PREPARATION OF SUBSTITUTED 3-ARYL-5-TRIFLUOROMETHYL-1,2,4-OXADIAZOLES

Abstract

The present invention relates to a process for the preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles of Formula I, which can be obtained by reacting amidoxime compounds of Formula II with a haloacetic ester in the presence of a solvent and a base. (see Formulas).

Description

PREPARATION OF SUBSTITUTED 3-ARYL-5-TRIFLUOROMETHYL-1,2,4-OXADIAZOLES The present invention relates to a process for the preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles of Formula I, which can be obtained by reacting amidoxime compounds of Formula II with a haloacetic ester in the presence of a solvent and a base. rnapnn / zznz / E / YiAi I II Substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles are known to be useful for controlling phytopathogenic fungi, for example, from WO 2015 / 185485 A1 and WO 2017 / 211649 A1. Typically, the preparation of 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles involves the formation of the oxadiazole ring by reacting amidoxime compounds, for example, compounds of Formula II, with an activated trifluoroacetic acid (TFA) derivative. In the first reaction step, the hydroxy group in the Formula II compounds is acylated. Subsequently, the intermediate otrifluoroacetyl amidoximes undergo ring closure with concomitant elimination of water to form the oxadiazole moiety. Trifluoroacetic acid anhydride (TFAA) is commonly used as an acylating agent. In the reaction above, at least two equivalents of acylating agent are required for complete conversion of compound II. Therefore, if TFAA is used, a total of at least three equivalents of TFAA are formed per equivalent of compound II, which must be discarded. TFAA is somewhat expensive, and for the sake of atom efficiency, there is an interest in reducing the amount of excess TFAA supplied during or after the ring-closing reaction. WO 2019 / 020451 A1 discloses the use of trifluoroacetic halides instead of TFAA, resulting in the formation of a comparatively smaller amount of TFA. However, the reaction still yields significant quantities of TFA along with hydrogen halides, which can lead to corrosion of the reaction equipment, and the hydrogen halides eventually need to be separated from the reaction product. Trifluoroacetic halides boil at low temperatures, making them difficult to handle, and, as they are also highly toxic, they pose risks to the operator, particularly in large-scale setups. The transformations described in the references above generate considerable amounts of TFA that must be separated from the reaction product and discarded. To increase atom efficiency, trifluoroacetic acid esters (TFAEs) can be used in these processes, as they are less reactive than TFAA or trifluoroacetic halides toward the amidoximes of Formula II. In theory, the use of esters instead of the corresponding acid halides or anhydrides requires, if anything, only a small excess of the acylating agent. Durden et al. in Journal of Organic Chemistry 1971, 36. 9, 1306-1307, describe a process in which (halo)acetic acid vinyl esters are used in reactions with benzamidoxime to obtain the corresponding oxadiazoles. The reported yields with trifluoroacetic acid vinyl esters are moderate (43%). WO 2017 / 22295 A1, WO 2017 / 222951 A1 and WO 2017 / 222952 A1 disclose the preparation of 3aryl-5-trifluoromethyl-1,2,4-oxadiazoles using methyl trifluoroacetate in the presence of potassium carbonate as the base, in a mixture of DMF and toluene as the solvent, and at a temperature of 80°C. The reported yields are also moderate. In view of the foregoing, it was an object of the present invention to overcome these disadvantages and provide an improved, more economical and plant-friendly production process, enabling the preparation of 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles on an industrial scale in high yield and with low amounts of by-products. The inventors discovered that alkyl esters of trifluoroacetic acid can be reacted with amidoxime compounds of Formula II in the presence of metal acoxylates, which surprisingly provide higher yields of the desired oxadiazoles than prior art procedures. The process of this invention is environmentally friendly and more cost-effective than previously reported processes, as it uses readily available, non-toxic, and inexpensive reagents. The reaction can be carried out with a comparatively low excess of the acylating agent, taking into account the amidoxime starting material. Furthermore, rapid conversion of the starting material is achieved at comparatively lower reaction temperatures. Accordingly, the present invention relates to a process for preparing compounds of Formula I, F ρηαΑηη / ζζηζ / Ε / γίΛΐ where A is phenyl or a 5- or 6-membered aromatic heterocycle; wherein the ring-membered atoms of the aromatic heterocycle include, in addition to carbon atoms, 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring-membered atoms provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein A is further unsubstituted or further substituted with n identical or different additional RA radicals; wherein n is 0, 1, 2, 3 or 4; RAse is selected independently from the group consisting of halogen, cyano, Ci-Cealkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy and Ci-Ce-haloalkoxy; R is methyl, chloromethyl, hydroxymethyl, trichloromethyl, ethyl, / so-propyl, OH, SH, cyano, halogen, CH2F, CHF2, 2,2,2-trifluoroethyl, cyclopropyl, -C(=O)H, -C(=NOR2)H, -C(=O)OH, -C(=O)OR1, 3 C(=W)NR1R2, -CR3R4NR1R2, -CR3R4OR1, -CR3(=NR1), -CR3(=O), -CR3R4C(=O)OH, -CR3R4C(=O)R1, -CR3R4C(=W)NR1R2, -OCR3R4C(=O)OH, -OCR3R4C(=O)R1, -OCR3R4C(=W)NR1R2, -CR3R4-N(R2)-C(=W)R1, -CR3R4S(=O)2R1or -CR3R4-N(R2)-S(=O)2R1; where W is O or S; R2 is hydrogen, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-alkoxy, Cs-Cu-cycloalkyl, -C(=O)-Ci-C6-alkyl, -C(=O)-C3-Cn-cycloalkyl or -C(=O)-O-Ci-Ce-alkyl; and wherein any of the aliphatic or cyclic groups in R2 are unsubstituted or are substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, Ci-Ce-alkyl, Ci-Ce-alkoxy and Cs-Cn-cycloalkyl; R1 is Ci-Ce-alkyl, Ci-Ce-alkoxy, Cs-Cn-cycloalkyl, Cs-Cs-cycloalkenyl, C2-Ce-alkenyl, C2-Cealkynyl, Ci-C6-alkoxyimino-Ci-C4-alkyl, C2-C6-alkenyloxymine-Ci-C4-alkyl, C2-Cealkynyloxymino-Ci-C4-alkyl, Ci-Ce-alkylamino, diCi-Ce-alkylamino, -C(=O)-Ci-Ce-alkyl, -C(=O)-O-Ci-C6-alkyl, phenyl-Ci-C4-alkyl, phenyl-Ci-C4-alkenyl, phenyl-Ci-C4-alkynyl, heteroaryl-Ci-C4-alkyl, phenyl, naphthyl or a saturated, partially unsaturated or aromatic 3 to 10-membered mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle include, in addition to carbon atoms, 1, 2, 3 or 4 other heteroatoms selected from N, O and S as ring member atoms, provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S;and wherein the heteroaryl group in the heteroaryl-C4-alkyl group is a 5- or 6-membered aromatic heterocycle, wherein the ring-membered atoms include, in addition to carbon atoms, 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring-membered atoms provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein any of the above-mentioned cyclic or aliphatic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different R1a groups; or; R1 and R2, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated mono- or bicyclic heterocycle of 3 to 10 members, wherein the heterocycle includes, in addition to a nitrogen atom and one or more carbon atoms, no additional heteroatoms or 1, 2, or 3 additional heteroatoms independently selected from N, O, and S as ring member atoms, provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or up to the maximum possible number of identical or different R1 groups; wherein R1aes halogen, oxo, cyano, NO2, OH, SH, NH2, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylthio, Ci-Cs-haloalkylthio, Cs-Cs-cycloalkyl, -NHSO2-C4-alkyl, -C(=O)-C4-alkyl, -C(=O)-O-C4-alkyl, Ci-Ce-alkylsulfonyl, hydroxyC4-alkyl, -C(=O)-NH2, -C(=O)-NH(C4-alkyl), Ci4-alkylthio-C4-alkyl, aminoC4-alkyl, Ci4-alkylamino-C4-alkyl, d¡Ci-C4-alkylamino-Ci-C4-alkyl, aminocarbon¡l-Ci-C4-alkyl or Ci-C4-alkoxy-Ci-C4-alkyl; ρηαΑηη / ζζηζ / Ε / γίΛΐ R3, R4, independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, Ci-C4-alkyl, Ci-C4-alkenyl, Ci-C4-alkynyl, Ci-C4-haloalkyl and Ci-C4-alkoxy; or R3 and R4 together with the carbon atom to which they are attached form a cyclopropyl group; whose process comprises reacting an amidoxime of Formula II, ρηαΑηη / ζζηζ / Ε / γίΛΐ H2N wherein the variables A and R are as defined above for compounds of Formula I, with a haloacetic ester of Formula II.a, wherein R5 is Ci-Ce-alkyl in the presence of a solvent and a base; whereas the process is characterized in that the base comprises a metal alkoxylate of Formula IV, [Ci-C6-alkyl-O]x Mx+ where the metal M is an alkali metal, where x is 1, or M is a divalent alkaline earth metal, where x is 2; and the solvent comprises an alkyl alcohol of Formula III, or mixtures thereof, Ci-Ce-alkyl-OH In one aspect of the present invention, variable A is phenyl in compounds of Formula I and II. In one embodiment of the present invention, the radical RA in compounds of Formula I and II is halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy or Ci-Ce-haloalkoxy; in particular fluorine. In one respect, n is 1 and RA is fluorine in compounds of Formula I and II. In a preferred embodiment, the variable n is 0 in compounds of Formula I and II. In one aspect, the present invention relates to a process as defined above, wherein the amidoxime is of Formula II.b, H2N ll.b HO— N where n is 0 or 1; and where the meaning of R is as defined or preferably defined herein for compounds of Formula I; and where RA is selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy and Ci-Ce-haloalkoxy; to obtain oxadiazoles of Formula Lb, ρηαΑηη / ζζηζ / Ε / γίΛΐ where the variables n, RAy R have the meaning as defined for compounds II.b. In another embodiment, n is 1 and RA is fluorine in compounds of Formula lb and II.b. In a preferred embodiment, n is 0 in compounds of Formula Lb and Il.b. In one embodiment, the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RA is fluorine; n is 0 or 1; R is methyl, chloromethyl, hydroxymethyl, trichloromethyl, -C(=O)H, -C(=NOR2)H, -C(=O)OH, OH, SH, cyano, halogen, -C(=O)NR1R2, -CH2-N(R2)-C(=O)R1, -CH2-N(R2)-S(=O)2R1, R1 is methyl, ethyl, n-propyl, / so-propyl, n-butyl, seo-butyl, / so-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl or phenyl; and wherein the phenyl group is unsubstituted or is substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl; R2 is hydrogen, methyl, ethyl, methoxy, ethoxy or cyclopropyl. In a further embodiment, the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RAes fluor; n is 0 or 1; R is methyl, -C(=O)OH, -C(=O)NR1R2, -CH2-N(R2)-C(=O)R1, -CH2-N(R2)-S(=O)2R1, R1 is Ci-Ce-alkyl, phenyl or cyclopropyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2, 3 or 4 identical or different halogen groups selected; R2 is hydrogen, methyl, ethyl, methoxy, ethoxy or cyclopropyl. In yet another embodiment, the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RAes fluor; n is 0 or 1; R is -CH2-N(R2)-C(=O)R1, -CH2-N(R2)-S(=O)2R1, ρηαρηη / ζζηζ / Ε / γίΛΐ R1es Ci-Ce-alkyl or cyclopropyl; R2 is hydrogen, methyl, methoxy, ethoxy or cyclopropyl. In another embodiment, the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RAes fluor; n is 0 or 1; R is methyl, -C(=O)OH orC(=O)NR1R2; R1 is methyl or phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2, 3 or 4 identical or different halogen groups selected; R2 is hydrogen, methyl, ethyl, methoxy or ethoxy. In yet another embodiment, the variables in the compounds of Formula I, II, lb and II.b have the following meaning: n is 0; R es-C(=O)NR1R2; R1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl or 2,4-difluorophenyl; in particular methyl or 2-fluoro-phenyl; R2 is hydrogen. In one embodiment of the invention, the radical R5 in haloacetic esters of Formula II.a is methyl, ethyl, n-propyl, / so-propyl or π-butyl; preferably methyl or ethyl; particularly ethyl. In one embodiment, the reaction is carried out with 1 to 5 molar equivalents of haloacetic ester II.a, depending on the amount of amidoxime II. Preferably, 1 to 3 molar equivalents are used, in particular 1.5 to 2.5 molar equivalents or 1.2 to 2 molar equivalents, and even more preferably 1.5 to 2.2 molar equivalents or 1.2 to 1.6 molar equivalents, depending on the amount of amidoxime II. Typically, the haloacetic ester of Formula II.a is added to a solution of amidoxime II and the base in the solvent. In one embodiment, the total amount of haloacetic ester II.a is added to the reaction mixture in portions or continuously within 2–8 hours. In another embodiment, the base or a solution of the base in the solvent is added to a mixture of amidoxime II and haloacetic ester II.a, both optionally dissolved or partially dissolved in the solvent. In one embodiment, the total amount of base is added to the reaction mixture in portions or continuously within 2–8 hours. In a preferred embodiment, the metal M in the metal alkoxylates of Formula IV is sodium, potassium, or magnesium; more preferably, sodium or potassium; in particular, sodium. In a more preferred embodiment, metal IV alkoxylates are sodium methoxide or sodium ethoxide, or a mixture of these. In one embodiment of the present invention, the alkoxylate base of Formula IV is the corresponding conjugate Bronsted base of the solvent of Formula III. In a particularly preferred embodiment, the metal IV alkoxylate is sodium methoxide and the solvent is methanol. In another particularly preferred embodiment, the metal IV alkoxylate is sodium ethoxide and the solvent is ethanol. Typically, the base is added to the reaction mixture as a solution in the alkyl alcohol of Formula III, which is the corresponding Bronsted acid conjugate of the base. The base is used in an amount of at least 80 mol% depending on the amount of the compound of Formula II, or at least 100 mol%, or at least 150 mol%. In another aspect of the present invention, the base is used in an amount that varies from 80 to 1000 mol%, preferably from 80 to 500 mol%, more preferably from 90 to 200 mol%, particularly from 90 to 140 mol%, depending on the amount of the compound of Formula II. The process can be carried out in the presence of an inert solvent, also referred to herein as an auxiliary solvent. Suitable auxiliary solvents include, for example, aliphatic, cycloaliphatic, and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated aliphatic hydrocarbons (methylene chloride, chloroform, di- and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol, diethyl ether, diethylene glycol dimethyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, dioxane, diethylene, monomethyl glycol, or monoethyl ether), / V-substituted lactams ( / V-methylpyrrolidone), carboxamides ( / V, / V-dimethylformamide, / V, / V-dimethylacetamide), acyclic ureas (dimethyl imidazoline), nitriles such as acetonitrile or propionitrile, and sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone). The preferred auxiliary solvents are benzene, toluene, xylene, cyclohexane, n-hexane, n-heptane, tetrahydrofuran, dioxane, A / , / V-dimethylformamide, / V-methylpyrrolidine or dimethyl sulfoxide. According to the invention, the solvent comprises an alkyl alcohol of Formula III, or mixtures thereof, Ci-Ce-alkyl-OH III. Specifically, in one embodiment of the present invention, the process is carried out in the presence of a solvent comprising methanol, ethanol, n-propanol, n-propanol, n-butanol, sec-butanol or tert-butanol, or mixtures thereof. In a particularly preferred embodiment, the process is carried out in the presence of a solvent comprising methanol or ethanol, or mixtures thereof. In one aspect, the process is carried out in the presence of a solvent comprising an alkyl alcohol of Formula III as defined or preferably defined above, wherein the solvent contains at least 1% by volume of the alkyl alcohol of Formula III, or mixtures thereof, depending on the total amount of solvents, i.e., in addition to any additional solvents; wherein such additional solvents include auxiliary solvents or the haloacetic ester of Formula II.a, or mixtures thereof. In another aspect, the process is carried out in the presence of a solvent comprising an alkyl alcohol of Formula III as defined or preferably defined above, wherein the solvent contains at least 5% by volume of the alkyl alcohol of Formula III, or mixtures thereof, depending on the total amount of solvents, i.e., in addition to any additional solvents; wherein such additional solvents include auxiliary solvents or the haloacetic ester of Formula II.a, or mixtures thereof. In one respect, the process is carried out in the presence of an alkyl alcohol of Formula III, or mixtures thereof, and in the absence of any additional auxiliary solvent. The reaction temperature of the above process is preferably in the range of 0°C to 60°C, preferably in the range of 10°C to 50°C or in the range of 20°C to 50°C. The reaction usually takes place within 10 minutes to 20 hours, or within 60 minutes to 14 hours, preferably within 1 to 10 hours or within 2 to 10 hours, with greater preference within 2 to 8 hours. In a particularly preferred embodiment, the process is carried out in the presence of a solvent comprising methanol or ethanol, or mixtures thereof; and wherein the metal IV alkoxylate is sodium methoxide or sodium ethoxide, or a mixture thereof; and wherein the reaction temperature of the above process is in the range of 0°C to 60°C. In another particularly preferred embodiment, the process is carried out in the presence of a solvent comprising an alkyl alcohol comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, sec-butanol, or tert-butanol, or mixtures thereof; and wherein the alkoxylate base of Formula IV corresponds to the conjugate Brønsted base of said alkyl alcohol; and wherein the reaction temperature of the above process is in the range of 0°C to 60°C; and wherein the solvent contains at least 1% by volume of the alkyl alcohol, or mixtures thereof, based on the total amount of solvents, i.e., in addition to any additional solvents; wherein such additional solvents include auxiliary solvents or the haloacetic ester of Formula II.a, or mixtures thereof. In yet another particularly preferred embodiment, the process is carried out in the presence of a solvent comprising methanol or ethanol, or mixtures thereof; and wherein the metal IV alkoxylate is sodium methoxide or sodium ethoxide, or a mixture thereof; and wherein the reaction temperature of the above process is in the range of 0°C to 60°C; and wherein the solvent contains at least 1% by volume of the alkyl alcohol of Formula III, or mixtures thereof, based on the total amount of solvents, i.e., in addition to any additional solvents; wherein such additional solvents include auxiliary solvents or the haloacetic ester of Formula IIa, or mixtures thereof; or even more preferentially, if the alkoxylate base of Formula IV corresponds to the conjugate Bronsted base of the solvent of Formula III. In yet another particularly preferred embodiment, the process is carried out in the presence of a solvent comprising methanol or ethanol, or mixtures thereof; and wherein the metal IV alkoxylate is sodium methoxide or sodium ethoxide, or a mixture thereof; and wherein the reaction temperature of the above process is in the range of 10°C to 50°C; and wherein the solvent contains at least 5% by volume of the alkyl alcohol of Formula III, or mixtures thereof, based on the total amount of solvents, i.e., in addition to any additional solvents; wherein such additional solvents include auxiliary solvents or the haloacetic ester of Formula IIa, or mixtures thereof; or even more preferably, if the alkoxylate base of Formula IV corresponds to the conjugate Brønsted base of the solvent of Formula III. The process of the present invention is generally carried out at atmospheric pressure. In another embodiment, the process is carried out in a closed reactor to prevent losses of the low-boiling compound III due to steam pressure or nitrogen purge. A small amount of overpressure is generated in this case by heating or dosing one of the starting materials. In a preferred embodiment (embodiment E.1) of the present invention, the metal M in the metal IV alkoxylates is sodium, potassium, or magnesium. Embodiment E.2: is based on embodiment E.1, wherein the radical R5 in haloacetic esters of Formula II.a is methyl or ethyl. Embodiment E.3: is based on embodiment E.2, wherein the amount of haloacetic ester of Formula II.a is between 1.5 and 2.5 equivalents depending on the amount of amidoxime II. Embodiment E.4: is based on embodiment E.3, wherein the metal IV alkoxylates are sodium methoxide or sodium ethoxide, or a mixture of these. Embodiment E.5: is based on embodiment E.4, wherein the solvent comprises an alkyl alcohol of Formula III, or mixtures thereof. Embodiment E.6: is based on embodiment E.5, wherein the solvent comprises methanol or ethanol, or mixtures thereof. Embodiment E.7: is based on embodiment E.6, wherein the alkoxylate base of Formula IV corresponds to the conjugate Bronsted base of the solvent of Formula III. Embodiment E.8: is based on Embodiment E.7, wherein the process is carried out in the presence of a solvent comprising an alkyl alcohol of Formula III as defined or preferably defined herein, wherein the solvent contains at least 1% by volume of the alkyl alcohol of Formula III, or mixtures thereof, depending on the total amount of solvents, i.e., in addition to any additional solvents; wherein such additional solvents include auxiliary solvents or the haloacetic ester of Formula II.a, or mixtures thereof. Embodiment E.9: is based on embodiment E.8, wherein the process is carried out at a temperature in the range of 0°C to 60°C. enaAnn / zznz / E / YiAi Embodiment E.10: is based on embodiment E.4, wherein the process is carried out at a temperature in the range of 0°C to 60°C. Embodiment E.11: is based on embodiment E.9, wherein the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RA is fluorine; n is 0 or 1; R is methyl, chloromethyl, hydroxymethyl, trichloromethyl, -C(=O)H, -C(=NOR2)H, -C(=O)OH, OH, SH, cyano, halogen, -C(=O)NR1R2, -CH2-N(R2)-C(=O)R1, -CH2-N(R2)-S(=O)2R1, ρηαΑηη / ζζηζ / Ε / γίΛΐ R1 is methyl, ethyl, n-propyl, / so-propyl, n-butyl, sec-butyl, / so-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl or phenyl; and wherein the phenyl group is unsubstituted or is substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl; R2 is hydrogen, methyl, ethyl, methoxy, ethoxy or cyclopropyl. Embodiment E.12: is based on embodiment E.9, wherein the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RA is fluorine; n is 0 or 1; R is methyl, -C(=O)OH orC(=O)NR1R2; R1 is methyl or phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2, 3 or 4 identical or different halogen groups selected; R2 is hydrogen, methyl, ethyl, methoxy or ethoxy. Embodiment E.13: is based on embodiment E.10, wherein the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RAes fluor; n is 0 or 1; R is methyl, chloromethyl, hydroxymethyl, trichloromethyl, -C(=O)H, -C(=NOR2)H, -C(=O)OH, OH, SH, cyano, halogen, -C(=O)NR1R2, -CH2-N(R2)-C(=O)R1, -CH2-N(R2)-S(=O)2R1, R1 is methyl, ethyl, n-propyl, / so-propyl, n-butyl, sec-butyl, / so-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl or phenyl; and wherein the phenyl group is unsubstituted or is substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl; R2 is hydrogen, methyl, ethyl, cyclopropyl, methoxy or ethoxy. Embodiment E.14: is based on embodiment E.10, wherein the variables in the compounds of Formula I, II, lb and II.b have the following meaning: RAes fluor; n is 0 or 1; R is methyl, -C(-O)OH or -C(-O)NR1R?; R1 is methyl or phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2, 3 or 4 identical or different halogen groups selected; R2 is hydrogen, methyl, ethyl, methoxy or ethoxy. In a further embodiment of the invention, a compound of Formula I or Lb, wherein R is methyl, is converted into valuable chemicals or intermediates. Accordingly, in one embodiment, the compounds of Formula lb, where n is 0 and R is methyl, can be further chlorinated to obtain a compound of Formula lc ρηαΑηη / ζζηζ / Ε / γίΛΐ Chlorination of the methyl group R of compounds of Formula I or lb can be achieved as described in WO 2019 / 020451 A1 and in the references cited therein. In a further embodiment, the compound of Formula lc is hydrolyzed to obtain a compound of Formula III.a. F3C\^N Illa In one embodiment, this transformation is carried out in the presence of catalytic amounts of a Lewis acid and water to obtain a compound of Formula III.a, as described in WO 2019 / 020451 A1 and in the references cited therein. Preferably, the Lewis acid is a metal salt, for example, aluminum(I11) chloride or iron(I11) chloride, in particular iron(III) chloride. In another embodiment, the compound of Formula lb, where n is 0 and R is -C(=O)OH, is chlorinated to obtain a compound of Formula III.a. These transformations are described in WO 2019 / 020451 A1 and WO 2017 / 211649 A1 and in the references cited therein. In one embodiment, the compound of Formula III.a is reacted with an amine of Formula IV, R1-NH-R2IV where R1is Ci-Ce-alkyl, Ci-Ce-alkoxy, Ca-Cn-cycloalkyl, Cs-Cs-cycloalkenyl, C2-C6-alkenyl, C2-C6alkynyl, Ci-C6-alkoxyimino-Ci-C4-alkyl, C2-C6-alkenyloxyimino-Ci-C4-alkyl, C2-C6alkynyloxyimino-Ci-C4-alkyl, Ci-Ce-alkylamino, diCi-Ce-alkylamino, -C(=O)-Ci-Ce-alkyl, -C(=O)-O-Ci-C6-alkyl, phenyl-Ci-C4-alkyl, phenyl-Ci-C4-alkenyl, phenyl-Ci-C4-alkynyl, heteroaryl-Ci-C4-alkyl, phenyl, naphthyl or a mono or heterocycle bicyclic of 3 to 10 members saturated, partially unsaturated or aromatic, wherein the ring member atoms of said mono- or bicyclic heterocycle include, in addition to carbon atoms, 1, 2, 3 or 4 other heteroatoms selected from N, O and S as ring member atoms provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S;and wherein the heteroaryl group in the heteroaryl-C4-alkyl group is a 5- or 6-membered aromatic heterocycle, wherein the ring-membered atoms include, in addition to carbon atoms, 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring-membered atoms provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein any of the above-mentioned cyclic or aliphatic groups are unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different R1a groups; or; R1 and R2, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated mono- or bicyclic heterocycle of 3 to 10 members, wherein the heterocycle includes, in addition to a nitrogen atom and one or more carbon atoms, no additional heteroatoms or 1, 2, or 3 additional heteroatoms independently selected from N, O, and S as ring member atoms, provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or up to the maximum possible number of identical or different R1 groups; wherein R1aes halogen, oxo, cyano, NO2, OH, SH, NH2, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylthio, Ci-Ce-haloalkylthio, Cs-Ce-cycloalkyl, -NHSO2-Ci-C4-alkyl, (C=O)-Ci-C6-alkyl, C(=O)-O-Ci-C6-alkyl, Ci-Ce-alkylsulfonyl, hydroxy¡Ci-C4-alkyl, C(=O)-NH2, C(=O)-NH(Ci-C4-alkyl), Ci-C4-alkylthio-Ci-C4-alkyl, aminoCi-C4-alkyl, Ci-C4-alkylamino-Ci-C4-alkyl, diCi-C4-alkylamino-Ci-C4-alkyl, aminocarbonyl-Ci-C4-alkyl or Ci-C4-alkoxy-Ci-C4-alkyl; R2 is hydrogen, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-alkoxy, Ce-Cn-cycloalkyl, C(=O)H, -C(=O)-Ci-Ce-alkyl, -C(=O)-C3-Cn-cycloalkyl or -C(=O)-O-Ci-C6-alkyl; and wherein any of the aliphatic or cyclic groups in R2 are unsubstituted or are substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, Ci-Ce-alkyl, Ci-Ce-alkoxy and C3-C11cycloalkyl; to obtain a compound of Formula V ρηαΑηη / ζζηζ / Ε / γίΛΐ ρηαΑηη / ζζηζ / Ε / γίΛΐ These transformations are also described in WO 2019 / 020451 A1 and WO 2017 / 211652 A1 and in the references cited therein. In another embodiment, the compound of Formula V is used to obtain a compound of Formula VI, as described in WO 2019 / 020451 A1 and WO 2017 / 211649 A1 and in the references cited therein. In a preferred embodiment, the variables R1 and R2 in the compounds of Formula I, Lb, II.b, IV, V and VI have the following meaning: R1 is methyl, ethyl, n-propyl, / so-propyl, n-butyl, sec-butyl, / so-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl or phenyl; and wherein the phenyl group is unsubstituted or is substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, OH, NH2, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy and cyclopropyl; and R2 is hydrogen, methyl or ethyl. In another preferred embodiment, the variables R1 and R2 in the compounds of Formula I, Lb, II.b, IV, V and VI have the following meaning: R1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl or 2,4-difluorophenyl; in particular methyl or 2-fluoro-phenyl; and R2 is hydrogen. Amidoxime compounds of Formula II or II.b can be prepared from cyano compounds of Formula V, NEC-AR V, wherein variables A and R are as defined or as preferably defined herein for compounds of Formula I or Lb, by treatment with hydroxylamine or its hydrochloride salt, in the presence of a base, preferably triethylamine, sodium hydroxide, or sodium methylate, 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. For related examples, see Kitamura, S. et al. Chem. Pharm. Bull. 2001, 49, 268 or any of the patent references cited above. The compounds of Formula V are either commercially available or can be prepared by standard procedures known to a person of average skill from readily available starting materials. In a particularly advantageous two-step approach (reaction scheme below), a cyano compound of Formula Va, wherein variables R1 and R2 are as defined or preferably defined herein, is reacted with hydroxylamine, or its hydrochloride salt, or its hydrogen sulfate salt in an alcohol solvent of Formula III as defined or preferably defined herein, and optionally in the presence of a base, to obtain compounds of Formula IIb, which can then be reacted with a trifluoroacetic ester of Formula IIa in the presence of a base IV according to the process of the present invention to prepare compounds of Formula 1b This two-step sequence can be carried out with the same solvent of Formula V in both consecutive steps and without the need to change the reaction vessel between steps, so isolation and handling of compound II.b is not required. This two-step transformation is particularly preferred with respect to compounds Va, II.b and lb, where R1 is hydrogen and R2 is 2-fluorophenyl; and where solvent III is methanol, ethanol, n-propanol, n-butanol or 2-butanol; in particular methanol or ethanol; and where base IV in the second step is sodium ethanolate or sodium methanolate. ρηαΑηη / ζζηζ / Ε / γίΛΐ The term auxiliary solvent herein refers to an inert solvent, that is, a solvent that does not take part in the reaction and is not an alkyl alcohol within the definition of compounds in Formula III. This means that the auxiliary solvent is not identical to the reactants (the amidoxime II and the haloacetic ester of Formula II.a). The expression Bronsted conjugate base refers to the common definition, while it is a member of a pair of compounds that transform into each other by gaining or losing a proton, while the conjugate base is the species that has emitted the proton. In the definitions of the variables given above, collective terms are used that are generally representative of the substituents in question. The expression Cn-Cm indicates the number of carbon atoms possible in each case in the substituent or the substituent portion in question. The term halogen refers to fluorine, chlorine, bromine, and iodine. The term oxo refers to an oxygen atom =0, which is bonded to a carbon atom or sulfur atom, forming, for example, a ketonyl group -C(=O)- or sulfinyl group -S(=O)-. The expression Ci-Ce-alkyl refers to a branched or linear chain saturated hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. The expression C2-C6-alkenyl refers to a branched or linear chain unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in 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. The expression C2-C6-alkynyl refers to a branched or linear chain unsaturated hydrocarbon radical 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. The expression Ci-Ce-haloalkyl refers to a branched or linear chain alkyl group having from 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, 3bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, CH2-C2F5, CF2-C2F5, CF(CF3)2, 1-(fluoromethyl)-2fluoroethyl, 1-(chloromethyl)-2-chloroethyl,1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl., The expression Ci-Ce-alkoxy refers to a branched or linear chain alkyl group having 1 to 6 carbon atoms (as defined above) that is attached by an oxygen, at any position in the alkyl group, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. The expression Ci-Ce-haloalkoxy refers to a Ci-Ce-alkoxy group as defined above, in which some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, e.g., 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, 2,3difluoropropoxy, 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-(CH2CI)-2chloroethoxy, 1-(CH2Br)-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy. The expressions phenyl-C4-alkyl or heteroaryl-C4-alkyl refer to an alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a phenyl or heteroaryl radical, respectively. The expression Ci-C4-alkoxy-Ci-C4-alkyl refers to an alkyl group having 1 to 4 carbon atoms (as defined above), where one hydrogen atom of the alkyl radical is replaced by a Ci-C4-alkoxy group (as defined above). Similarly, the expression C1C4-alkylthio-Ci-C4-alkyl refers to an alkyl group having 1 to 4 carbon atoms (as defined above), where one hydrogen atom of the alkyl radical is replaced by a Ci-C4-alkylthio group. As used herein, the term Ci-Ce-alkylthio refers to branched or straight-chain alkyl groups having 1 to 6 carbon atoms (as defined above) linked by a sulfur atom. Accordingly, as used herein, the term Ci-Ce-haloalkylthio refers to branched or straight-chain haloalkyl groups having 1 to 6 carbon atoms (as defined above) linked by a sulfur atom at any position on the haloalkyl group. The expression Ci-C4-alkoxymin refers to a divalent amino radical (Ci-C4-alkyl-ON-) that carries a Ci-C4-alkoxy group as a substituent, for example, methylimino, ethylimino, propylimino, 1-methylethylimino, butilimino, 1-methylpropylimino, 2-methylpropylimino, 1,1-dimethylethylimino and the like. The expression Ci-C6-alkoxyimino-Ci-C4-alkyl refers to an alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent Ci-Ce-alkoxyimino radical (Ci-C6-alkyl-ON=) as defined above. The expression C2-C6-alkenyloxyimino-C1-C4-alkyl refers to an alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C2-C6-alkenyloxyimino radical (C2-C6-alkenyl-ON=). The expression C2-C6-alkynyloxyimino-C1-C4-alkyl refers to an alkyl having 1 to 4 carbon atoms, wherein two hydrogen atoms of one carbon atom of the alkyl radical are replaced by a divalent C2-C6-alkynyloxyimino radical (C2-C6-alkynylO-N=). The expression hydroxyCi-C4-alkyl refers to an alkyl having 1 to 4 carbon atoms, where one hydrogen atom of the alkyl radical is replaced by an OH group. The expression aminoCi-C4-alkyl refers to an alkyl having 1 to 4 carbon atoms, where one hydrogen atom of the alkyl radical is replaced by an NH2 group. The expression Ci-Ce-alkylamino refers to an amino group substituted with a residue selected independently of the group defined by the expression Ci-Ce-alkyl. Similarly, the expression diCi-Ce-alkylamino refers to an amino group substituted with two residues selected independently of the group defined by the expression Ci-Ce-alkyl. The expression Ci-C4-alkylamino-Ci-C4-alkyl refers to an alkyl group having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a Ci-C4-alkyl-NH- group attached through the nitrogen. Similarly, the expression dCi-C4-alkylamino-Ci-C4-alkyl refers to an alkyl group having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a (Ci-C4-alkyl)2N- group attached through the nitrogen. The expression aminocarbonyl-Ci-C4-alkyl refers to an alkyl having 1 to 4 carbon atoms, wherein one hydrogen atom of the alkyl radical is replaced by a -(C=O)-NH2 group. The expression Cs-Cn-cycloalkyl refers to a saturated univalent hydrocarbon radical monocyclic, bicyclic or tricyclic having 3 to 11 members of the carbon ring that is connected by the substitution of a hydrogen atom to one of the carbon atoms of the ring, 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). The expressions -C(=0)-Ci-C6-alkyl, -C(=0)-0-Ci-C6-alkyl and -C(=O)-C3-Cn-cycloalkyl refer to aliphatic radicals that are attached by a carbon atom of the -C(=O)- group. The term aliphatic refers to compounds or radicals composed of carbon and hydrogen that are non-aromatic. An alicyclic compound or radical is an organic compound that is both aliphatic and cyclic. They contain one or more single-carbon rings that can be saturated or unsaturated, but lack aromatic character. The expressions cyclic portion or cyclic group refer to a radical that is an alicyclic ring or an aromatic ring, such as, for example, phenyl or heteroaryl. The expression where any of the aliphatic or cyclic groups are either unsubstituted or substituted with... refers to aliphatic groups, cyclic groups, and groups containing both an aliphatic and a cyclic portion in one group, such as, for example, in C3-C8-cycloalkyl-C4-alkyl; therefore, in a group containing both an aliphatic and a cyclic portion, both portions may be substituted or unsubstituted independently of each other. The term phenyl refers to an aromatic ring system that includes six carbon atoms (usually called a benzene ring). The term heteroaryl refers to monocyclic or polycyclic aromatic ring systems that include, in addition to carbon atoms, 1, 2, 3 or 4 heteroatoms selected independently from the group consisting of N, O and S. The expression "3- to 7-membered saturated carbocycle" should be understood as monocyclic saturated carbocycles having 3, 4, or 5 carbon ring members. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The expression “saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocycle of 3 to 10 members, wherein the ring member atoms of said mono- or bicyclic heterocycle include in addition to carbon atoms another 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms” should be understood as mono- and bicyclic aromatic heteroaromatic ring systems, as well as saturated and partially unsaturated heterocycles, for example: a saturated heterocycle of 3 or 4 members containing 1 or 2 heteroatoms of the group consisting of N, O and S as ring members such as oxirane, aziridine, thirane, oxethane, azetidine, thiethane, [1,2]dioxethane, [1,2]dthiethane, [1,2]diazetidine; and a saturated or partially unsaturated 5- or 6-membered heterocycle containing 1, 2, or 3 heteroatoms of 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-oxadiazolidin-3-yl, 1,2,4oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-Soxazolin-4-yl, 4-soxazolin-4-yl, 2-soxazolin-5yl, 3-soxazolin-5-yl, 4-soxazolin-5-yl, 2-isothiazol in-3-yl, 3-isothiazol in-3-yl, 4-isothiazolin-3-yl, 2isothiazolin-4-yl, 3-sothiazolin-4-lo, 4-sothiazolin-4-lo, 2-sothiazolin-5-yl, 3-isothiazolin-5-yl, 4-sothiazolin-5ρηαΑηηη / ζζηζ / Ε / γίΛΐ ilo, 2,3-dihydrop¡razol-1 -yl, 2,3-dihydrop¡razol-2-¡lo, 2,3-dihydrop¡razol-3-¡lo, 2,3-dihydrop¡razol-4-¡lo, 2,3 dihydrop¡razol-5-yl, i dihydropyrazol-5-yl, dihydropyrazol-5-yl, 2,3-dihydroxazol-5-yl, 3,4-d¡ h hydropyrazol-1 -yl, 4,5-d¡drop¡razol-1 -yl, 2,3-dihydroxazol-2-¡lo, , 3,4-dihydroxazol-2-¡lo, 3,4-dihydrop¡razol-3-yl, 4,5-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-¡lo, 3,44,5-dihydropyrazol-4-¡lo, 4,52,3-dihydroxazol-3-¡lo, 2,3-dihydrooxazol-4-10, 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-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydropyrimidinyl, 3hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydrotriazín-2-yl and 1,2,4-hexahydrotriazin-3-yl and also the corresponding —ylidene radicals;and a saturated or partially unsaturated 7-membered heterocycle such as tetra- 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, tetra- and hexahydrooxepinyl such as 2,3,4,5-tetrahydro[1 H]oxepin-2-,-3-,-4-,-5-,-6- or -7-yl, 2,3,4,7-tetrahydro[1 H]oxepin-2-,-3-,-4-,-5-,-6- or -7-yl, 2,3,6,7-tetrahydro[1 H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, hexahydroazepin-1-, -2-, -3- or -4-yl, tetra- and hexahydro-1,3-diazepinyl, tetra- and hexahydro-1,4-diazepinyl, tetra- and hexahydro-1,3-oxazepinyl, tetra- and hexahydro-1,4-oxazepinyl, tetra- and hexahydro-1,3-dioxepinyl, tetra- and hexahydro-1,4-dioxepinyl and the corresponding -ylidene radicals.; The expression “5- or 6-membered heteroaryl” or “5- or 6-membered aromatic heterocycle” refers to aromatic ring systems that include, in addition to carbon atoms, 1, 2, 3, or 4 heteroatoms selected independently from the group consisting of N, O, and S, for example, a 5-membered heteroaryl, such as pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, thien-2-yl, thien-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, thiazol2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-triazolyl-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; a 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-triazin3-ílo. Work examples The present invention is further illustrated by the following working examples. Analytical Method 1: HPLC Agilent 1100 series; column: Agilent Zorbax Phenyl-Hexyl 1.8 pm 50*4.6 mm, column flow: 1 mL / min, time: 25 min, pressure: 20000 kPa; temperature: 20°C; wavelength 200 nm; injector volume: 2 µL; retention time of the respective products as a function of the reference material. Eluent: A: Water with 0.1% by volume H3PO4; B: Acetonitrile ρηαΑηη / ζζηζ / Ε / γίΛΐ Time (min) % B Speed ​​(mL / min) 0.0 14 1.0 16.0 86 1.0 20.0 86 1.0 20.1 14 1.0 Analytical Method 2: HPLC Agilent 1100 series; column: Agilent Zorbax Eclipse XDB-C18 1.8 pm 50*4.6 mm von Agilent, column flow: 1.3 mL / min, time: 10 min, pressure: 23000 kPa; temperature: 20°C; wavelength 195 nm; injector volume: 1 uL; retention time of the respective products based on the reference material and provided below. Eluent: A: Water with 0.1% by volume H3PO4; B: Acetonitrile Time (min) % B Rate (mL / min) 0.0 0 1.3 2.0 0 1.3 5.0 80 1.3 6.0 100 1.3 8.0 100 1.3 8.1 0 1.3 Example 1) Preparation of 3-(p-tolyl)-5-(tnfluoromethyl)-1,2,4-oxadiazole A vessel was charged at 22°C with 40.0 g (256 mmol, 96.0% purity) of β-hydroxy-4-methylbenzamidine and 181 g (1.28 mol) of ethyl trifluoroacetate. 27.6 g of sodium methanolate (151 mmol, 30% w / w in methanol) was added within 30 minutes, and the reaction mixture was stirred for 1.5 hours at 30°C. Then, another portion of 13.8 g of sodium methanolate (75.5 mmol, 30% w / w in methanol) was added within 10 minutes, and the mixture was stirred for an additional 40 minutes. A final portion of 13.8 g of sodium methanolate (75.5 mmol, 30% w / w in methanol) was added within 10 minutes, and the mixture was stirred for an additional 30 minutes. 2.3 g of hydrochloric acid (32% w / w) was added, and all volatiles were removed under reduced pressure. Water (60 g) was added, and the phases separated. 57.4 g (94.8%, HPLC purity (Method 1): 96.37°) of the title compound was isolated from the organic phase. Example 2) Preparation of N-(2-fluorophenyl)-4-[5-(tr¡fluoromet¡l)-1,2,4-oxadiazol-3-l]benzam¡de enaAnn / zznz / E / YiAi Example 2.1) TFAE as reagent: A flask was charged with 500 mg (1.83 mmol) of A / -(2-fluorophenyl)-4-[(Z)-A / hydroxycarbamimidoylbenzamide] and 5 mL of A / -M-dimethylformamide at room temperature. To this reaction mass, 416 mg (2.93 mmol) of ethyl trifluoroacetate was added at room temperature, followed by the dropwise addition of 527 mg of sodium methanolate (2.93 mmol, 307 g / w in methanol). A mild exothermic reaction was observed during this addition, and the reaction mass turned reddish-brown. The reaction mass was stirred at room temperature for an additional 1 h. HPLC analysis confirmed complete conversion. Water was then added to the reaction mass, causing the product to precipitate. The product was filtered and the filter cake was washed with water to remove A / ,A / -dimethylformamid, followed by drying to obtain 0.53 g (84.67°, HPLC purity (method 1): 97.27°) of the title compound. Example 2.2) TFAE as a solvent: A vessel was charged at 20°C with 18.9 g (67.4 mmol, 97.57% purity) of A / -(2-fluorophenyl)-4[(Z)-A / -hydroxycarbamimidoyl]benzamide and 200 g (1.39 mol, 997% purity) of ethyl trifluoroacetate. 13.4 g of sodium methanolate (74.4 mmol, 307% w / w in methanol) was added within 3 minutes, and the reaction was stirred for 16 hours. All volatiles were then removed under reduced pressure, methanol (100 mL) and water (20 mL) were added, and the solids were collected by filtration. The filter cake was washed with water (2 x 20 mL) and dried. Dry weight of isolated titer product: 20.4 g (83.47º), HPLC purity (method 1): 96.87º Example 2.3) TFAE as a solvent: A vessel was charged at 20°C with 18.9 g (67.6 mmol, 97.87% purity) of M-(2-fluorophenyl)-4[(Z)-A / '-hydroxycarbamimidoyl]benzamide and 200 g (1.39 mol, 997% purity) of ethyl trifluoroacetate. 18.3 g of sodium methanol (100 mmol, 307% w / w in methanol) was added within 5 minutes, and the reaction mixture was stirred for 3 hours, after which an additional portion of sodium methanol (6.1 g, 33.3 mmol) was added. 200 mL of propanol was added, the mixture was heated to 70°C, and some of the volatiles were removed. The resulting mixture was cooled to room temperature and stirred for 16 hours before adding water (200 mL), which caused the product to precipitate. The titrant product was collected by filtration. The filter cake was washed with water (2 x 50 mL) and dried. Dry weight of isolated titrant product: 20.4 g (93.47°), HPLC purity (method 1): 98.17°. Example 2.4) TFAE as a reagent: A flask was charged with A / -(2-fluorophenyl)-4(Z)-A / -hydroxycarbamimidoylbenzamide (5 g, 1 equivalent), ethanol (60 mL), and ethyl trifluoroacetate (6.5 g, 2.5 equivalents) at room temperature under a nitrogen atmosphere. Sodium ethanolate (21% w / w in ethanol, 8.3 mL, 1.4 equivalents) was added to this reaction mixture for 13 minutes at room temperature, and then the reaction mixture was stirred for 60 minutes at room temperature. After the reaction was complete, water (100 mL) was added, and the resulting mixture was stirred for 30 minutes at room temperature, causing the product to precipitate. The titrant product was collected by filtration. The filter cake was washed with water (50 mL) and vacuum dried, which produced the title product as a colorless solid in 98% (HPLC purity (method 1): 99.9%). Example 2.5) TFAE as a reagent: A flask was charged with A / -(2-fluorophenyl)-4-[(Z)-A / -hydroxycarbamimidoyl]benzamide (5 g, 1 equivalent) and toluene (100 mL) at room temperature in a nitrogen atmosphere before adding sodium ethanolate (21% in ethanol, 11.9 mL, 2.0 equivalents). Ethyl trifluoroacetate (5.2 g, 2.0 equivalents) was added, and the resulting mixture was stirred for 3 hours at room temperature. After the reaction was complete, toluene was removed under reduced pressure, water (100 mL) was added, and the resulting mixture was stirred for 30 minutes at room temperature. The solids were collected by filtration and washed with water (50 mL). Vacuum drying yielded the title product as a colorless solid with a purity of 96.9% (HPLC purity (Method 1): 99.4%). Example 2.6) TFAE as a reagent: A flask was charged with A / -(2-fluorophenyl)-4-[(Z)- / / -hydroxycarbamimidoyl]benzamide (27.5 g, 1 equivalent) and ethanol (224 g) in a nitrogen atmosphere. Sodium ethanolate (21% w / w in ethanol, 41 g, 1.30 equivalents) was added over a period of 10 minutes at room temperature, and the resulting mixture was heated to 51 °C. After 15 minutes at 51 °C, ethyl trifluoroacetate (99%, 35 g, 2.5 equivalents) was added over a period of 35 minutes, and the reaction temperature was maintained at 51 °C for 5 hours. Water (400 g) was then added over a period of 2 hours. The mixture was slowly cooled to room temperature and then further cooled to 10 °C. The solids were collected by filtration and washed with water (2 x 100 mL). Vacuum drying yielded the desired product as a colorless solid with a purity of 96.5% (HPLC purity (method 1): 98.6%). Example 2.7) TFAE as a reagent: A flask was charged with A / -(2-fluorophenyl)-4-[(Z)-A / -hydroxycarbamimidoyl]benzamide (33.2 g, 98.8% purity, 1 equivalent). A mixture of methanol (76.8 g) and ethyl trifluoroacetate (37.5 g, 100% purity, 2.2 equivalents) was added under a nitrogen atmosphere. The reaction mixture was cooled to below 20°C, and sodium methanol (30% w / w in methanol, 25.9 g, 1.20 equivalents) was added over a period of 8 minutes at a temperature below 25°C. The resulting mixture was stirred at 25°C for 5 hours. Demineralized water (48 g) was then added at 25°C with stirring. Suspended solids were collected by filtration. Vacuum drying yielded the desired product as a colorless solid at 96.2% (HPLC purity (method 1): 93.4%). Example 3) Preparation of 3-[4-(trichloromethyl)phen¡l]-5-(trifluoromethyl)-1,2,4-oxadiazole ρηαΑηη / ζζηζ / Ε / γίΛΐ 300 g (1.31 mol) of 3-(p-tol)-5-(trifluoromethyl)-1,2,4-oxadiazole were placed in a 500 mL quartz glass round-bottom flask. 427 g of chlorine (6.0 mol) were added to the reactor, heated to 125°C, and irradiated with a 150-watt Heraeus TQ UV lamp (mercury medium pressure emitter) for 8 hours. After the reaction was complete, the reaction mass was extracted with nitrogen to remove the remaining chlorine and hydrogen chloride gas. GC analysis showed 98.7% product. Yield: 437 g crystalline product; 99%; melting point: 75–78°C; 1HNMR (CDCI3): 8.1 ppm (m, 2H, 2xCH). 8.3 ppm (m, 2H, 2xCH). Example 4) Preparation of A / -(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide 150 g (0.446 mol) of solid 3-[4-(trichloromethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole and 3.75 g (0.023 mol) of iron(III) chloride were poured into a 0.75 L reactor equipped with an overhead stirrer, reflux condenser, and waste gas scrubber. The reactor was heated to 120°C, and 7.6 g (0.422 mol) of water was added to the reaction mixture within 3 hours, followed by stirring for another 30 minutes. The reaction mixture was then cooled to 25°C, and 300 g (4.156 mol) of tetrahydrofuran was added, and the reaction mixture was cooled to 10°C. Next, a solution of 56 g of 2-fluoroaniline (0.489 mol), 50 g of triethylamine (0.489 mol), and 200 g of tetrahydrofuran (2.771 mol) was added over approximately 40 minutes, while the temperature of the reaction mixture was maintained between 10°C and 25°C and the lines were cleaned with 100 g (1.4 mol) of tetrahydrofuran. After stirring overnight, the mixture was cooled to 5°C and 450 mL of water were added.The solid was filtered and washed twice with 100 g of cold water. A solid material was obtained, which was dried (80°C, 2 kPa) to yield 130 g (0.363 mol) of the titer product. HPLC analysis (method 2) showed >98% product. Example 5) Preparation of A / -methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Five g (0.015 mol) of solid 3-[4-(trichloromethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole and 0.12 g (0.74 mol) of iron(III) chloride were placed in a 0.75 L reactor equipped with an overhead stirrer, reflux condenser, and waste gas scrubber. The reactor was heated to 85°C, and 0.26 g (0.014 mol) of water was added to the reaction mixture within 1 hour, followed by stirring for another 40 minutes. The temperature was then cooled to 25°C, and 14.6 g (0.222 mol) of tetrahydrofuran was added, and the reaction mixture was cooled to 0°C. Then, 27 mL (5 M, 0.074 mmol) of a methylamine in tetrahydrofuran solution was added and stirred overnight at room temperature. Water and ethyl acetate were added, and the phases separated. The organic phase was washed with water and dried on magnesium sulfate / activated carbon. Filtration and removal of volatiles yielded 2.9 g (HPLC analysis (method 2): 88% ar%, 0.091 mol, retention time = 0.93 min, M+ = 271) / V-methyl-4-[5(trifluoromethyl)-l ,2,4-oxadiazol-3-¡l]benzamide. Example 6) Preparation of A / -methl-4-[5-(thfluoromethl)-1,2,4-oxad¡azol-3-l]benzenocarboam¡oam¡da 15 g (54.8 mmol) of α-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide and 3.8 g (16.9 mmol) of phosphorus(V) sulfide were dissolved in 87 g of toluene and heated to 112°C for 1 hour. The reaction mixture was treated at less than 100°C with 100 g of water and 100 g of toluene. After phase separation at 75°C, the organic phase was separated and washed with 100 g of water. The volatiles were removed under vacuum (80°C, 200 to 5 mbar) to obtain 15.8 g of crude product, which was suspended in 50 mL of diisopropyl ether and heated to 60°C for 1 hour. After cooling to room temperature, the precipitate was filtered and washed with 20 mL of diisopropyl ether. After drying at 80°C and reduced pressure, 13.5 g (44.2 mmol, HPLC analysis (method 2): 94%) of A / -methyl-4-[5(trifluoromethi)-l,2,4-oxadiazol-3-yl]benzenecarbohydrateamide were obtained. 1H-NMR (δ / ppm, CDCL, 400 MHz): 3.4 ppm, s, 3H; 7.8, s, br 1H; 7.9, d, 2H; 8.1, d, 2 H)

Claims

1. A process for preparing oxadiazole compounds of Formula I, wherein A is phenyl or a 5- or 6-membered aromatic heterocycle; wherein the ring-membered atoms of the aromatic heterocycle include, in addition to carbon atoms, 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring-membered atoms, provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein A is further unsubstituted or further substituted with n additional identical or different RA radicals; wherein n is 0, 1, 2, 3, or 4; RA is selected independently from the group consisting of halogen, cyano, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy and Ci-Ce-haloalkoxy;R is methyl, chloromethyl, hydroxymethyl, trichloromethyl, ethyl, / so-propyl, OH, SH, cyano, halogen, CH2F, CHF2, 2,2,2-trifluoroethyl, cyclopropyl, -C(=O)H, -C(=NOR2)H, -C(=O)OH, -C(=O)OR1, -C(=W)NR1R2, -CR3R4NR1R2, -CR3R4OR1, -CR3(=NR(), -CR3(=O), CR3R4C(=O)OH, -CR3R4C(=O)R1, -CR3R4C(=W)NR1R2, -OCR3R4C(=O)OH, OCR3R4C(=O)R1, -OCR3R4C(=W)NR1R2, -CR3R4-N(R2)-C(=W)R1, -CR3R4S(=O)2R1 or -CR3R4-N(R2)-S(=O)2R1; wherein W is O or S; R2 is hydrogen, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Ce-alkoxy, C3-Cn-cycloalkyl, -C(=O)-Ci-C6-alkyl, -C(=O)-C3-Cn-cycloalkyl or -C(=O)-O-Ci-Cealkyl; and wherein any of the aliphatic or cyclic groups at R2 are unsubstituted or are substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, Ci-Ce-alkyl, Ci-Ce-alkoxy and Cs-Cn-cycloalkyl;R1 is Ci-Ce-alkyl, Ci-Ce-alkoxy, Cs-Cn-cycloalkyl, Cs-Cs-cycloalkenyl, C2-C6-alkenyl, C2-Ce-alkynyl, Ci-Ce-alkoxyimino-Ci-C4-alkyl, C2-C6-alkenyloxymino-Ci-C4-alkyl, C2-Ce-alkylox¡m¡no-Ci-C4-alkyl, Ci-Ce-alkylamino, diCi-Ce-alkylamino, -C(=O)Ci-Ce-alkyl, -C(=O)-O-Ci-Ce-alkyl, phenyl-Ci-C4-alkyl, phenyl-Ci-C4-alkenyl, phenylCi-C4-alkynyl, heteroaryl-Ci-C4-alkyl, phenyl, naphthyl or a 3 to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle include, in addition to carbon atoms, 1, 2, 3 or 4 other heteroatoms selected from N, O and S as ring member atoms, provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S;and wherein the heteroaryl group in the heteroaryl-Ci-C4alkyl group is a 5- or 6-membered aromatic heterocycle, wherein the ring-membered atoms include, in addition to carbon atoms, 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring-membered atoms, provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein any of the above-mentioned cyclic or aliphatic groups are either unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different R1a groups;or R1 and R2, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated mono- or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle includes, in addition to a nitrogen atom and one or more carbon atoms, no additional heteroatoms or 1, 2 or 3 additional heteroatoms independently selected from N, O and S as ring-member atoms, provided that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is either unsubstituted or substituted with 1, 2, 3, 4 or up to the maximum possible number of identical or different R1a groups;where R1a is halogen, oxo, cyano, NO2, OH, SH, NH2, Ci-Ce-alkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Ci-Ce-alkylthio, Ci-Ce-haloalkylthio, Cs-Cs-cycloalkyl, -NHSO2-C4-alkyl, -C(=O)-C4-alkyl, -C(=O)-O-C4-alkyl, C1-Ce-alkylsulfonyl, hydroxyC4-alkyl, -C(=O)-NH2, -C(=O)-NH(C4-alkyl), C1-C4-alkylthio-C4-alkyl, aminoC4-alkyl, Ci-C4-alkylamino-C4-alkyl, dCi-C4-alkylamino-Ci-C4-alkyl, aminocarbonyl-Ci-C4-alkyl or Ci-C4-alkoxy-Ci-C4-alkyl; R3, R4, independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, Ci-C4-alkyl, Ci-C4-alkenyl, Ci-C4-alkynyl, Ci-C4-haloalkyl and Ci-C4-alkoxy; or R3 and R4 together with the carbon atom to which they are attached form a cyclopropyl group;whose process comprises reacting an amidoxime of Formula II, H2N HO.N^ II, wherein the variables A and R are as defined above for compounds of Formula I, with a haloacetic ester of Formula II.a, enaAnn / zznz / E / YiAi, wherein R5 is Ci-Ce-alkyl, in the presence of a solvent and a base; whereas the process is characterized in that the base comprises a metal alkoxylate of Formula IV, [Ci-C6-alkylO]x Mx+ IV, wherein the metal M is an alkali metal, wherein x is 1, or M is an alkaline earth metal, wherein x is 2; and the solvent comprises an alkyl alcohol of Formula III, or mixtures thereof, Ci-Ce-alkyl-OH III.

2. The process according to claim 1, wherein the metal M in the metal IV alkoxylates is sodium, potassium, or magnesium.

3. The process according to claim 1 or 2, wherein the alkoxylate base of Formula IV is sodium methoxide or sodium ethoxide, or a mixture thereof.

4. The process according to any of claims 1 to 3, wherein the solvent comprises methanol or ethanol, or mixtures thereof.

5. The process according to any of claims 1 to 4, wherein the solvent contains at least 1% by volume of the alkyl alcohol of Formula III, or mixtures thereof, depending on the total amount of solvents, while the additional solvents include auxiliary solvents or the haloacetic ester of Formula II.a, or mixtures thereof.

6. The process according to any of claims 1 to 5, wherein the alkoxylate base of Formula IV is the corresponding conjugate Bronsted base of the solvent of Formula III.

7. The process according to any of claims 1 to 6, wherein the process is carried out at a temperature in the range of 0°C to 60°C.

8. The process according to any of claims 1 to 7, wherein the R5 radical in haloacetic esters of Formula II.a is methyl or ethyl.

9. The process according to any of claims 1 to 8, wherein the amount of the haloacetic ester of Formula II.a is between 1 and 5 equivalents depending on the amount of amidoxime II.

10. The process according to any one of claims 1 to 9, wherein the amidoxime compound is of Formula II.b, wherein n is 0 or 1, and the meaning of RA and R is as defined in claim 1 for compounds of Formula I for obtaining oxadiazoles of Formula II.b, wherein the variables n, RA and R have the meaning as defined for compounds II.b.

11. The process according to claim 10, wherein the variables have the following meaning: RA is fluorine; n is 0 or 1; R is methyl, -C(=O)OH, -C(=O)NR1R2, -CH2-N(R2)-C(=O)R1, -CH2-N(R2)-S(=O)2R1, R1 is cycloalkyl, phenyl or cyclopropyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2, 3 or 4 identical or different halogen groups; R2 is hydrogen, methyl, ethyl, methoxy, ethoxy or cyclopropyl.

12. The process according to claim 10, wherein the variables have the following meaning: n is 0; R is-C(=O)NR1R2; R1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl; in particular methyl or 2-fluorophenyl; R2 is hydrogen.

13. The process according to claim 12, further comprising the step of reacting a compound of Formula Va, wherein the variables R1 and R2 are as defined for the compound of Formula II.b, to obtain the compound of Formula II.b. Va 14. The process according to claim 10, wherein n is 0 and R is methyl in compounds of Formula lb and II.b, and further comprising the step of reacting the compound of Formula lb to obtain the compound of Formula lc 15. The process according to claim 10, wherein n is 0 and R is -C(=O)OH in compounds of Formula lb and II.b, and further comprising the step of reacting the compound of Formula lb to obtain the compound of Formula III.a.

16. The process according to claim 14, further comprising the step of reacting the compound of Formula 1c to obtain the compound of Formula III.a. 3 > your NCNNCC <c σ c (a 17. The process according to claim 15 or 16, further comprising the step of reacting the compound of Formula III.a with a compound of Formula IV R1-NH-R2 IV, wherein R1 and R2 in the compound of Formula IV are defined as the compounds of Formula I in any of the preceding claims to obtain a compound of Formula V.

18. The process according to claim 17, further comprising the step of reacting the compound of Formula V to obtain a compound of Formula VI.

19. The process according to claim 17 or 18, wherein in compounds of Formulas IV, V and VI R1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl; in particular methyl or 2-fluorophenyl; and R2 is hydrogen.