Preparation of Substituted 4-(N′-Hydroxycarbamimidoyl)benzoic Acid

Abstract

The present invention relates to a method for preparing substituted 4-(N'-hydroxycarbamimidoyl)benzoic acid, which can be obtained by hydration of substituted terephthalonitrile of formula II in an aqueous medium catalyzed by nitrilase to provide 4-cyanobenzoic acid (ammonium) IIa. After hydration, the aqueous reaction medium is treated with hydroxylamine or a salt thereof to provide amide oxime I.

Description

[0001] The present invention relates to a process for preparing substituted 4-(N′-hydroxycarbamimidoyl)benzoic acids, which can be obtained by hydration of substituted terephthalonitriles of formula II in aqueous medium catalyzed by nitrilase to provide 4-cyanobenzoic acid (ammonium) IIa. After hydration, the aqueous reaction medium is treated with hydroxylamine or a salt thereof to provide amide oxime I.

[0002]

[0003] 4-(N′-Hydroxycarbamimidoyl)benzoic acid is also referred to herein as the amidoxime of formula I. Amideoxime I is a versatile synthetic intermediate. For example, the compound of formula I can be used as a preparation of the known benzamide-type trifluoromethyl-1,2,4- Oxadiazoles, for example, precursors of compounds disclosed in WO 2015 / 185485 and WO 2017 / 211649 that are useful for controlling phytopathogenic fungi.

[0004] It is known that amide oxime I can be obtained from 4-cyanobenzoic acid IIa by treatment with hydroxylamine or its salt in the presence of an auxiliary base and in a suitable solvent, such as methanol, ethanol or water or a mixture of these solvents. For relevant examples, see Kitamura, S. et al., Chem. Pharm. Bull. 2001, 49, 268.

[0005] The synthesis of 4-(N′-hydroxycarbamimidoyl)benzoic acid is described in WO 2017 / 211649 and WO 2013 / 008162, in which the authors react 4-cyanobenzoic acid and hydroxylamine hydrochloride in a mixture of water and ethanol in the presence of potassium carbonate and a substoichiometric amount of 8-hydroxyquinoline under reflux conditions.

[0006] The chemical reaction starting from technical 4-cyanobenzoic acid IIa requires the presence of a base to provide an appreciable yield of the amide oxime I. The base can be an auxiliary base or an excess of hydroxylamine. However, due to its high price, the use of hydroxylamine is not efficient from an economic point of view.

[0007] The inventors of the present invention have surprisingly found that the formation of the amidoxime of the formula I is carried out in high overall yield and purity by adding hydroxylamine to an aqueous medium obtained directly from the biocatalyzed monohydration of terephthalonitrile of the formula II, wherein the hydration is catalyzed by a nitrilase. This efficient two-step process constitutes a particularly advantageous method for obtaining the amidoxime I on an industrial scale, since it does not require the addition of a solvent or an auxiliary base together with the hydroxylamine in the addition step. In addition, it is not necessary to isolate the intermediate 4-cyanobenzoic acid (ammonium) IIa in a tedious manner.

[0008] Accordingly, the present invention relates to a method for preparing an amide oxime compound of formula I,

[0009]

[0010] in

[0011] R is halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy;

[0012] n is 0, 1, or 2;

[0013] The method comprises the following steps:

[0014] i. providing an aqueous medium comprising water, one or more nitrilase enzymes and a terephthalonitrile of formula II, wherein the variables n and R have the meanings defined for the compound of formula I,

[0015]

[0016] ii. culturing the aqueous medium to obtain 4-cyanobenzoic acid of formula IIa or a salt thereof in an aqueous medium, wherein the variables n and R in 4-cyanobenzoic acid IIa have the meanings defined for the compound of formula I,

[0017]

[0018] iii. removing biological material from said aqueous medium;

[0019] iv. treating the aqueous medium obtained in step iii with hydroxylamine or a salt thereof.

[0020] Nitrilases are a class of enzymes that catalyze the hydration of nitriles to produce carboxylic acids. Various nitrilase-producing organisms have been described, including bacteria, filamentous fungi, yeast, and plants, and some of these microbial cell factories are used for commercial production of carboxylic acids on an industrial scale. Enzymatic hydration of nitriles to produce carboxylic acids can be achieved by nitrilases or by a biocatalytic cascade involving a nitrile hydratase followed by an amidase.

[0021] The selective enzymatic hydration of terephthalonitrile to produce ammonium 4-cyanobenzoate is described in the prior art. PCT / EP2020 / 051288 provides an overview of the prior art and particularly efficient conditions for the selective monohydration of terephthalonitrile by nitrilase. The contents of PCT / EP2020 / 051288 should be deemed to be incorporated herein by reference to supplement the disclosure of the present invention.

[0022] In one embodiment of the invention, process steps i and ii correspond to the process for producing 4-cyanobenzoic acid or a salt thereof as defined or preferably defined in PCT / EP2020 / 051288, and the nitrilase in steps i and ii comprises a sequence as defined or preferably defined in PCT / EP2020 / 051288, preferably those mentioned in claim 7 or 8, in particular those specified in Table 1 on page 4.

[0023] The nitrilase used in the method of the present invention may be isolated from an organism that naturally expresses the nitrilase. Alternatively, the nitrilase may be added to the aqueous medium by adding cells comprising the nitrilase or by adding a suspension comprising inactivated, e.g., disrupted, cells. In another embodiment of the present invention, the nitrilase may be produced in a recombinant organism, preferably a microorganism, expressing the nitrilase of the present invention from a heterologous structure. The nitrilase thus produced may be isolated from the recombinant organism and added to the aqueous medium, or the nitrilase may be added by inactivating the cells, e.g., disrupting, and adding the suspension.

[0024] The cells or the suspension comprising the inactivated cells may be at least partially concentrated, for example by drying, before being added to the aqueous medium used in the method of the invention or to the composition of the invention.

[0025] The nitrilase may be (partially) immobilized, e.g. embedded in a gel, or it may be used, e.g. as a free cell suspension. For immobilization, well-known standard methods may be used, e.g. embedding crosslinking, e.g. glutaraldehyde-polyethyleneimine (GA-PEI) crosslinking, crosslinking to a matrix and / or carrier binding, etc., including variants and / or combinations of the above methods. The methods mentioned. Alternatively, the nitrilase may be extracted and used directly, e.g., for the preparation of an ammonium salt or an acid. When inactivated or partially inactivated cells are used, these cells may be inactivated by heat treatment or chemical treatment.

[0026] The aqueous medium in process steps i to iv may be a solution or a suspension or a solution and a suspension, wherein any substance contained in the aqueous medium may be completely or partially dissolved and / or partially or completely suspended.

[0027] In one embodiment, the aqueous medium in process steps i and ii has a pH value of 4 to 9. In a preferred embodiment, the aqueous medium in process steps i and ii has a pH value of 6 to 9. In another preferred embodiment, the aqueous medium in process steps i and ii has a pH value of 6.5 to 8. In yet another preferred embodiment, the aqueous medium in process steps i and ii has a pH value of 6.8 to 7.5. In a preferred embodiment, the aqueous medium in process steps i and ii has a pH value of 6.8 to 7.2.

[0028] If the process is carried out at a pH above 7, a base, for example an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, or an aqueous solution of an alkaline earth metal hydroxide may be added to the aqueous medium to maintain a pH above 7. Alternatively, a suitable buffer system may be used to maintain a specific pH range, for example a phosphate buffer, in particular a potassium phosphate buffer.

[0029] The aqueous medium in method step i may further contain divalent cations, such as Mg 2+ , Mn 2+ , Ca 2+ , Fe 2+ 、Zn 2+ or Co 2+ The divalent cation is preferably Mg 2+ or Mn 2+ , the divalent cation is most preferably Mg 2+ The divalent cation may have a concentration of 1 mM to 500 mM, for example 10 mM to 450 mM. The concentration of the divalent cation is preferably between 20 mM and 400 mM, preferably between 30 mM and 300 mM, more preferably between 40 mM and 250 mM, more preferably between 40 mM and 200 mM, most preferably between 40 mM and 150 mM.

[0030] In a preferred embodiment, the culturing step ii is carried out at a temperature of 10°C to 50°C, preferably 15°C to 40°C, more preferably 20°C to 40°C, still more preferably 24°C to 37°C, still more preferably 28°C to 36°C, still more preferably 29°C to 34°C, most preferably 30°C to 33°C.

[0031] In a preferred embodiment, the culturing step ii is performed for 30 minutes to 48 hours, preferably 1 hour to 36 hours, more preferably 2 hours to 24 hours, most preferably 3 hours to 15 hours.

[0032] At the beginning of the cultivation step ii, the aqueous medium contains at least 0.05% terephthalonitrile, preferably at least 0.1% terephthalonitrile, more preferably at least 0.5% terephthalonitrile, and most preferably at least 1.0% terephthalonitrile (w / w). Throughout the cultivation, the concentration of terephthalonitrile can be maintained at a concentration of about 0.5% to 1.5%, preferably about 1.0% terephthalonitrile by continuously feeding terephthalonitrile.

[0033] Alternatively, the concentration of terephthalonitrile in the aqueous medium at the start of the culture may be between 1 wt % and 30 wt %, preferably between 5 wt % and 10 wt % (inclusive), still more preferably between 6 wt % and 9 wt % (inclusive), and most preferably between 7 wt % and 8.5 wt % (inclusive).

[0034] After the biocatalytic conversion in step ii is complete, the biological components are removed from the aqueous medium. This is achieved, for example, by standard filtration methods, such as ultrafiltration. The 4-cyanobenzoic acid IIa obtained in step ii may have a tendency to precipitate, which may result in a loss of desired material when removing the biological material in step iii.

[0035] In one embodiment of the present invention, in order to prevent the precipitation of benzoic acid IIa, the pH value of the aqueous medium is increased to 8-10, preferably 8.5-9, for example by adding an aqueous solution of a suitable base such as sodium hydroxide or potassium hydroxide to the resulting aqueous medium after completion of step ii and before filtering step iii.

[0036] Typically, process step iv is carried out with hydroxylamine or a salt thereof with hydrochloric acid or sulfuric acid; in particular with hydroxylamine as the free base. In one aspect, an aqueous solution of hydroxylamine or a salt thereof is added to the aqueous medium obtained in step iii.

[0037] In one embodiment, process step iv is carried out using 1 to 3 molar equivalents of hydroxylamine or its salt, based on the amount of terephthalonitrile II. Based on the amount of terephthalonitrile II, preferably 1 to 2 molar equivalents, more preferably 1 to 1.5 equivalents, in particular 1 to 1.3 molar equivalents are used.

[0038] The reaction temperature of process step iv is in the range of 0°C to 100°C; preferably in the range of 10°C to 80°C; more preferably in the range of 20°C to 50°C.

[0039] Process step iv is generally carried out within 1 to 12 hours, preferably within 2 to 8 hours.

[0040] Process step iv is generally carried out under atmospheric pressure.

[0041] In one embodiment of the invention, no auxiliary base is added to the aqueous medium obtained in step iii, so that the pH of the aqueous medium in step iv of the process corresponds to the pH of the aqueous medium obtained after step iii.

[0042] In another embodiment, process step iv is carried out in the presence of an auxiliary base, which may be an inorganic base or an organic base. Examples of preferred inorganic bases are carbonates, hydroxides and phosphates of alkali metals and alkaline earth metals. Preferred alkali metal carbonates are sodium carbonate and potassium carbonate, in particular sodium carbonate. Preferred alkaline earth metal carbonates are magnesium carbonate and calcium carbonate. Preferred alkali metal hydroxides are sodium hydroxide and potassium hydroxide, in particular sodium hydroxide. Preferred alkaline earth metal carbonates are magnesium hydroxide and calcium hydroxide. Preferred alkali metal phosphates are trisodium phosphate (Na3PO4) and disodium hydrogen phosphate (Na2HPO4).

[0043] In another aspect, the base is an organic base, such as a tri-(C1-C6)-alkylamine or an N-heteroaromatic hydrocarbon. Examples of tri-(C1-C6)-alkylamines are, for example, trimethylamine, triethylamine, tripropylamine, tributylamine, trihexylamine, trioctylamine, tridecylamine, N,N-dimethylethylamine, dimethylpropylamine; aromatic amines, such as dimethylaniline or tribenzylamine; cyclic amines, such as N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N,N′-dimethylpiperazine.

[0044] N-heteroaromatic bases are also suitable, such as pyridine, imidazole, N-methylimidazole or quinoline. Examples of suitable substituted pyridines are collidine, lutidine, 2-picoline, 3-picoline, 4-picoline, N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine.

[0045] Further suitable bases are 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0046] In one embodiment, the process of the present invention is carried out in the presence of a base selected from alkali metal C1-C6-alkoxides, alkali metal and alkaline earth metal carbonates, alkali metal and alkaline earth metal hydroxides, tri-(C1-C6)-alkylamines, pyridine, N-methylimidazole or quinoline, pyridine, collidine, dimethylpyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine, DBU and TBD.

[0047] In one aspect, the base is selected from alkali metal C1-C6-alkoxides; in particular sodium methoxide or sodium ethoxide.

[0048] The auxiliary base is used in an amount of at least 80 mol %, or at least 100 mol %, or at least 150 mol % based on the amount of terephthalonitrile II. In another aspect of the invention, the base is used in an amount between 80 and 1000 mol % based on the amount of terephthalonitrile II. In another aspect of the invention, the base is used in an amount between 80 and 500 mol % based on the amount of terephthalonitrile II. In yet another aspect, the base is used in an amount between 90 and 200 mol % based on the amount of terephthalonitrile II.

[0049] After the reaction in step iv is complete, the following work-up procedure enables the isolation of the amide oxime I: the reaction medium is cooled to ambient temperature and the pH is adjusted to below pH 5. Water is optionally added to the reaction medium to ensure stirring of the suspension. After the suspension has cooled, the solid amide oxime I is collected by filtration.

[0050] In a preferred embodiment, the variable n is zero.

[0051] In a preferred aspect of the invention, the variable n is 1 and R is methyl, trifluoromethyl, fluoro or chloro.

[0052] In one aspect, n is 1 and R is fluoro.

[0053] In one embodiment of the process of the present invention, the compound of formula I is further reacted with an activated derivative of trifluoroacetic acid, such as trifluoroacetic anhydride or trifluoroacetyl chloride, to obtain a compound of formula III

[0054]

[0055] These transformations are described in Kitamura, S. et al., Chem. Pharm. Bull. 2001, 49, 268, WO 2013 / 008162, WO 2015 / 185485, WO 2017 / 211652 or WO 2019 / 020451 and the references cited therein.

[0056] In one embodiment, the method of the present invention further comprises the step of reacting a compound of formula III as described in WO 2017 / 211652 or WO 2019 / 020451 and the references cited therein to obtain a compound of formula IV

[0057]

[0058] In one embodiment, the method of the present invention further comprises the step of reacting a compound of formula III or IV with an amine of formula V,

[0059] R 1 -NH-R 2 V

[0060] in

[0061] R 1 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-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 ring heterocycle, wherein the ring member atoms of the monocyclic or bicyclic heterocycle further include, 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 cannot 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 further include, 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 cannot contain 2 adjacent atoms selected from O and S; and wherein any of the above aliphatic or cyclic radicals is unsubstituted or replaced by 1, 2, 3 or up to the maximum possible number of identical or different radicals R 1a replace; or

[0062] 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 heterocyclic ring, wherein said heterocyclic ring apart from one nitrogen atom and one or more carbon atoms does not comprise further heteroatoms or comprises 1, 2 or 3 further heteroatoms independently selected from N, O and S as ring member atoms, provided that said heterocyclic ring cannot contain 2 adjacent atoms selected from O and S; and wherein said heterocyclic ring is unsubstituted or replaced by 1, 2, 3, 4 or up to the maximum possible number of identical or different radicals R 1a Replace;

[0063] 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)-O-C1-C4-alkyl, C1-C6- 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, diC1-C4-alkylamino-C1-C4-alkyl, aminocarbonyl-C1-C4-alkyl or C1-C4-alkoxy-C1-C4-alkyl;

[0064] 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 R 2 Any aliphatic or cyclic radical in is unsubstituted or replaced by 1, 2, 3 or up to the maximum possible number of radicals selected from halogen, hydroxy, oxo, cyano, C1-C6-alkyl, C1-C6-alkoxy and C3-C 11 - substitution of cycloalkyl groups by the same or different groups;

[0065] To obtain the compound of formula VI

[0066]

[0067] These transformations are also described in WO 2013 / 008162, WO 2015 / 185485, WO 2017 / 211652 or WO 2019 / 020451 and the references cited therein.

[0068] In another embodiment, the compound of formula VI is used to obtain the compound of formula VII as described in WO 2019 / 020451 and WO 2017 / 211649 and the references cited therein

[0069]

[0070] In a preferred embodiment, the variable R in the compounds of formula V, VI and VII is 1 and R 2 Has the following meanings:

[0071] 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 phenyl is unsubstituted or substituted by 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from fluorine, chlorine, cyano, OH, NH2, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl;

[0072] R 2 is hydrogen, methyl or ethyl.

[0073] In another preferred embodiment, the variable R in the compounds of formula V, VI and VII 1 and R 2 Has the following meanings:

[0074] R 1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pent-1-yl, 2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl; in particular methyl or 2-fluorophenyl;

[0075] R 2 It's hydrogen.

[0076] In a preferred embodiment of the present invention (embodiment E.1), the aqueous medium in process steps i and ii has a pH value of 4 to 9.

[0077] Embodiment E.2: Based on embodiment E.1, wherein terephthalonitrile II is added to the aqueous medium before culturing at a concentration of 1% to 30% by weight.

[0078] Embodiment E.3: Based on embodiment E.2, wherein the aqueous medium is cultured at a temperature of 10°C to 50°C in step ii.

[0079] Embodiment E.4: Based on embodiment E.3, wherein 1 to 3 molar equivalents of hydroxylamine or a salt thereof, based on the amount of terephthalonitrile II, are used in step iv.

[0080] Embodiment E.5: Based on embodiment E.4, wherein the temperature in step iv is in the range of 0°C to 100°C.

[0081] Embodiment E.6: Based on embodiment E.5, wherein no auxiliary base is added to the aqueous medium obtained in step iii, so that the pH value of the aqueous medium in step iv of the process corresponds to the pH of the aqueous medium obtained after step iii.

[0082] Embodiment E.7: Based on Embodiment E.6, wherein in the compounds of Formula V, VI and VII, 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 phenyl is unsubstituted or substituted by 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from fluorine, chlorine, cyano, OH, NH2, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl;

[0083] R 2 is hydrogen, methyl or ethyl.

[0084] Embodiment E.8: Based on Embodiment E.6, wherein in the compounds of Formula V, VI and VII, R 1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pent-1-yl, 2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl; in particular methyl or 2-fluorophenyl;

[0085] R 2 It's hydrogen.

[0086] In the definitions of the variables given above, collective terms are used which generally represent the substituents involved.

[0087] The term "auxiliary base" in the present invention refers to an inert organic or inorganic base that acts as a proton scavenger. For the avoidance of doubt, the auxiliary base in the present invention is different from the ammonia molecule formed during the biocatalytic conversion, and it is different from hydroxylamine or its salts.

[0088] The term "C n -C m ” indicates in each case the possible number of carbon atoms in the substituent or substituent moiety in question.

[0089] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0090] The term "oxo" refers to an oxygen atom =0, which is bonded to a carbon atom or a sulfur atom, thereby forming, for example, a keto group -C(=O)- or a sulfinyl group -S(=O)-.

[0091] The term "C1-C6-alkyl" refers to a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl.

[0092] 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 ethenyl, 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.

[0093] The term "C2-C6-alkynyl" 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 (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl.

[0094] The term "C1-C6-haloalkyl" refers to straight-chain or branched alkyl groups (as defined above) having 1 to 6 carbon atoms, wherein some or all of the hydrogen atoms in these groups may 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.

[0095] The term "C1-C6-alkoxy" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as defined above) bonded via an oxygen in any position of the alkyl group, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

[0096] The term "C1-C6-haloalkoxy" refers to a C1-C6-alkoxy group as defined above in which some or all of the hydrogen atoms may 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- ... , 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.

[0097] 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 of the hydrogen atoms of the alkyl group is replaced by a phenyl or heteroaryl group, respectively.

[0098] The term "C1-C4-alkoxy-C1-C4-alkyl" refers to an alkyl group (as defined above) having 1 to 4 carbon atoms in which one of the hydrogen atoms 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 (as defined above) having 1 to 4 carbon atoms in which one of the hydrogen atoms of the alkyl group is replaced by a C1-C4-alkylthio group.

[0099] The term "C1-C6-alkylthio" as used herein refers to a straight-chain or branched alkyl group (as defined above) having 1 to 6 carbon atoms bonded via a sulfur atom. Accordingly, the term "C1-C6-haloalkylthio" as used herein refers to a straight-chain or branched haloalkyl group (as defined above) having 1 to 6 carbon atoms bonded via a sulfur atom at any position in the haloalkyl group.

[0100] The term "C1-C4-alkoxyimino" refers to a divalent imino group (C1-C4-alkyl-ON=) having a C1-C4-alkoxy group as a substituent, for example, methylimino, ethylimino, propylimino, 1-methylethylimino, butylimino, 1-methylpropylimino, 2-methylpropylimino, 1,1-dimethylethylimino, and the like.

[0101] 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 group (C1-C6-alkyl-ON=) as defined above.

[0102] The term "C2-C6-alkenyloxyimino-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-alkenyloxyimino group (C2-C6-alkenyl-ON=).

[0103] The term "C2-C6-alkynyloxyimino-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-alkynyloxyimino group (C2-C6-alkynyl-ON=).

[0104] The term "hydroxy C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms in which one of the hydrogen atoms of the alkyl group is replaced by an OH group.

[0105] The term "amino C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms wherein one of the hydrogen atoms of the alkyl group is replaced by an NH2 group.

[0106] The term "C1-C6-alkylamino" refers to an amino group substituted by one residue independently selected from the group defined by the term C1-C6-alkyl. Similarly, the term "diC1-C6-alkylamino" refers to an amino group substituted by two residues independently selected from the group defined by the term C1-C6-alkyl.

[0107] The term "C1-C4-alkylamino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms (as defined above) in which one of the hydrogen atoms of the alkyl group is replaced by a C1-C4-alkyl-NH-group bonded via nitrogen. Similarly, the term "diC1-C4-alkylamino-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms (as defined above) in which one of the hydrogen atoms of the alkyl group is replaced by a (C1-C4-alkyl)2N-group bonded via nitrogen.

[0108] The term "aminocarbonyl-C1-C4-alkyl" refers to an alkyl group having 1 to 4 carbon atoms wherein one of the hydrogen atoms of the alkyl group is replaced by a -(C=O)-NH2 group.

[0109] The term "C3-C 11"-Cycloalkyl" refers to a monocyclic, bicyclic or tricyclic saturated monovalent hydrocarbon radical having 3 to 11 carbon ring members attached via one of the ring carbon atoms by replacing one 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).

[0110] The terms "-C(=O)-C1-C6-alkyl", "-C(=O)-O-C1-C6-alkyl" and "-C(=O)-C3-C 11 "-Cycloalkyl" refers to an aliphatic group attached via a carbon atom of a -C(=O)- group or via an oxygen atom of a -C(=O)-O- group.

[0111] The term "aliphatic" refers to compounds or groups that are composed of carbon and hydrogen and are non-aromatic compounds. "Alicyclic" compounds or groups are organic compounds that are both aliphatic and cyclic. They contain one or more all-carbon rings that may be saturated or unsaturated but do not have aromatic character.

[0112] The term "cyclic moiety" or "cyclic group" refers to a group that is an alicyclic ring or an aromatic ring, such as phenyl or heteroaryl.

[0113] The term "and wherein any aliphatic or cyclic group is unsubstituted or substituted by..." refers to aliphatic groups, cyclic groups and groups containing aliphatic and cyclic moieties in one group, such as in, for example, C3-C8-cycloalkyl-C1-C4-alkyl; thus, groups containing aliphatic and cyclic moieties - these moieties can be substituted or unsubstituted independently of each other.

[0114] The term "phenyl" refers to an aromatic ring system (commonly referred to as a benzene ring) comprising 6 carbon atoms.

[0115] The term "heteroaryl" refers to an aromatic monocyclic or multicyclic ring system which includes 1, 2, 3 or 4 heteroatoms independently selected from N, O and S in addition to carbon atoms.

[0116] The term "saturated 3- to 7-membered carbocycle" is understood to mean a monocyclic saturated carbocycle having 3, 4 or 5 carbon ring members. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0117] 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 include, besides carbon atoms, further 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms" is understood to mean aromatic monocyclic and bicyclic heteroaromatic ring systems, and saturated and partially unsaturated heterocycles, for example:

[0118] 3- or 4-membered saturated heterocycles containing 1 or 2 heteroatoms selected from N, O and S as ring members, such as oxirane, aziridine, thiirane, oxetane, azetidine, thiethane, [1,2]dioxetane, [1,2]dithietane, [1,2]diazetidine;

[0119] and a 5- or 6-membered saturated or partially unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members, such as 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isothiophene, Oxazolidinyl, 4-iso Oxazolidinyl, 5-iso oxazolidinyl, 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- oxadiazolidine-3-yl, 1,2,4- 1,2,4-thiadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4- oxadiazolidin-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-pyrrolidine-2-yl, 2-pyrrolidine-3-yl, 3-pyrrolidine-2-yl, 3-pyrrolidine-3-yl, 2-isothiophene-2-yl, 2-isothiophene ...3-yl, 2-isothiophene-2-yl, 2-isothiophene-3-yl, 2-isothiophene-3-yl, 2-isothiophene-3-yl, 2-isothiophene-2-yl, 2- Oxazoline-3-yl, 3-iso Oxazoline-3-yl, 4-iso Oxazoline-3-yl, 2-iso Oxazoline-4-yl, 3-iso Oxazolin-4-yl, 4-iso Oxazoline-4-yl, 2-iso Oxazoline-5-yl, 3-iso Oxazoline-5-yl, 4-iso oxazolin-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 ...2,3-dihydropyrazol-5-yl, 2,3-dihydropyrazol-5-yl, 2,3-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-dihydropyrazol-5-yl, 2,3-dihydropyrazol-5-yl, 2,3-dihydropyrazol- Oxazol-2-yl, 2,3-dihydro Oxazol-3-yl, 2,3-dihydro Oxazol-4-yl, 2,3-dihydro Oxazol-5-yl, 3,4-dihydro Oxazol-2-yl, 3,4-dihydro Oxazol-3-yl, 3,4-dihydro Oxazol-4-yl, 3,4-dihydro Oxazol-5-yl, 3,4-dihydro Oxazol-2-yl, 3,4-dihydro Oxazol-3-yl, 3,4-dihydro oxazol-4-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 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-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl and the corresponding -subunits; and 7-membered saturated or partially unsaturated heterocycles, such as tetrahydro- and hexahydroazepines 2,3,4,5-tetrahydro[1H]azepine -1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro[2H]azepine -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]azepine -1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]azepine -1-, -2-, -3-, -4-, -5-, -6- or -7-yl, hexahydroazepine -1-, -2-, -3- or -4-yl, tetrahydro- 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, hexahydroazepine -1-, -2-, -3- or -4-yl, tetrahydro- and hexahydro-1,3-diazepines 1,4-diazepine, tetrahydro- and hexahydro-1,4-diazepine 1,3-oxazepine Oxazepinyl, tetrahydro- and hexahydro-1,4-oxazepinyl 1,4-dioxepinyl, tetrahydro- and hexahydro-1,3-dioxepinyl, tetrahydro- and hexahydro-1,4-dioxepinyl and the corresponding -ylidenes.

[0120] The term "5- or 6-membered heteroaryl" or the term "5- or 6-membered aromatic heterocycle" refers to an aromatic ring system which, in addition to carbon atoms, comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, for example a 5-membered heteroaryl 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-5-yl Oxazol-3-yl, iso Oxazol-4-yl, iso oxazol-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- oxadiazole-3-yl, 1,2,4- oxadiazole-5-yl and 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl; or

[0121] 6-membered heteroaryl, 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.

[0122] Operation Example

[0123] The present invention is further illustrated by means of the following working examples.

[0124] Example 1) Preparation of 4-(N′-hydroxycarbamimidoyl)benzoic acid

[0125] Terephthalonitrile (108.9 g, 0.85 mol) and water (881 g) were placed in a glass reactor at 25°C and heated to 30°C. Once the temperature reached 30°C, a biocatalyst suspension (10 g, E. coli TG10 + pDHE-Com expressing the nitrilase from Comamonas testosteroni) in 50 mM potassium phosphate buffer @ pH 7 was added. The mixture was stirred for 23 hours using a three-stage horizontal arm stirrer. The reaction was complete as indicated by the absence of residual solid terephthalonitrile (visual test). After the reaction, a 50 wt% aqueous NaOH solution (10 g) was added to adjust the pH to 8.73. Mixing was continued for 30 minutes. The suspension was filtered through a 0.22 μm disposable filter to remove the biocatalyst. The clear filtrate of 4-cyanobenzoic acid ammonium salt was used in the next step without further purification.

[0126] The aqueous filtrate of 4-cyanobenzoate (516 g, 0.43 mol, 500.05 mL-c=0.85 mol / L-ρ=1.03 kg / L) was placed in a glass reactor and hydroxylamine (37.9 g, 0.57 mol, 1.35 eq., 50% aqueous solution) was added over 5 minutes (slightly exothermic, T~29.5°C). The resulting solution was warmed to 40°C and stirred for 6 hours. The solution was then cooled to 25°C and the pH of the solution was then adjusted to 4.4 using aqueous HCl (63.4 g, 0.64 mol, 37 wt% in water). Water (20 g) was added to ensure proper stirring of the suspension. The mixture was then cooled to 5°C and filtered (suction filter). The solid was washed with pre-cooled water (110 mL, 5°C) and dried under reduced pressure at 50°C to provide the desired product (74.5 g, 94.7%, purity 97.4%).

[0127] Example 2)

[0128] Terephthalonitrile (89 g, 0.695 mol) and water (900 g) were placed in a glass reactor at 25°C and heated to 30°C. Once the temperature reached 30°C, a biocatalyst suspension (11 g, E. coli TG10 + pDHE-Com expressing the nitrilase from Comamonas testosteroni) in 50 mM potassium phosphate buffer pH 7 was added. The mixture was stirred for 23 hours using a three-stage horizontal arm stirrer. The reaction was complete as indicated by the absence of residual solid terephthalonitrile (visual test). After the bioconversion, the reaction suspension was removed from the reactor and filtered through Celite 535 to remove most of the biocatalyst. The material was then filtered through a 0.22 μm disposable filter to remove residual biocatalyst. The clear filtrate contained 4-cyanobenzoic acid ammonium salt in a concentration equivalent to 8.82 wt% 4-cyanobenzoic acid and was used in the next step without further purification.

[0129] A portion of the aqueous filtrate of 4-cyanobenzoate (130 g, 8.82 wt-%, 77.9 mmol) was placed in a glass reactor and hydroxylamine (8 g, 121.1 mmol, 1.55 equiv., 50% aqueous solution) was added at 50 ° C for 20 minutes. The resulting mixture was stirred at a constant temperature for 4 hours. The solution was then cooled to 21 ° C and the pH of the solution was adjusted to <3 by adding 50% sulfuric acid solution (13 g, 66 mmol, 50% by weight in water) to precipitate the product. The resulting suspension was then cooled to 5 ° C and filtered. The solid was washed twice with pre-cooled water (50 mL each, 5 ° C) and dried under reduced pressure (70 ° C / 25 mbar) for 12 hours to provide the desired product (14.1 g, a yield of 94.2% of theoretical value, and a purity of 93.8% determined by quantitative NMR).

[0130] The nitrilase from Comamonas testosteroni used in Examples 1 and 2 above was retrieved from sequences in publicly accessible databases (its primary structure / sequence was deposited in GenBank on November 29, 1995, with accession numbers L32589.1 (nucleotides) and AAA82085.1 (amino acids)) and corresponds to Seq. ID 2, SEQ amino acid 29, SEQ ID nucleic acid 28, 90% identity in Table 1 of PCT / EP2020 / 051288. Comamonas testosteroni is a ubiquitous soil bacterium that has been sampled before August 1990 and has no known Nagoya Protocol responsibility (DSMZ entry DSM 38, country of origin unknown).

Claims

1. A method for preparing an amide oxime compound of formula I, in R is halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-haloalkoxy; n is 0, 1, or 2; The method comprises the following steps: i. providing an aqueous medium comprising water, one or more nitrilase enzymes and a terephthalonitrile of formula II, wherein the variables n and R have the meanings defined for the compound of formula I; ii. culturing an aqueous medium to obtain 4-cyanobenzoic acid of formula IIa or a salt thereof in an aqueous medium, wherein the variables n and R in 4-cyanobenzoic acid IIa have the meanings defined for the compound of formula I; iii. Removing biological material from aqueous media; iv. treating the aqueous medium obtained in step iii with hydroxylamine or a salt thereof.

2. The method according to claim 1, wherein n in the compounds of formula I, II and IIa is 0.

3. The method according to claim 1, wherein terephthalonitrile II is added to the aqueous medium before culturing at a concentration of 1 wt% to 30 wt%.

4. The method according to claim 2, wherein terephthalonitrile II is added to the aqueous medium before culturing at a concentration of 1 wt% to 30 wt%.

5. The process according to claim 1, wherein the aqueous medium in process steps i and ii has a pH value of 4 to 9.

6. The method according to any one of claims 1 to 4, wherein the aqueous medium is incubated at a temperature of 10°C to 50°C in step ii.

7. The method according to claim 5, wherein the aqueous medium is cultured at a temperature of 10°C to 50°C in step ii.

8. The process according to claim 1, wherein 1 to 3 molar equivalents of hydroxylamine or a salt thereof, based on the amount of terephthalonitrile II, are used in step iv.

9. The process according to claim 7, wherein 1 to 3 molar equivalents of hydroxylamine or a salt thereof, based on the amount of terephthalonitrile II, are used in step iv.

10. The process according to any one of claims 1 to 4, wherein the temperature in step iv is in the range of 0°C to 100°C.

11. The process according to any one of claims 1 to 4, wherein after step iv the compound of formula I is isolated by filtration or centrifugation.

12. The process according to any one of claims 2 to 4, for further reacting a compound of formula I to obtain a compound of formula III 13. The process according to claim 12, for further reacting the compound of formula III to obtain the compound of formula IV 14. The process according to claim 13, for further reacting a compound of formula III or IV with a compound of formula V, R 1 -NH-R 2 V in R 1 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-alkenyloxyimino-C1-C4-alkyl, C2-C6-alkynyloxyimino-C1-C4-alkyl, C1-C6-alkylamino, diC1-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 3- to 10-membered saturated, partially unsaturated and or an aromatic monocyclic or bicyclic heterocycle, wherein the ring member atoms of the monocyclic or bicyclic heterocycle further include, 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 cannot 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 further include, 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 cannot contain 2 adjacent atoms selected from O and S; and wherein any of the above aliphatic or cyclic groups is unsubstituted or replaced by 1, 2 or 3 identical or different groups R 1a replace; 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 heterocyclic ring, wherein the heterocyclic ring, apart from one nitrogen atom and one or more carbon atoms, does not comprise any other heteroatoms or comprises 1, 2 or 3 other heteroatoms independently selected from N, O and S as ring member atoms, provided that the heterocyclic ring cannot contain 2 adjacent atoms selected from O and S; and wherein the heterocyclic ring is unsubstituted or replaced by 1, 2, 3 or 4 identical or different radicals R 1a Replace; 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)-O-C1-C4-alkyl, C1-C6- 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, diC1-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 R 2 Any aliphatic or cyclic group in is unsubstituted or replaced by 1, 2 or 3 groups selected from halogen, hydroxy, oxo, cyano, C1-C6-alkyl, C1-C6-alkoxy and C3-C 11 - substitution of cycloalkyl groups by the same or different groups; To obtain the compound of formula VI 15. The process according to claim 14, for further reacting the compound of formula VI to obtain the compound of formula VII 16. The method according to claim 15, wherein in the compounds of formula V, VI and VII 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 phenyl is unsubstituted or substituted by 1, 2 or 3 identical or different groups selected from fluorine, chlorine, cyano, OH, NH2, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl; R 2 is hydrogen, methyl or ethyl.

17. The method according to claim 15, wherein in the compounds of formula V, VI and VII R 1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pent-1-yl, 2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl; R 2 It's hydrogen.

18. The method according to claim 17, wherein in the compounds of formula V, VI and VII R 1 is methyl or 2-fluorophenyl.

Images