoms bonded at any position of the haloalkyl group via a sulfur atom (as defined above).

[0113] The term "C1-C4-alkoxyimino" refers to a divalent imino group (C1-C4-alkyl-O-N=) bearing a C1-C4-alkoxy group as a substituent, such as methylimino, ethylimino, propylimino, 1-methylethylimino, butylimino, 1-methylpropylimino, 2-methylpropylimino, 1,1-dimethylethylimino, etc.

[0114] The term "C1-C6-alkoxyimino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl group are replaced by a divalent C1-C6-alkoxyimino group (C1-C6-alkyl-O-N=) as defined above.

[0115] The term "C2-C6-alkenyloxyimino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl group are replaced by a divalent C2-C6-alkenyloxyimino group (C2-C6-alkenyl-O-N=).

[0116] The term "C2-C6-alkynyloxyimino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl group are replaced by a divalent C2-C6-alkynyloxyimino group (C2-C6-alkynyl-O-N=).

[0117] The term "hydroxy 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 an OH group.

[0118] The term "amino C1-C4-alkyl" means an alkyl group having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl group is replaced by an NH2 group.

[0119] The term "C1-C6-alkylamino" means an amino group substituted by the residue of a group independently selected from the groups defined by the term C1-C6-alkyl. Similarly, the term "di-C1-C6-alkylamino" means an amino group substituted by the residues of two groups independently selected from the groups defined by the term C1-C6-alkyl.

[0120] The term "C1-C4-alkylamino-C1-C4-alkyl" means an alkyl group having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl group is replaced by a C1-C4-alkyl-NH- group bonded through nitrogen. Similarly, the term "di-C1-C4-alkylamino-C1-C4-alkyl" means an alkyl group having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl group is replaced by a (C1-C4-alkyl)2N- group bonded through nitrogen.

[0121] The term "aminocarbonyl C1-C4-alkyl" means an alkyl group having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl group is replaced by a -(C=O)-NH2 group.

[0122] The term "C3-C 11 -cycloalkyl" means a monocyclic, bicyclic or tricyclic saturated monovalent hydrocarbon group having 3 to 11 carbon ring members, which is attached by replacement of one of the ring carbon atoms by 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).

[0123] The terms "-C(=O)-C1-C6-alkyl", "-C(=O)-O-C1-C6-alkyl" and "-C(=O)-C3-C 11 -cycloalkyl" mean aliphatic groups attached through the carbon atom of the -C(=O)- group.

[0124] The term "aliphatic" means a compound or group composed of carbon and hydrogen and which are non-aromatic compounds. An "alicyclic" compound or group is an organic compound that is both aliphatic and cyclic. They contain one or more all-carbon rings which may be saturated or unsaturated but do not have aromatic character.

[0125] The term "ring moiety" or "ring group" refers to a group that is an alicyclic ring or an aromatic ring, such as a phenyl group or a heteroaryl group.

[0126] The term "and wherein either the aliphatic or the ring group is unsubstituted or substituted by..." refers to aliphatic groups, ring groups, and groups containing aliphatic and ring moieties in one group (such as C3-C8-cycloalkyl-C1-C4-alkyl); thus, for a group containing aliphatic and ring moieties, these two moieties can be independently substituted or unsubstituted.

[0127] The term "phenyl" refers to an aromatic ring system containing six carbon atoms (commonly referred to as a benzene ring).

[0128] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic system that contains, in addition to carbon atoms, 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S as ring member atoms.

[0129] The term "saturated 3- to 7-membered carbocycle" should be understood to mean a monocyclic saturated carbocycle having 3, 4, or 5 carbon ring members. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0130] The term "3- to 10-membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic heterocycle, wherein the ring member atoms of the monocyclic or bicyclic heterocycle contain, in addition to carbon atoms, an additional 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms" should be understood to mean aromatic monocyclic and bicyclic heteroaromatic ring systems, as well as both saturated and partially unsaturated heterocycles, such as:

[0131] 3- or 4-membered saturated heterocycles containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S as ring members, such as ethylene oxide, aziridine, thiirane, oxetane, azetidine, thietane, [1,2]dioxetane, [1,2]dithietane, [1,2]diazetane;

[0132] and 5- or 6-membered saturated or partially unsaturated heterocycles containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S as ring members, such as 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-triazol-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-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydro-1,3,5-triazin-2-yl and 1,2,4-hexahydro-1,2,4-triazin-3-yl, and also the corresponding -ylidene; and,

[0133] 7-membered saturated or partially unsaturated heterocycles such as tetrahydroazepinyl and hexahydroazepinyl, such as 2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, hexahydroazepin-1-, -2-, -3- or -4-yl, tetrahydrooxepinyl and hexahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, hexahydroazepin-1-, -2-, -3- or -4-yl, tetrahydro- and hexahydro-1,3-diazepinyl, tetrahydro- and hexahydro-1,4-diazepinyl, tetrahydro- and hexahydro-1,3-oxazepinyl, tetrahydro- and hexahydro-1,4-oxazepinyl, tetrahydro- and hexahydro-1,3-dioxepinyl, tetrahydro- and hexahydro-1,4-dioxepinyl and the corresponding -ylidene.

[0134] The term "5- or 6-membered heteroaryl" or the term "5- or 6-membered aromatic heterocycle" refers to an aromatic ring system that contains, in addition to carbon atoms, 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S. For example, 5-membered heteroaryls such as pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, and 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl; or

[0135] 6-membered heteroaryls 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.

[0136] Working Examples

[0137] The present invention is further illustrated by the following working examples.

[0138] Analysis Method

[0139] Quantitative UHPLC method for Examples 1 - 2

[0140] Column: Xselect HSS PFP, 100 * 2.1 mm, 1.8 μm, Flow rate: 0.5 mL / min, Time: 7 min, Temperature: 45 °C; Wavelength 240 nm; Syringe volume: 1 μL; The retention time of the corresponding product is based on reference materials. Eluent: A: Water with 0.1 vol% HCOOH; B: Methanol with 0.1 vol% HCOOH.

[0141] Time (min) ％B Rate (mL / min) 0.0 15 0.5 3.0 95 0.5 5.0 95 0.5 5.1 15 0.5

[0142] Qualitative HPLC method for Examples 3 - 7

[0143] Column: Agilent Zorbax Extend C18, 4.6 * 50 mm, 1.8 μm, flow rate: 1.2 mL / min, time: 11 min, pressure: 400 bar; temperature: 25 °C; wavelength 240 nm; syringe volume: 1 μL; retention time of the corresponding product is based on reference materials. Eluent: A: water with 0.1 vol% H3PO4; B: acetonitrile with 0.1 vol% H3PO4.

[0144] Time (min) ％B Rate (mL / min) 8.0 95 1.2 10.0 90 1.2 10.1 100 1.2 10.9 100 1.2 11.0 5 1.2

[0145] Sample preparation: Before analysis, all acyl chloride samples were converted to the corresponding methyl esters: the samples were quenched with an excess of methanol for 30 minutes.

[0146] Quantitative GC method using the internal standard n-decane, for Example 4

[0147]

[0148]

[0149] Example 1: Preparation of potassium methyl terephthalate

[0150]

[0151] 180 g (0.927 mol) of dimethyl terephthalate was charged into a mixture of 489.4 g of methanol and 593.3 g of toluene. The mixture was heated to 50 °C with stirring. Then, 67.3 g of KOH (85%, 1.02 mol) was added in 5 portions over 45 minutes. After stirring the reaction mixture at 50 °C for 4 hours, the reaction vessel was cooled to 20 °C, and the precipitated product was filtered out. The solid on the suction filter was washed with 250 g of methanol and dried overnight in a drying oven at 95 °C / 30 mbar. 199 g of the title product was obtained, with a purity of 97.7% according to quantitative HPLC analysis, which is equivalent to a yield of 96.1%.

[0152] Example 2: Preparation of potassium 4-carbamoylbenzoate

[0153]

[0154] Charge a pressure reactor with 12 g (0.054 mol) of potassium monomethyl terephthalate and 109 g of the mother liquor from the last batch of the same reaction (where formamide solvent has been used instead of the first batch) and 12 g of fresh formamide. Purge the reactor three times with nitrogen at 5 bar, pressurize with 27.8 g (1.632 mol) of gaseous ammonia, and heat to 110 °C over 7 hours. During the reaction, the pressure inside the reactor increases to 18 bar. After the reaction is complete, cool the reaction mixture to 30 °C and reduce the pressure. Purge the reactor three times with nitrogen at 5 bar and transfer the mixture to another reactor for work-up. After cooling the suspension to 5 °C with stirring over 3 hours, then filtering and washing the solid product with 10 g of methanol, wet potassium 4-carbamoylbenzoate is obtained, which is dried overnight in an oven at 65 °C / 50 mbar to yield 10.5 g of the title product, with a purity of 97.8% according to quantitative HPLC, which is equivalent to a yield of 94.1%.

[0155] The first batch using pure solvent formamide instead of the recycled mother liquor gave a significantly lower yield because this batch was used to saturate the solvent with the product. Thereafter, more than 15 recycles of the mother liquor were carried out with similar yields and purities. Methanol did not accumulate further in the mother liquor under the work-up conditions used due to its low boiling point.

[0156] Example 3: Preparation of 4-cyanobenzoyl chloride with phosgene

[0157]

[0158] Charge 0.6 g (0.0029 mol) of potassium 4-carbamoylbenzoate, 4.8 g (0.0073 mol) of phosgene in toluene (15%) and 0.022 g (0.0003 mol) of N,N-dimethylformamide into 12.3 g of toluene in a round-bottom flask. Heat the mixture with stirring to 90 °C and maintain at 90 °C for 3 hours. HPLC reaction control shows complete conversion of the starting materials and 95.9 area% of the desired product.

[0159] Example 4: Preparation of 4-cyanobenzoyl chloride with triphosgene

[0160]

[0161] 7.1 g (97%, 0.0339 mol) of potassium 4-carbamoylbenzoate, 10.2 g (0.0339 mol) of triphosgene and 0.025 g (0.0003 mol) of N,N-dimethylformamide were added to 94.6 g of toluene in a round-bottom flask. The mixture was heated to 70 °C with stirring and maintained at 70 °C for 7 h. HPLC reaction control showed complete conversion of the starting material and 94.2 area % of the desired product. The mixture was cooled to room temperature and the precipitated potassium chloride was filtered off and washed. Toluene was partially evaporated from the combined filtrates under vacuum (85 °C / 15 mbar) and a sample was taken for GC quantification of the product, which indicated a crude yield of 92.6% in solution. After evaporation of the remaining toluene, 16.7 g of cyclohexane were added. The mixture was heated to reflux and cooled to 23 °C over 3 h. The product was filtered off, washed twice with 5 g of cyclohexane each and finally dried under vacuum (60 °C / 15 mbar) to give 4.4 g of the title product (96.1% purity according to quantitative HPLC, corresponding to an isolated yield of 80.9%).

[0162] Example 5: Preparation of 4-cyanobenzoyl chloride with triphosgene and subsequent conversion with 2-fluoroaniline

[0163]

[0164] 0.2 g (0.001 mol) of potassium 4-carbamoylbenzoate, 0.3 g (0.001 mol) of triphosgene and 0.007 g (0.0001 mol) of N,N-dimethylformamide were added to 4.1 g of toluene in a round-bottom flask. The mixture was heated to 90 °C with stirring and maintained at 90 °C for 4.5 h. HPLC reaction control showed complete conversion of the starting material and 96.8 area % of the desired product. 0.12 g (0.00108 mol) of 2-fluoroaniline was added and the mixture was heated to reflux over 5 h. HPLC showed complete conversion of 4-cyanobenzoyl chloride to the desired 4-cyano-N-(2-fluorophenyl)-benzamide

[0165] Example 6: (not an example according to the invention) Preparation of 4-cyanobenzoyl chloride with phosphorus oxychloride

[0166]

[0167] 4 g (0.0195 mol) of potassium 4-carbamoylbenzoate and 21.1 g (0.1364 mol) of phosphoryl trichloride were charged into a round-bottomed flask. The mixture was heated to 80 °C with stirring and maintained at 80 °C for 2 h. HPLC reaction control showed complete conversion of the starting materials, but no formation of the desired product. Instead, the formation of terephthaloyldichloride was observed (93.0 area% of dimethyl terephthalate was analyzed after quenching with methanol).

[0168] Example 7: (not an example according to the invention) Preparation of 4-cyanobenzoyl chloride with thionyl chloride

[0169]

[0170] 1.5 g (0.0073 mol) of potassium 4-carbamoylbenzoate, 2.2 g (0.0183 mol) of thionyl chloride and 0.005 g (0.0001 mol) of N,N-dimethylformamide were added to 27 g of toluene in a round-bottomed flask. The mixture was heated to 90 °C with stirring and maintained at 90 °C for 5 h. HPLC reaction control showed complete conversion of the starting materials, but only 65.2 area% of the desired product. 13.3 area% of terephthaloyl chloride (structure see Example 7) was formed together with other by-products (structures not elucidated).

Claims

1. A process for preparing 4-cyanobenzoyl chloride of formula I, wherein R is halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy; n is 0, 1, or 2; the process comprising reacting an alkali metal 4-carbamoylbenzoate of formula II with a chlorinating agent, Wherein in the alkali metal benzoate of formula II, the variables n and R are as defined above for the compounds of formula I, and wherein M + is an alkali metal cation, the chlorinating agent being selected from the group consisting of phosgene, trichloromethyl chloroformate and bis(trichloromethyl) carbonate; the process further comprising the presence of a co-solvent and a sub-stoichiometric amount of a carboxamide catalyst of formula C based on the amount of the alkali metal benzoate of formula II, wherein R C1 is hydrogen, methyl, or NR C4 R C5 ; wherein R C4 and R C5 are each independently selected from the group consisting of hydrogen and C1-C4-alkyl; R C2 is a C1-C4-alkyl; or R C1 and R C2 together with the group -NR C3 -C(=O)- form a saturated or partially unsaturated 5- or 6-membered heterocycle, wherein the heterocycle optionally further contains 1 or 2 heteroatoms independently selected from N, O and S as ring member atoms in addition to one nitrogen atom, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and wherein one or two CH2 groups of the heterocycle may be replaced by one or two groups independently selected from C(=O) and C(=S); R C3 is hydrogen or a C1-C4-alkyl group; or R C2 and R C3 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated 5- or 6-membered heterocycle, which heterocycle optionally further contains 1 or 2 heteroatoms independently selected from N, O and S as ring member atoms in addition to one nitrogen atom, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and wherein one or two CH2 groups of the heterocycle may be replaced by one or two groups independently selected from C(=O) and C(=S).

2. The method according to claim 1, wherein the alkali metal cation in the alkali metal benzoate of formula II is potassium or sodium.

3. The method according to claim 1 or 2, wherein The chlorinating agent is phosgene.

4. The method according to any one of claims 1 to 3, wherein, The amount of the chlorinating agent is between 2 and 5 equivalents based on the amount of the alkali metal benzoate of formula II.

5. The method according to any one of claims 1 to 4, wherein These co-solvents are selected from the group consisting of: nitriles, ethers, sulfoxides, sulfones, aliphatic hydrocarbons, cycloaliphatic hydrocarbons and aromatic hydrocarbons having 1 to 10 carbon atoms - and these hydrocarbons are halogenated or non-halogenated; or mixtures thereof.

6. The method according to any one of claims 1 to 4, wherein, The co-solvent is selected from the group consisting of: dioxane, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran, benzene, toluene, xylene, mesitylene, chlorobenzene, n-hexane, n-heptane, n-octane, n-nonane, n-decane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, dichloroethane; or mixtures thereof.

7. The method according to any one of claims 1 to 6, wherein, The reaction is carried out in the presence of a sub-stoichiometric amount of N,N-dimethylformamide or N,N-dimethylacetamide based on the amount of the alkali metal benzoate of formula II.

8. The method according to any one of claims 1 to 7, wherein The temperature is in the range of 20 °C to the reflux temperature.

9. The method according to any one of claims 1 to 8, wherein The temperature is in the range of 50 °C to 80 °C.

10. The method according to any one of claims 1 to 9, wherein, The variable n is 0 or 1, and in the compounds of formula I and II, R is fluorine.

11. The method according to any one of claims 1 to 9, wherein, In the compounds of formula I and II, the variable n is 0.

12. The method according to any one of claims 1 to 11, further comprising reacting a compound of formula IIb, wherein R* is C1-C8-alkyl, wherein the alkyl is unsubstituted or substituted by 1 or 2 hydroxyl groups, and M + is an alkali metal cation, To produce 4-carbamoylbenzoate of formula II.

13. The process according to claim 12, further comprising reacting a compound of formula IIa, with an alkali metal hydroxide to produce a compound of formula IIb.

14. The method according to any one of claims 11 to 13, further comprising the following steps: Reacting the compound of formula I with an amine of formula III, R 1 -NH-R 2 III wherein R 1 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-alkenyloxyimino-C1-C4-alkyl, C2-C6-alkynyloxyimino-C1-C4-alkyl, C1-C6-alkylamino, di-C1-C6-alkylamino, -C(=O)-C1-C6-alkyl, -C(=O)-O-C1-C6-alkyl, phenyl-C1-C4-alkyl, phenyl-C1-C4-alkenyl, phenyl-C1-C4-alkynyl, heteroaryl-C1-C4-alkyl, phenyl, naphthyl, or a 3- to 10-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocycle, where the ring member atoms of the monocyclic or bicyclic heterocycle contain, in addition to carbon atoms, 1, 2, 3 or 4 further heteroatoms selected from N, O and S as ring member atoms, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and where the heteroaryl in the group heteroaryl-C1-C4-alkyl is a 5- or 6-membered aromatic heterocycle, where the ring member atoms of the heterocycle contain, in addition to carbon atoms, 1, 2, 3 or 4 heteroatoms selected from N, O, and S as ring member atoms, provided that the heterocycle does not contain 2 adjacent atoms selected from O and S; and where any of the above-mentioned aliphatic or cyclic groups is unsubstituted or substituted by 1, 2, 3, or up to the maximum possible number of identical or different groups R 1a substituted; or R 1 and R 2 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated monocyclic or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle contains no additional heteroatoms other than one nitrogen atom and one or more carbon atoms or further contains 1, 2 or 3 additional heteroatoms independently selected from N, O, and S as ring member atoms, provided that the heterocycle cannot contain 2 adjacent atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4, or up to the maximum possible number of identical or different groups R 1a substituted; wherein R 1a is 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)-C1-C4-alkyl, C1-C6-alkylsulfonyl, hydroxy-C1-C4-alkyl, -C(=O)-NH2, -C(=O)-NH(C1-C4-alkyl), C1-C4-alkylthio-C1-C4-alkyl, amino-C1-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; R 2 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C3-C 11 -cycloalkyl, -C(=O)H, -C(=O)-C1-C6-alkyl, -C(=O)-C3-C 11 -cycloalkyl, or -C(=O)-O-C1-C6-alkyl; and wherein any of the aliphatic or cyclic groups in R 2 is unsubstituted or substituted by 1, 2, 3, or up to the maximum possible number of identical or different groups selected from the group consisting of: halogen, hydroxy, oxo, cyano, C1-C6-alkyl, C1-C6-alkoxy, and C3-C 11 -cycloalkyl; to obtain a compound of formula IV 15. The process according to claim 14, further comprising reacting the compound of formula IV to obtain a compound of formula V 16. The method according to claim 15, further comprising the following steps: Reacting the compound of formula V to obtain a compound of formula VI 17. The method according to any one of claims 14 to 16, wherein, In the compounds of formula III, IV, V and VI R 1 is methyl or 2-fluoro-phenyl; and R 2 is hydrogen.

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