Process for the preparation of microbicidal oxadiazole derivatives

Abstract

The present invention provides, inter alia, a process for the preparation of substituted oxadiazole derivatives of formula (I), which can be obtained by reacting an amidoxime of formula (II) in the presence of an organic guanidine base, wherein the substituents are as defined in the claims. The present invention further provides intermediate compounds used in said process and processes for the production of said intermediate compounds.

Description

[0001] The present invention relates to a method for preparing substituted oxadiazole derivatives having formula (I), which can be obtained by reacting a methylamine oxime having formula (II) in the presence of an organic guanidine base.

[0002] (I) (II)

[0003] The substituted oxadiazole derivatives are versatile intermediates that can be converted into substituted 3-aryl-5-trifluoro-1,2,4-oxadiazoles, which are known, for example, from the following patents for the control of plant pathogenic fungi: WO 2015 / 185485, WO2017 / 055473 A1, WO 2017 / 211649, WO 2017 / 178245, WO 2018 / 177894, WO 2019 / 022061, WO2021 / 100745, WO 2022 / 207494, WO 2022 / 239725.

[0004] Methods for preparing oxadiazole compounds have been disclosed in, for example, WO 2017 / 055473, WO 2018 / 177894, WO 2019 / 020501, WO 2019 / 020451, and WO 2020 / 212513.

[0005] WO 2019 / 020501 and WO 2019 / 020451 describe the formation of 1,2,4-oxadiazole derivatives by reacting a metallo-oxime with a trifluoroacetic acid halide in the presence of an organic solvent or in bulk. All synthetic examples disclose the use of at least two equivalents of trifluoroacetic acid halide, which results in the formation of at least one equivalent of free trifluoroacetic acid (TFA) as a byproduct, along with hydrogen halides. This requires specialized reaction equipment to avoid corrosion.

[0006] WO 2020 / 212513 describes the formation of 1,2,4-oxadiazole derivatives by reacting a metal oxime with trifluoroacetate in the presence of a metal alkoxylate. Metal alkoxylates are non-recyclable bases, further limiting the solvents that can be used for this conversion.

[0007] WO 2021 / 156174 describes the formation of 1,2,4-oxadiazole derivatives by reacting a metallo-oxime with trifluoroacetate in the presence of a base. All synthetic examples disclose the use of at least two equivalents of trifluoroacetate based on the amount of metallo-oxime in the presence of sodium methoxide as a base. Sodium methoxide is a non-recyclable base and further limits the solvents that can be used for this conversion.

[0008] WO 2021 / 156175 describes the formation of 1,2,4-oxadiazole derivatives by reacting a metallo-oxime with a trifluoroacetate in the presence of a base, such as a metal alkoxylate. All synthetic examples disclose the use of a trifluoroacetate in an amount of 5 equivalents based on the metallo-oxime in the presence of sodium methoxide as a base. Sodium methoxide is a non-recyclable base, further limiting the solvents that can be used for this conversion.

[0009] Besides using metal alkoxylates as non-recyclable bases, the use of such metal alkoxylates or sodium methoxide as bases limits the solvents that can be used for this conversion, thus limiting the versatility and industrial effectiveness of the conversion.

[0010] Trifluoroacetates are known to be less reactive than trifluoroacetic acid halides or trifluoroacetic anhydrides (TFAA), and therefore the presence of a base and the use of an excess of acylation agent are required to achieve high yields of the desired product.

[0011] Therefore, there is a need for an economical, industrially viable, large-scale production method for 3-aryl-1,2,4-oxadiazole derivatives that overcomes the shortcomings of existing technologies and enables the production of 1,2,4-oxadiazole derivatives with low waste products.

[0012] This invention provides an industrially large-scale, environmentally friendly, and cost-effective production method using readily available, non-toxic, recyclable, and inexpensive reagents. The reaction process can be carried out with a low excess of acylation reagents based on a methylamine oxime starting material, resulting in less waste products. Furthermore, rapid conversion of the desired 3-aryl-1,2,4-oxadiazole derivative in high yields is achieved at moderate reaction temperatures. Moreover, the organic solvents that can be used in the method of this invention are not limited due to the nature of the base used.

[0013] According to a first aspect of the present invention, a method for preparing a compound having formula (I) is provided.

[0014] (I)

[0015] in

[0016] R 1 Selected from hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R) 3 R 4 -CH2-C(=W)N(R) 3 R 4 -CH2-N(R) 3 )-C(=W)R4 ,

[0017]

[0018] The interlacing lines indicate connections to the phenyl group;

[0019] R 2 Selected from C1-C2-haloalkyl groups;

[0020] R 3 Selected from hydrogen, C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or cyclopropyl;

[0021] R 4 The group is selected from C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, C3-C6-cycloalkyl, C1-C2-alkoxy-C1-C3-alkyl, or phenyl, wherein the phenyl group is unsubstituted or substituted by one or two substituents independently selected from halogens;

[0022] R 5 Selected from hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy, or C1-C4-alkoxy-C1-C2-alkoxy; and

[0023] W is selected from O or S;

[0024] The method includes reacting a methylamine oxime compound having formula (II) with a methylamine oxime compound.

[0025] (II),

[0026] Where R 1 R 3 R 4 and R 5 As defined for compounds having formula (I), and haloacetic esters having formula (III)

[0027] (III),

[0028] Where R 2 As defined for compounds having formula (I), and R 6 Selected from C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogens or C1-C4-alkyl; the reaction is carried out in the presence of at least one base, wherein the method is characterized by the at least one base being selected from guanidine bases.

[0029] Surprisingly, it has now been found that the method of the present invention advantageously provides a method for preparing compounds having formula (I) with high separation yield.

[0030] Furthermore, it has been unexpectedly discovered that the method of the present invention can be carried out with a low excess of acylation reagent based on a methylamine oxime starting material, resulting in less waste product. In addition, rapid conversion of the desired 3-aryl-1,2,4-oxadiazole derivative in high yield has been achieved at moderate reaction temperatures. Moreover, for the method of the present invention, the organic solvents that can be used are unrestricted due to the nature of the base used, and the base is non-toxic and recyclable, thus providing an environmentally friendly and cost-effective method for large-scale industrial production.

[0031] As used herein, the term "halogen" or "halogenated" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo), preferably fluorine, chlorine, or bromine. Accordingly, this also applies to halogens combined with other meanings, such as halogenated alkyl and halogenated alkoxy groups.

[0032] As used in this article, thiol refers to the -SH group.

[0033] As used in this article, cyano refers to the -CN group.

[0034] As used herein, the term "hydroxyl" or "hydroxyl" refers to the -OH group.

[0035] As used in this article, the term "carboxylic acid" refers to the -COOH group.

[0036] As used in this article, the term "C1-C" n "-alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to n carbon atoms attached via any one of the carbon atoms, such as any one of the following groups: methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0037] As used in this article, the term "C2-C" n"-Alkenyl" refers to a straight-chain or branched alkenyl chain portion having two to n carbon atoms and one or two double bonds, such as vinyl, prop-1-alkenyl, and but-2-alkenyl.

[0038] As used in this article, the term "C3-C" n "-cycloalkyl" refers to tri(3) to n-membered cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0039] As used in this article, the term "C1-C" n "-alkoxy" refers to a straight-chain or branched saturated alkyl group (as mentioned above) having one (1) to n carbon atoms attached via an oxygen atom, i.e., any one of the following groups: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy and 1,1-dimethylethoxy.

[0040] As used in this article, the term "C1-C" n -alkoxy C1-C n "-alkoxy" refers to a compound with the formula R a -OR b - groups, where R a It is as C1-C is generally defined above. n Alkyl, and R b It is as C1-C is generally defined above. n Alkyl group.

[0041] As used in this article, the term "C1-C" n "-Halogenated alkyl" refers to a straight-chain or branched saturated alkyl group (as mentioned above) having 1 to n carbon atoms attached via any one carbon atom, wherein some or all of the hydrogen atoms in these groups may be replaced by fluorine, chlorine, bromine and / or iodine, i.e., any one of the following: chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 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.

[0042] As used in this article, the term "C1-C" is used in this article. n "-Haloalkoxy" refers to a C1-C group that is substituted by one or more halogen atoms that may be the same or different. n -alkoxy group.

[0043] As used herein, the singular forms “a / an” and “the” are intended to also include the plural forms, unless the context clearly indicates otherwise.

[0044] As used herein, the term “control” refers to reducing the number of pests, eliminating pests, and / or preventing further pest damage, thereby reducing damage to plants or plant-derived products.

[0045] As used herein, the term "pest" refers to insects and mollusks present in the storage of agricultural, horticultural, forestry, and plant-derived products (such as fruits, grains, and timber); as well as pests associated with damage to man-made structures. The term "pest" encompasses all stages of the pest life cycle.

[0046] As used herein, the term "effective amount" refers to the amount of a compound or its salt that provides the desired effect when applied in a single or multiple doses.

[0047] The effective amount is readily determined by those skilled in the art using known techniques and by observing results obtained under similar conditions. In determining the effective amount, many factors are considered, including but not limited to, the type of plant or derivative to be applied; the pest to be controlled and its life cycle; the specific compound applied; the type of application; and other relevant circumstances.

[0048] As used herein, the terms “room temperature” or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15°C to about 35°C. For example, rt can refer to a temperature of about 20°C to about 30°C.

[0049] Compounds having formula (I) can be used in the agricultural sector and related application areas as, for example, multipurpose intermediates or as active ingredients for controlling plant pests, or on non-living materials for controlling putrefactive microorganisms or organisms that are potentially harmful to humans.

[0050] In one embodiment of the invention, compounds having formula (I) can be used as versatile intermediates for the preparation of 3-aryl-1,2,4-oxadiazole derivatives, which exhibit very favorable levels of bioactivity for protecting plants from fungal diseases, particularly plant pathogenic fungi, especially Phakopsorapachyrhizi, Corynespora cassiicola, or Diaporthe spp., such as Diaporthe miriciae, also known as Diaporthe ueckeri or Diaportheueckerae.

[0051] In another embodiment of the invention, for practical purposes, compounds having formula (I) have a very advantageous level of bioactivity for protecting plants from fungal diseases. Therefore, compounds having formula (I) are particularly suitable for use as fungicides. In one embodiment, compounds having formula (I) are suitable for controlling diseases caused by plant pathogenic fungi, particularly *Solanum spp.* (the pathogen of Asian soybean rust), and for a method of controlling diseases on useful plants, particularly soybeans. In another embodiment, compounds having formula (I) are suitable for controlling diseases caused by plant pathogenic fungi, particularly the plant pathogenic microorganism *Cyclocarya paliurus*, and for a method of controlling diseases on useful plants, such as soybeans or cotton.

[0052] In one embodiment of the invention, the compound having formula (I) is suitable for controlling rust fungi in genetically modified plants. Preferably, the genetically modified plant is a soybean plant. More preferably, the genetically modified soybean plant is a Bt soybean plant, and even more preferably a Bt soybean plant selected from Intacta RR2 PRO® or Conkesta Enlist E3®.

[0053] In another embodiment, the compound having formula (I) is suitable for controlling the plant pathogenic microorganism *Cyclophorus multipathiophora* in genetically modified plants (e.g., soybeans or cotton). Preferably, the genetically modified plant is a soybean plant. More preferably, the genetically modified soybean plant is a Bt soybean plant, and even more preferably a Bt soybean plant selected from Intacta RR2 PRO® or Conkesta Enlist E3®.

[0054] As used herein, the term "fungicide" refers to a compound that controls, alters, or prevents the growth of fungi. According to this particular aspect of the invention, this use may not include methods of treating a human or animal body by surgery or therapy.

[0055] In one embodiment of the present invention, in the method for preparing a compound having formula (I), the compound having formula (III) is a haloacetate having formula (II).

[0056] (III)

[0057] Where R 2 As defined for compounds having formula (I), and R 6 It is C1-C 12 -alkyl, vinyl, or benzyl.

[0058] Preferably, in compounds having formula (III), R2 It is trifluoromethyl or difluoromethyl; and R 6 It is a C1-C4-alkyl group.

[0059] Preferably, in compounds having formula (III), R 2 It is trifluoromethyl or difluoromethyl; and R 6 It is methyl, ethyl, or butyl.

[0060] Preferably, in compounds having formula (III), R 2 It is trifluoromethyl, and R 6 It is methyl, ethyl, or butyl.

[0061] Preferably, the compound having formula (III) is selected from methyl trifluoroacetate, ethyl trifluoroacetate or butyl trifluoroacetate.

[0062] In one embodiment of the invention, in the method according to the invention for preparing a compound having formula (I), the amount of haloacetate having formula (III) can be 1.0 to 3.0 equivalents, 1.0 to 2.0 equivalents, 1.0 to 1.5 equivalents, 1.0 to 1.25 equivalents, 1.0 to 1.1 equivalents, or 1.0 to 1.05 equivalents based on the number of moles (mol) of the amygdoxime compound having formula (II).

[0063] The molar ratio of a haloacetate having formula (III) to a amine oxime compound having formula (II) can be 3:1 to 1:1, or 2.5:1 to 1:1, or 2:1 to 1:1, or 1.5:1 to 1:1, or 1.25:1 to 1:1, or 1.1:1 to 1:1, or 1.05:1 to 1:1.

[0064] In one embodiment of the invention, in the method according to the invention for preparing a compound having formula (I), the method is carried out in the presence of at least one base, wherein the base is a guanidine base.

[0065] In one embodiment of the invention, in the method according to the invention for preparing a compound having formula (I), the guanidine base is different from a compound having formula (I), (II), (III) or an inert organic solvent as defined herein.

[0066] Guanidines have been known to chemists for over 150 years (Strecker, A. Liebigs Ann. Chem. [Liebig's Chronicle of Chemistry] 1861, 118, 151) and are primarily recognized as very strong organic bases ('superbases') (Ishikawa, T. In Superbases for Organic Synthesis; Ishikawa, T., ed.; John Wiley & Sons Ltd: Chichester, 2009, 93-143). Guanidine bases are available as reagents and catalysts in organic synthesis (I, P. Selig (ed.), Topics in Heterocycl. Chem. [Topics in Heterocycline Chemistry], Springer, 2017, Vol. 50). Guanidines act as very strong nucleophiles, and given their most interesting potential, it is quite surprising that the use of guanidines as nucleophiles in the methods of this invention has not been reported to date. The guanidine bases suitable for preparing compounds having formula (I) according to the present invention include, but are not limited to, 1,1,3,3-tetramethylguanidine (TMG), 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton base), 1,1,2,3-tetramethylguanidine, guanidine carbonate (diguanidine carbonate), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (mTBD or 7-methyl-TBD), 1,1,2,3-tetramethylguanidine, 2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole, 1,5,6,7-tetrahydroimidazo[1,2-a]pyrimidine, 1-formamidinyl-3-(o-tolyl)guanidine, and N-isopropylhexahydropyrimidine-2-imine, as shown in Table 1.

[0067] Table 1: Guanidines

[0068]

[0069] In one embodiment of the invention, a compound having formula (II) is prepared by reacting a compound having formula (III) with a compound having formula (III). The compound is prepared in the presence of at least one base, wherein the base is a guanidine base selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton's base), 1,1,2,3-tetramethylguanidine, guanidine carbonate (diguanidine carbonate), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (mTBD; 7-methyl-TBD), 2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole, 1,5,6,7-tetrahydroimidazo[1,2-a]pyrimidine, 1-formamidin-3-(o-tolyl)guanidine, or N-isopropylhexahydropyrimidine-2-imine, or combinations thereof.

[0070] Preferably, the method for preparing the compound having formula (I) according to Scheme 1 is carried out in the presence of 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, or guanidine carbonate. More preferably, the method for preparing the compound having formula (I) is carried out in the presence of 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0071] In a preferred embodiment of the invention, the preparation of the compound having formula (I) by reacting a compound having formula (II) with a compound having formula (III) is carried out in the presence of 1,1,3,3-tetramethylguanidine.

[0072] In another preferred embodiment of the invention, the preparation of the compound having formula (I) by reacting the compound having formula (II) with the compound having formula (III) is carried out in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).

[0073] In another preferred embodiment of the invention, the preparation of the compound having formula (I) by reacting a compound having formula (II) with a compound having formula (III) is carried out in the presence of 2-tert-butyl-1,1,3,3-tetramethylguanidine.

[0074] In another preferred embodiment of the invention, the preparation of the compound having formula (I) by reacting a compound having formula (II) with a compound having formula (III) is carried out in the presence of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0075] In one embodiment of the invention, in the method according to the invention for preparing a compound having formula (I), the amount of the guanidine base may be 0.05 to 3.0 equivalents, 0.1 to 2.5 equivalents, 0.1 to 2.0 equivalents, 0.1 to 1.5 equivalents, or 0.1 to 1.25 equivalents based on the number of moles (mol) of the amygdoxime compound having formula (II).

[0076] The molar ratio of the guanidine base to the amylopectin having formula (II) can be 3:1 to 0.1:1, or 1.25:1 to 0.2:1, preferably 1.25:1 to 0.2:1, or 1.25:1 to 0.25:1, or 0.02:1 to 0.2:1.

[0077] In one embodiment of the invention, the method for preparing a compound having formula (I) may be carried out in the presence of an additional base, wherein the additional base is selected from inorganic or organic bases, and wherein the additional base is not a guanidine base.

[0078] Examples of suitable second bases include inorganic and organic bases. Those skilled in the art will readily understand that the selection of a suitable additional base for the method of the present invention should be based on several factors, such as desired reaction conditions, compatibility with other reactants, and regulatory considerations.

[0079] Suitable examples of inorganic bases are, for example, but not limited to, alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal formates; alkali metal and alkaline earth metal acetates; alkali metal and alkaline earth metal carbonates; alkali metal and alkaline earth metal citrates; alkali metal and alkaline earth metal sulfates; and any combination thereof. Preferably, the inorganic base is selected from alkali metal carbonates or alkali metal acetates, or any combination thereof. Particularly preferred are sodium carbonate, potassium carbonate, or sodium acetate.

[0080] As used herein, the term "alkali metal" refers to an element in Group 1 of the periodic table, preferably lithium (Li), sodium (Na), or potassium (K).

[0081] Examples of suitable organic bases are, for example, but not limited to, tertiary amines, substituted or unsubstituted pyridines, bicyclic amines, alkali metal C1-C6 alkoxylates, and mixtures thereof. Preferably, the organic base is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 5-ethyl-2-methylpyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or mixtures thereof. Preferably, the organic base is selected from triethylamine.

[0082] In one embodiment of the invention, the method for preparing a compound having formula (I) can be carried out in the presence of an acid.

[0083] Examples of suitable acids are, for example, but not limited to, organic or inorganic acids.

[0084] Examples of suitable organic acids are, for example, but not limited to, acetic acid, citric acid, formic acid, benzoic acid, lactic acid, trifluoroacetic acid, propionic acid, and any combination thereof. Those skilled in the art will readily understand that the selection of a suitable acid for the method of the present invention should be based on several factors, such as desired reaction conditions, compatibility with other reactants, and regulatory considerations.

[0085] Examples of suitable inorganic acids are, for example, but not limited to, sulfuric acid, hydrochloric acid, phosphoric acid, and any combination thereof. Those skilled in the art will readily understand that the selection of a suitable acid for the method of the present invention should be based on several factors, such as desired reaction conditions, compatibility with other reactants, and regulatory considerations.

[0086] Preferably, the acid is selected from acetic acid, citric acid, or trifluoroacetic acid.

[0087] In one embodiment of the invention, a compound having formula (I) is prepared by reacting a compound having formula (II) with a compound having formula (III) in the presence of at least one base (wherein the base is a guanidine base), which can be carried out in the presence of an inert organic solvent or a mixture of such solvents.

[0088] As used herein, the term "inert organic solvent" means an organic solvent that does not react significantly with either the reactants or the products under the reaction conditions of the method of the present invention.

[0089] The organic solvents that can be used in the methods of the present invention are suitable for dissolving compounds having formula (II) and are miscible with the base used. Those skilled in the art will recognize that a variety of organic solvents exist that satisfy these specifications.

[0090] Examples of suitable organic solvents are, but are not limited to, polar protic solvents, polar aprotic solvents, or nonpolar solvents.

[0091] Examples of polar protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, tert-butanol, or 2-pentanol.

[0092] Examples of polar aprotic solvents include, but are not limited to, acetone, acetonitrile, dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethyl carbonate, N,N-dimethylformamide (DMF), methyl isobutyl ketone (MIBK), ethyl acetate, butyl acetate, propyl acetate, ethyl valerate, ethyl propionate, pyridine, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), or tetramethylene sulfone (sulfolane).

[0093] Examples of nonpolar solvents are, but are not limited to, hydrocarbon solvents, such as alkanes and aromatic solvents, such as pentane, hexane, methylcyclohexane, toluene, and xylene; and ether solvents, such as 1,4-dioxane, diethyl ether, or chloroform.

[0094] In one embodiment of the present invention, the organic solvent may be selected from 2-butanol, n-butanol, ethanol, isobutanol, 2-pentanol, dimethyl carbonate, toluene, benzonitrile, methyl isobutyl ketone, acetonitrile, 2-methyltetrahydrofuran, dioxolane, N-methylpyrrolidone, sulfolane, ethyl acetate, butyl acetate, propyl acetate, ethyl valerate, ethyl propionate, pentyl acetate, methylcyclohexane, diethoxymethane, or mixtures thereof.

[0095] The method of the present invention can be carried out at atmospheric pressure or under pressure or depressurization. Typically, atmospheric pressure and pressurization are used. In a preferred embodiment, the method of the present invention can be carried out at pressures typically ranging from 0.8 atm to 80 atm, preferably from 1.0 atm to 20 atm, and particularly from 1.0 to 7 atm.

[0096] The temperature used in the method of the present invention can vary widely and is preferably -30°C to 150°C, more preferably -10°C to 120°C, or even more preferably 0°C to 100°C, 20°C to 80°C, or 25°C to 75°C.

[0097] Typical reaction times range from 1 to 20 hours, preferably 1 to 15 hours, or more preferably 1 to 10 hours, or 1 to 5 hours.

[0098] The following list provides the substituents R of compounds having formula (I) according to the present invention. 1 R 2 R 3 R 4 R 5The definitions of W, including preferred definitions, are provided below. Any definition given below for any of these substituents may be combined with any definition of any other substituent given below or elsewhere in this document.

[0099] In one embodiment of the present invention, R 1 Selected from hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R) 3 R 4 -CH2-C(=W)N(R) 3 R 4 -CH2-N(R) 3 )-C(=W)R 4 ,

[0100]

[0101] The interlaced lines indicate connections to the phenyl group. Preferably, R 1 Selected from hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, -C(=O)N(R) 3 R 4 -CH2-C(=O)N(R) 3 R 4 -CH2-N(R) 3 )-C(=O)R 4 ,

[0102]

[0103] The interlaced lines indicate connections to the phenyl group.

[0104] In one embodiment of the present invention, R 1 Selected from hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl or -CH2-N(R) 3 )-C(=O)R 4 Preferably, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl or -C(=O)N(R) 3 R 4 ).

[0105] In one embodiment of the present invention, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl or -C(=O)N(R) 3 R 4 Preferably, R1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl or -C(=O)N(R) 3 R 4 ).

[0106] In one embodiment of the present invention, R 1 Selected from CH2-N(R) 3 )-C(=O)R 4 .

[0107] In one embodiment of the present invention, R 1 Selected from -C(=O)N(R) 3 R 4 ).

[0108] In one embodiment of the present invention, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, -CH2-C(=O)N(R) 3 R 4 ),

[0109]

[0110] The interlaced lines indicate connections to the phenyl group. Preferably, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -CH2-C(=O)N(R) 3 R 4 ),

[0111]

[0112] The interlaced lines indicate connections to the phenyl group.

[0113] In one embodiment of the present invention, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, or -CH2-C(=O)N(R) 3 R 4 Preferably, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, or -CH2-C(=O)N(R) 3 R 4 ).

[0114] In one embodiment of the present invention, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, -C(=O)H, or

[0115]

[0116] The interlaced lines indicate connections to the phenyl group. Preferably, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, or

[0117]

[0118] The interlaced lines indicate connections to the phenyl group.

[0119] In one embodiment of the present invention, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, -C(=O)H,

[0120]

[0121] The interlaced lines indicate connections to the phenyl group. Preferably, R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H,

[0122]

[0123] The interlaced lines indicate connections to the phenyl group.

[0124] In one embodiment, R 1 yes

[0125]

[0126] The interlaced lines indicate connections to the phenyl group.

[0127] In one embodiment, R 1 yes

[0128]

[0129] The interlaced lines indicate connections to the phenyl group.

[0130] In one embodiment, R 1 yes

[0131]

[0132] The interlaced lines indicate connections to the phenyl group.

[0133] In one embodiment of the present invention, R 1 It is -C(=O)N(R) 3 R 4 ), where R 3 It is methyl or 2-fluorophenyl; and

[0134] R 4 It is hydrogen. In one embodiment, R 1 It is -C(=O)NH(2-fluorophenyl). In another embodiment, R 1 It is -C(=O)NH (methyl).

[0135] In one embodiment of the present invention, R 1 It is -CH2-N(R) 3 )-C(=O)R 4 , where R 3 It is hydrogen or methoxy; and R 4 It is cyclopropyl or 1-methoxyethyl. Preferably, R 1 It is -CH2-N(R) 3 )-C(=O)R 4 , where R 3 It is a methoxy group; and R 4 It is cyclopropyl or 1-methoxyethyl.

[0136] In one embodiment of the present invention, R 2 Selected from C1-C2-haloalkyl groups. Preferably, R 2 It is CF3 or CF2Cl. In one embodiment of the invention, R 2 It is CF3. In another embodiment of the invention, R 2 It is CF2Cl.

[0137] In one embodiment of the present invention, R 3 Selected from hydrogen, C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or cyclopropyl. Preferably, R 3 It is hydrogen, methyl, ethyl, methoxy, ethoxy, or cyclopropyl.

[0138] In one embodiment of the present invention, R 4 The group is selected from C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, C3-C6-cycloalkyl, C1-C2-alkoxy-C1-C3-alkyl, or phenyl, wherein the phenyl group is unsubstituted or substituted with one or two substituents independently selected from halogens. Preferably, R 4 It is methyl, ethyl, methoxy, ethoxy, cyclopropyl, 1-methoxyethyl, or 2-fluoro-phenyl.

[0139] In one embodiment of the present invention, R 5 Selected from hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy, or C1-C4-alkoxy-C1-C2-alkoxy. Preferably, R 5 It is hydrogen, C1-C3-alkoxy, or C1-C3-haloalkoxy. More preferably, R5 It is hydrogen, methoxy, ethoxy, or methoxy-ethoxy.

[0140] In one embodiment of the invention, W is selected from O or S. In another embodiment of the invention, W is O. In yet another embodiment of the invention, W is S.

[0141] In one embodiment of the present invention, R 6 Selected from C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl, or benzyl, wherein the phenyl and benzyl groups are unsubstituted or substituted by one or two substituents independently selected from halogens or C1-C4-alkyl groups. Preferably, R 6 It is C1-C 12 -alkyl, vinyl, or benzyl. More preferably, R 6 It is methyl, ethyl, isopropyl, n-butyl, tert-butyl, vinyl, or benzyl. Even more preferably, R 6 It is methyl, ethyl, n-butyl, or tert-butyl.

[0142] Therefore, the present invention makes it possible to obtain compounds having formula (I) that have R as defined above in all combinations / permutations. 1 R 2 R 3 R 4 R 5 And W.

[0143] Embodiments of the present invention are provided, as listed below.

[0144] Method for preparing compounds having formula (I)

[0145] A method for preparing a compound of formula (I) from a methylamine oxime compound of formula (II) by reacting it with a haloacetate of formula (III) in the presence of at least one base is shown in Scheme 1, wherein the method is characterized in that the at least one base is selected from guanidine bases.

[0146] Option 1 Method for preparing compounds of formula (I) from compounds of formula (II).

[0147]

[0148] In one embodiment, the present invention relates to a method for preparing a compound having formula (I).

[0149] (I)

[0150] in

[0151] R 1 Selected from hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R) 3 R 4 -CH2-C(=W)N(R) 3 R 4 -CH2-N(R) 3 )-C(=W)R 4 ,

[0152]

[0153] The interlacing lines indicate connections to the phenyl group;

[0154] R 2 Selected from C1-C2-haloalkyl groups;

[0155] R 3 Selected from hydrogen, C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or cyclopropyl;

[0156] R 4 The group is selected from C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, C3-C6-cycloalkyl, C1-C2-alkoxy-C1-C3-alkyl, or phenyl, wherein the phenyl group is unsubstituted or substituted by one or two substituents independently selected from halogens;

[0157] R 5 Selected from hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy, or C1-C4-alkoxy-C1-C2-alkoxy; and

[0158] W is selected from O or S;

[0159] The method includes reacting a methylamine oxime compound having formula (II) with a methylamine oxime compound.

[0160] (II)

[0161] Where R 1 R 3 R 4 and R 5 As defined for compounds having formula (I), and haloacetic esters having formula (III)

[0162] (III)

[0163] Where R 2As defined for compounds having formula (I), and R 6 Selected from C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl;

[0164] The reaction is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0165] In one embodiment, the present invention relates to a method for preparing a compound having formula (I) from compounds having formulas (II) and (III),

[0166] (I) (II) (III)

[0167] The variables in compounds having formulas (I), (II), and (III) have the following meanings

[0168] R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, -C(=O)N(R) 3 R 4 -CH2-C(=O)N(R) 3 R 4 -CH2-N(R) 3 )-C(=O)R 4 ,

[0169]

[0170] The interlacing lines indicate connections to the phenyl group;

[0171] R 2 It is CF3 or CF2Cl;

[0172] R 3 It is hydrogen, methyl, ethyl, methoxy, ethoxy, or cyclopropyl;

[0173] R 4 It is methyl, ethyl, methoxy, ethoxy, cyclopropyl, 1-methoxyethyl, or 2-fluoro-phenyl;

[0174] R 5It is hydrogen, methoxy, ethoxy, or methoxy-ethoxy; and

[0175] R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl;

[0176] The method is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0177] In one embodiment, the present invention relates to a method for preparing a compound having formula (I) from compounds having formulas (II) and (III),

[0178] (I) (II) (III)

[0179] The variables in compounds having formulas (I), (II), and (III) have the following meanings

[0180] R 1 It is CH2-N(R) 3 )-C(=O)R 4 ;

[0181] R 2 It's CF3;

[0182] R 3 It is hydrogen or C1-C2-alkoxy;

[0183] R 4 It is a C3-C6-cycloalkyl or a C1-C2-alkoxy-C1-C3-alkyl; and

[0184] R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl;

[0185] The method is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0186] In one embodiment, the present invention relates to a method for preparing a compound having formula (I) from compounds having formulas (II) and (III),

[0187] (I) (II) (III)

[0188] The variables in compounds having formulas (I), (II), and (III) have the following meanings

[0189] R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl or -CH2-N(R) 3 )-C(=O)R 4 ;

[0190] R 2 It's CF3;

[0191] R 3 It is hydrogen or methoxy;

[0192] R 4 It is cyclopropyl or 1-methoxyethyl; and

[0193] R 6 It is methyl, ethyl, isopropyl, n-butyl, tert-butyl, vinyl, or benzyl;

[0194] The method is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0195] In one embodiment, the present invention relates to a method for preparing a compound having formula (I) from compounds having formulas (II) and (III),

[0196] (I) (II) (III)

[0197] The variables in compounds having formulas (I), (II), and (III) have the following meanings

[0198] R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl or -C(=O)N(R) 3 R 4 );

[0199] R 2 It's CF3;

[0200] R 3 It is methyl or 2-fluorophenyl;

[0201] R 4 It is hydrogen; and

[0202] R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl;

[0203] The method is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0204] In one embodiment, the present invention relates to a method for preparing a compound having formula (I) from compounds having formulas (II) and (III),

[0205] (I) (II) (III)

[0206] The variables in compounds having formulas (I), (II), and (III) have the following meanings

[0207] R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -CH2-C(=O)N(R) 3 R 4 ),

[0208] The interlacing lines indicate connections to the phenyl group;

[0209] R2 It is CF3 or CF2Cl;

[0210] R 3 It is hydrogen, cyclopropyl, or C1-C2-alkoxy;

[0211] R 4 It is a C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, C3-C6-cycloalkyl, or C1-C2-alkoxy-C1-C3-alkyl; and

[0212] R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl;

[0213] The method is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0214] In one embodiment, the present invention relates to a method for preparing a compound having formula (I) from compounds having formulas (II) and (III),

[0215] (I) (II) (III)

[0216] The variables in compounds having formulas (I), (II), and (III) have the following meanings

[0217] R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H, or

[0218]

[0219] The interlacing lines indicate connections to the phenyl group;

[0220] R 2 It is CF3 or CF2Cl;

[0221] R 5 It is hydrogen, methoxy, ethoxy, or methoxy-ethoxy; and

[0222] R 6It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl;

[0223] The method is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0224] In one embodiment, the present invention relates to a method for preparing a compound having formula (I) from compounds having formulas (II) and (III),

[0225] (I) (II) (III)

[0226] The variables in compounds having formulas (I), (II), and (III) have the following meanings

[0227] R 1 It is hydroxyl, thiol, cyano, halogen, hydroxymethyl, methyl, trichloromethyl, -C(=O)H,

[0228]

[0229] The interlacing lines indicate connections to the phenyl group;

[0230] R 2 It is CF3; and

[0231] R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl;

[0232] The method is carried out in the presence of at least one base, wherein the base is a guanidine base, and wherein the guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0233] In one embodiment of the invention, the compound having formula (I) is selected from N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropaneformamide according to structure (IA).

[0234] (IA);

[0235] Based on the structure (IB) of N,2-dimethoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl] propionamide

[0236] (IB);

[0237] According to the structure (IC) of N-(2,2,2-trifluoroethyl)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]oxazol-4-carboxamide

[0238] (IC);

[0239] Ethyl 1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy]methyl]pyrazole-4-carboxylate according to structure (ID)

[0240] (ID);

[0241] Based on the structure (IE) of 4-(2-methoxyethoxy)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyridazin-3-one

[0242] (IE);

[0243] Ethyl 1-[[4-[5-[chloro(difluoro)methyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyrazole-4-carboxylate according to its structure (IF)

[0244] (IF); or

[0245] Based on the structure (IG) of 5,5-dimethyl-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]isoxazolidine-3-one

[0246] (IG),

[0247] Based on the structure (IH), N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide

[0248] (IH);

[0249] Based on the structure (IJ) of N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiobenzamide

[0250] (IJ);

[0251] Based on the structure (IK) of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0252] (IK);

[0253] In a preferred embodiment of the invention, the compound having formula (I) is N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropaneformamide according to structure (IA).

[0254] In another preferred embodiment of the invention, the compound having formula (I) is N,2-dimethoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]propionamide according to structure (IB).

[0255] In another preferred embodiment of the invention, the compound having formula (I) is N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide according to structure (IH).

[0256] In another preferred embodiment of the invention, the compound having formula (I) is N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiobenzamide according to structure (IJ).

[0257] In another preferred embodiment of the invention, the compound having formula (I) is ethyl 1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy]methyl]pyrazole-4-carboxylate according to structure (ID).

[0258] In another preferred embodiment of the invention, the compound having formula (I) is 4-(2-methoxyethoxy)-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyridazin-3-one according to structure (IE).

[0259] In another preferred embodiment of the invention, the compound having formula (I) is ethyl 1-[[4-[5-[chloro(difluoro)methyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]pyrazole-4-carboxylate according to structure (IF).

[0260] In another preferred embodiment of the invention, the compound having formula (I) is 5,5-dimethyl-2-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]isoxazolidine-3-one according to structure (IG).

[0261] In another preferred embodiment of the invention, the compound having formula (I) is 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole according to structure (IK).

[0262] In one embodiment of the invention, a compound having formula (I) (wherein R) is used. 1 (I) is methyl) is converted into a valuable chemical product or other intermediate. Therefore, in one embodiment, a compound having formula (I) (where R) is used. 1 (I) can be further chlorinated to obtain a compound having formula (Ia), and wherein R is methyl. 2 As defined for compounds having formula (I)

[0263] (Ia)

[0264] The methyl group (R) of compounds having formula (I) 1 It can be converted to trichloromethyl, as disclosed in WO 2019 / 020451 A1 and the references cited therein.

[0265] In another embodiment of the invention, a compound having formula (Ia) can be further converted into a compound having formula (Ib), wherein R 1 It is -C(=O)Cl, and where R 2 As defined for compounds having formula (I).

[0266] (Ib)

[0267] This has been disclosed in WO 2019 / 020451 A1 and the references cited therein.

[0268] The present invention also relates to intermediates having any of formulas (V) and (VI), which are formed in the method of the present invention by a step (Scheme 1) of reacting a compound having formula (II) with a compound having formula (III) in the presence of a guanidine base. The intermediates thus obtained can be characterized by any suitable analytical technique such as NMR and IR spectroscopy. The compound having formula (III) reacts with a guanidine base to give the corresponding acetamide having formula (V), and then, in the case of forming an intermediate having formula (VI), the acyl moiety is transferred to the compound having formula (II). The guanidine base can act as an acyl transfer reagent. The intermediate having formula (V), upon cyclization, results in the compound having formula (I). Scheme 1 illustrates the mechanism and intermediate using 1,1,3,3-tetramethylguanidine as a base. Those skilled in the art will readily understand that this mechanism applies to the use of other guanidine bases.

[0269]

[0270] Option 1

[0271] Those skilled in the art will readily understand that these intermediates having formulas (V) and (VI) (as shown in Scheme 1) are all within the scope of this invention, wherein R 1 R 2 and R 6 As defined for compounds having formulas (I), (II) and (III) according to the invention.

[0272] Furthermore, those skilled in the art will readily understand that the above mechanism applies to any guanidine that can be used in the methods of this invention.

[0273] According to another aspect of the invention, an intermediate compound having the formula (Va) is provided.

[0274] (Va)

[0275] Where R 2 As defined for compounds according to the invention having formulas (I), (II) and (III), and wherein R 7 R 8 R 9 R 10 It is independently selected from hydrogen or C1-C4-alkyl.

[0276] In one embodiment of the invention, in an intermediate compound having the formula (Va), R 7R 8 R 9 R 10 Independently selected from hydrogen or methyl, and R 2 It is a C1-C2-haloalkyl group.

[0277] Preferably, in the intermediate compound having the formula (Va), R 7 R 8 R 9 R 10 Independently selected from hydrogen or methyl, and R 2 It is trifluoromethyl or difluoromethyl.

[0278] The disclosures in this application make available the various embodiments disclosed herein and each combination thereof. Example

[0279] The following examples further illustrate (but do not limit) the invention. Those skilled in the art will quickly recognize from these procedures suitable variations in the reactants, reaction conditions, and techniques.

[0280] abbreviation

[0281]

[0282] Preparation Examples

[0283] The compounds having formula (I) according to the present invention can be prepared using the synthetic techniques described above and below.

[0284] Throughout this specification, temperatures are given in degrees Celsius, and "mp" indicates melting point. Free radicals represent methyl groups. Recorded on a Bruker 400MHz spectrometer (or as indicated). 1 H NMR and 19 F NMR measurements, chemical shift relative to TMS ( 1 H) and CFCl3 ( 19 F) Standards are given in ppm. Spectra are measured in the specified deuterated solvent.

[0285] Example P1: Preparation of N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3- from ethyl trifluoroacetate [By]phenyl]methyl]-cyclopropaneformamide (compound P-1, see table P)

[0286] At room temperature, a suspension was prepared by adding N-[[4-[(Z)-N'-hydroxymethylammonyl]phenyl]methyl]-N-methoxy-cyclopropaneformamide (geminoxime) (94%, 280 mg, 1 mmol) and butyl acetate (2 mL) to a screening vial. Ethyl trifluoroacetate (99%, 287 mg, 2 mmol) and TMG (99%, 144 mg, 1.25 mmol) were added to the suspension, and the resulting reaction mixture was stirred at 75°C for 5 hr (homogeneous after 10 min). After the reaction was complete (monitored by NMR), the crude reaction mixture was quenched by adding acetic acid (99.5%, 162 mg, 2.7 equivalents), and the chemical yield was determined by quantitative NMR analysis (using 1,3,5-trimethoxybenzene as an internal standard). The desired product, N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropaneformamide, was formed in 82% chemical yield.

[0287] 1 H NMR (400 MHz, CDCl3) δ ppm: 8.09 (d, 2H), 7.53 (d, 2H), 4.87 (s,2H), 3.73 (s, 3H), 2.19 (m, 1H), 1.05 (m, 2H), 0.86 (m, 2H). 19 F NMR (400 MHz, CDCl3) δ ppm: -65.33 (s)

[0288] Example P2: Preparation of N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3- from methyl trifluoroacetate [By]phenyl]-methyl]-cyclopropaneformamide (compound P-1, see table P)

[0289] At room temperature, a suspension was prepared by adding N-[[4-[(Z)-N'-hydroxymethylammonyl]phenyl]methyl]-N-methoxy-cyclopropaneformamide (geminoxime) (94%, 280 mg, 1 mmol) and butyl acetate (2 mL). Methyl trifluoroacetate (99%, 259 mg, 2 mmol) and TMG (99%, 144 mg, 1.25 mmol) were added to this suspension, and the resulting reaction mixture was stirred at 75°C for 5 hr (homogeneous after 10 min). After the reaction was complete (monitored by NMR), the crude reaction mixture was quenched by adding acetic acid (99.5%, 162 mg, 2.7 equivalents), and the chemical yield was determined by quantitative NMR analysis (using 1,3,5-trimethoxybenzene as an internal standard). The desired product, N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropaneformamide, was formed in 83% chemical yield.

[0290] Example P3: Preparation of N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazole-3- from ethyl trifluoroacetate [By]phenyl]methyl]-cyclopropaneformamide (compound P-1, see table P)

[0291] N-[[4-[(Z)-N'-hydroxymethylammonium]phenyl]methyl]-N-methoxy-cyclopropaneformamide (98%, 4 mmol, 1.07 g), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 50°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 50°C for 4 hr. Water (1 g) was then added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). The chemical yield (products in the aqueous and organic layers) was 94%. The separation yield (products in the organic layer) was 93%.

[0292] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.04 (d, 2H), 7.50 (d, 2H), 4.90 (s,2H), 3.75 (s, 3H), 2.23-2.16 (m, 1H), 0.88-081 (m, 4H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -64.9 (s).

[0293] Example P4: N,2-Dimethoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]-methyl Preparation of 1,4-propionamide (compound P-2, Table P)

[0294]

[0295] N-[[4-[(Z)-N'-hydroxymethylammonium]phenyl]methyl]-N,2-dimethoxy-propionamide (97%, 4 mmol, 1.16 g), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 50°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 50°C for 4 hr. Water (1 g) was then added, and the layers were separated. The two layers were analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). The chemical yield was 93% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 87%.

[0296] 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.05 (d, 2H), 7.51 (d, 2H), 4.99 (d,1H), 4.83 (d, 1H), 4.28 (q, 1H), 3.73 (s, 3H), 3.22 (s, 3H), 1,22 (d, 3H). 19 FNMR (376 MHz, d6-DMSO) δ ppm: -64.85 (s).

[0297] Example P5: Preparation of 3-(p-Tolyl)-5-(Trifluoromethyl)-1,2,4-oxadiazole (Compound P-3, Table P)

[0298]

[0299] N'-hydroxy-4-methylbenzamidinium (97%, 4 mmol, 796.7 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL). The resulting suspension was then stirred at 60°C for 2 min, followed by the addition of TMG (99%, 4.4 mmol, 511.9 mg), and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was then added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 93% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 92%.

[0300] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 7.94 (d, 2H), 7.41 (d, 2H), 2.40 (s, 3H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -65.14 (s).

[0301] Example P6: Preparation of 5-[chloro(difluoro)methyl]-3-(p-tolyl)-1,2,4-oxadiazole (compound P-4, Table P)

[0302]

[0303] N'-hydroxy-4-methylbenzamidinium (97%, 4 mmol, 796.7 mg), BuOAc (2 mL), and ethyl dichlorofluoroacetate (97%, 8.4 mmol, 1.37 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 h. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 92% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 90%.

[0304] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 7.94 (d, 2H), 7.42 (d, 2H), 2.40 (s, 3H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -54.45 (s).

[0305] Example P7: Preparation of 3-phenyl-5-(trifluoromethyl)-1,2,4-oxadiazole (compound P-5, Table P)

[0306]

[0307] N'-hydroxybenzomidine (98%, 4 mmol, 555.7 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 92% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 91%.

[0308] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.05 (d, 2H), 7.66-7.58 (m, 3H). 19 FNMR (376 MHz, d6-DMSO) δ ppm: -65.26 (s).

[0309] Example P8: Methyl 4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzoate (compound P-6, Table P) preparation

[0310]

[0311] Methyl 4-[N'-hydroxymethylammonium]benzoate (97%, 4 mmol, 800.8 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 89% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 88%.

[0312] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.19-8.14 (m, 4H), 3.90 (s, 3H). 19 FNMR (376 MHz, d6-DMSO) δ ppm: -65.17 (s).

[0313] Example P9: Preparation of 4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile (compound P-7, Table P)

[0314]

[0315] 4-Cyano-N-hydroxybenzylamidinium (97%, 4 mmol, 664.6 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 95% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 94%.

[0316] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.22 (d, 2H), 8.07 (d, 2H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -65.10 (s).

[0317] Example P10: Preparation of 3-(4-bromophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (compound P-8, Table P)

[0318]

[0319] 4-Bromo-N'-hydroxybenzomididine (98%, 4 mmol, 878.0 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 94% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 90%.

[0320] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 7.99 (d, 2H), 7.82 (d, 2H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -65.07 (s).

[0321] Example P11: Preparation of 3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (compound P-9, Table P)

[0322]

[0323] 4-Chloro-N'-hydroxybenzomididine (97%, 4 mmol, 703.5 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 93% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 92%.

[0324] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.07 (d, 2H), 7.69 (d, 2H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -64.92 (s).

[0325] Example P12: [4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methanol (compound P-11, Table P) Preparation

[0326]

[0327] N-hydroxy-4-(hydroxymethyl)benzylamidinium (97%, 4 mmol, 685.4 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 93% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 91%.

[0328] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.02 (d, 2H), 7.56 (d, 2H), 4.61 (s, 2H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -64.95.

[0329] Example P13: N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide (compound P-12, Preparation of Table P)

[0330]

[0331] 4-(N-hydroxymethylamidinyl)-N-methylbenzamide (95%, 4 mmol, 813.5 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated at 50°C. The two layers were analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 94% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 90%.

[0332] 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.65 (br q, 1H), 8.15 (d, 2H), 8.06 (d, 2H), 2.83 (d, 3H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -65.10 (s).

[0333] Example P14: N-[[4-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-N-methoxy-cyclo Preparation of propaneformamide (compound P-13, Table P)

[0334]

[0335] N-[[4-[(Z)-N'-hydroxymethylammonium]phenyl]methyl]-N-methoxy-cyclopropaneformamide (98%, 4 mmol, 1.07 g), BuOAc (3 mL), and ethyl trifluoroacetate (98%, 8.4 mmol, 1.06 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 h. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 92% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 91%.

[0336] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.03 (d, 2H), 7.54 (t, 1H), 7.49 (d,2H), 4.89 (s, 3H), 3.75 (s, 3H), 2.23-2.16 (m, 1H), 0.85-0.82 (m, 4H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -121.90 (d).

[0337] Example P15: N-[[4-[5-[chloro(difluoro)methyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl]-N-methoxy Preparation of alkyl-cyclopropaneformamide (compound P-14, Table P)

[0338]

[0339] N-[[4-[(Z)-N'-hydroxymethylammonium]phenyl]methyl]-N-methoxy-cyclopropaneformamide (98%, 4 mmol, 1.07 g), BuOAc (2 mL), and ethyl dichlorofluoroacetate (97%, 8.4 mmol, 1.37 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 h. Water (1 g) was added, and the layers were separated and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 88% (products in the aqueous and organic layers). Separation yield (products in the organic layer): 87%.

[0340] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.03 (d, 2H), 7.50 (d, 2H), 4.90 (s,2H), 3.75 (s, 3H), 2.23-2.16 (m, 1H), 0.85-0.82 (m, 4H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -54.49 (s).

[0341] Example P16: N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide (compound) Preparation of substance P-15 (Table P)

[0342]

[0343] N-(2-fluorophenyl)-4-[(Z)-N-hydroxymethylammonium]benzamide (95%, 4 mmol, 1150.6 mg), BuOAc (4 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL), and the resulting suspension was stirred at 60°C for 2 min. TMG (99%, 4.4 mmol, 511.9 mg) was then added, and the reaction mixture was stirred at 60°C for 4 hr. The reaction mixture was cooled to room temperature, and the final product was filtered and analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield 97% (products in the aqueous and organic layers). Separate yield 90% (products in the organic layer).

[0344] 1H NMR (400 MHz, d6-DMSO) δ ppm: 10.38 (br s, 1H), 8.24-8.19 (m, 4H), 7.63 (dt, 1H), 7.34-7.22 (m, 3H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -64.72 (s), -120.97 (dd).

[0345] Example P17: 3-[4-(trifluoromethoxy)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (compound P-10, Preparation of Table P)

[0346]

[0347] N-hydroxy-4-(trifluoromethoxy)benzylamidinium (98%, 4 mmol, 898.6 mg), BuOAc (2 mL), and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g) were added to a screening vial (20 mL). The resulting suspension was stirred at 60°C for 2 min, followed by the addition of 1 TMG (99%, 4.4 mmol, 511.9 mg), and the reaction mixture was stirred at 60°C for 4 hr. Water (1 g) was added, and the layers were separated. Both layers were analyzed by quantitative NMR (using 1,3,5-trimethoxybenzene as an internal standard). Chemical yield: 91% (products in the aqueous and organic layers). Separation yield: 89% (products in the organic layer).

[0348] 1 H NMR (400 MHz, d6-DMSO) δ ppm: 8.19 (d, 2H), 7.60 (d, 2H). 19 F NMR (376 MHz, d6-DMSO) δ ppm: -56.96 (s), -64.99 (s).

[0349] General procedure for alkali screening

[0350] N-[[4-[(Z)-N'-hydroxymethylammonium]phenyl]methyl]-N-methoxy-cyclopropaneformamide (4 mmol, a methylamine oxime) and butyl acetate (0.5 mL / mmol methylamine oxime) were added to screening vials at room temperature to obtain a suspension. Ethyl trifluoroacetate (based on 2.1 equivalents of methylamine oxime) and TMG (based on 1.1 equivalents of methylamine oxime) were added to this suspension, and the resulting reaction mixture was stirred at 60°C for 4 hr (homogeneous after 10 min). After the reaction was complete (monitored by NMR), the crude reaction mixture was quenched by adding acetic acid (based on 2.7 equivalents of base), and the chemical yield was determined by quantitative NMR analysis (using 1,3,5-trimethoxybenzene as an internal standard). Table B1 summarizes the results obtained for the different bases used.

[0351]

[0352] Table B1 Alkali screening results

[0353]

[0354] The results above demonstrate that high yields of the desired oxadiazole derivatives were achieved by using TMG as a base at moderate reaction temperatures. This TMG outperforms other strong bases in terms of both chemical yield and mass balance. Under the applied reaction conditions, the use of NaOEt (sodium ethoxide) resulted in the decomposition of the starting material.

[0355] General Solvent Screening Procedure

[0356] At room temperature, N-[[4-[(Z)-N'-hydroxymethylammoni]phenyl]methyl]-N-methoxy-cyclopropaneformamide (4 mmol, a methylamine oxime) and solvent were added to a screening vial to obtain a suspension. Ethyl trifluoroacetate (based on 2 to 2.2 equivalents of the methylamine oxime) and 1,1,3,3-tetramethylguanidine (based on 1.1 to 1.25 equivalents of the methylamine oxime) were added to the suspension, and the resulting reaction mixture was stirred at 30°C to 75°C (see Example) for 4 to 5 hr (homogeneous after 10 min). After the reaction was complete (monitored by NMR), the crude reaction mixture was quenched by adding acetic acid (based on 2.7 equivalents of base), and the chemical yield was determined by quantitative NMR analysis (using 1,3,5-trimethoxybenzene as an internal standard). Tables B2, B3, and B4 summarize the results obtained for the different solvents used.

[0357] Example Solvent - Screening 1:

[0358]

[0359] Table B2:Solvent screening was performed using 2.1 equivalents of ethyl trifluoroacetate, 1.1 equivalents of TMG, and 0.75 mL solvent / mmol of ammonia oxime.

[0360]

[0361] Table B3 Solvent screening was performed using 2.2 equivalents of ethyl trifluoroacetate, 1.25 equivalents of TMG, and 2 mL solvent / mmol of amine oxime.

[0362]

[0363] [b]: Determined by quantitative HPLC analysis. [c]: Determined by quantitative NMR analysis of the reaction mixture (using 1,2,3-trimethoxybenzene as an internal standard).

[0364] Table B4: Solvent screening was performed using 45 mmol of ammonium oxime, 2.1 equivalents of ethyl trifluoroacetate, 1.1 equivalents of TMG, and 0.5 mL solvent / mol ammonium oxime (60°C).

[0365]

[0366] The above results demonstrate that, in the method of the present invention, the organic solvents that can be used are not limited due to the nature of the base used. The above results also demonstrate that high yields of the desired oxadiazole derivatives were achieved by using TMG as a base in various solvents at moderate reaction temperatures.

[0367] Although the invention has been described with reference to its preferred embodiments and examples, the scope of the invention is not limited to those described embodiments. As will be appreciated by those skilled in the art, modifications and rewrites can be made to the above invention without departing from the spirit and scope of the invention, which is defined and limited by the appended claims. For all purposes, all publications cited herein are hereby incorporated in their entirety by reference as if each individual publication were specifically and individually indicated to be so incorporated by reference.

[0368] Examples of compounds having formula (I) synthesized according to the present invention are shown in Table P.

[0369] Table P: Synthesized compounds and their spectral and physicochemical data

[0370] .

Claims

1. A method for preparing a compound having formula (I): (I) in R 1 Selected from hydroxyl, thiol, cyano, halogen, hydroxymethyl, C1-C3-alkyl, C1-C2-haloalkyl, cyclopropyl, -C(=O)H, -C(=O)OH, -C(=O)Hal, -C(=W)N(R) 3 R 4 -CH2-C(=W)N(R) 3 R 4 ), -CH2-N(R 3 )-C(=W)R 4 , The interlacing lines indicate connections to the phenyl group; R 2 Selected from C1-C2-haloalkyl groups; R 3 Selected from hydrogen, C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, or cyclopropyl; R 4 The group is selected from C1-C3-alkyl, C1-C2-haloalkyl, C1-C2-alkoxy, C3-C6-cycloalkyl, C1-C2-alkoxy-C1-C3-alkyl, or phenyl, wherein the phenyl group is unsubstituted or substituted by one or two substituents independently selected from halogens; R 5 Selected from hydrogen, C1-C4-alkoxy, C1-C4-haloalkoxy, or C1-C4-alkoxy-C1-C2-alkoxy; and W is selected from O or S; The method includes reacting a methylamine oxime compound having formula (II) with a methylamine oxime compound. (II) Where R 1 R 3 R 4 and R 5 As defined for compounds having formula (I), and haloacetic esters having formula (III) (III) Where R 2 As defined for the compound having formula (I), and R 6 Selected from C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogen or C1-C4-alkyl; The reaction is carried out in the presence of at least one base, wherein the method is characterized in that the at least one base is selected from guanidine bases.

2. The method according to claim 1, wherein, The guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine (barton base), 1,1,2,3-tetramethylguanidine, guanidine carbonate, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole, 1,5,6,7-tetrahydroimidazo[1,2-a]pyrimidine, 1-formamidin-3-(o-tolyl)guanidine, or N-isopropylhexahydropyrimidine-2-imine.

3. The method according to claim 1 or 2, wherein, The guanidine base is selected from 1,1,3,3-tetramethylguanidine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.

4. The method according to claim 3, wherein, The guanidine base is 1,1,3,3-tetramethylguanidine.

5. The method according to any one of claims 1 to 4, wherein, The amount of the guanidine base is 0.1 to 2.5 equivalents based on the number of moles (mol) of the amygdoxime compound having formula (II).

6. The method according to any one of claims 1 to 5, wherein, The amount of the guanidine base is 0.1 to 1.5 equivalents based on the number of moles (mol) of the amygdoxime compound having formula (II).

7. The method according to any one of claims 1 to 6, wherein, The amount of the guanidine base is 0.1 to 1.25 equivalents based on the number of moles (mol) of the amygdoxime compound having formula (II).

8. The method according to any one of claims 1 to 7, wherein, R 1 It is CH2-N(R) 3 )-C(=O)R 4 R 2 It's CF3; R 3 It is hydrogen or C1-C2-alkoxy; R 4 It is a C3-C6-cycloalkyl or a C1-C2-alkoxy-C1-C3-alkyl; and R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogens or C1-C4-alkyl.

9. The method according to claim 8, wherein, R 1 It is CH2-N(R) 3 )-C(=O)R 4 R 2 It's CF3; R 3 It is a methoxy group; R 4 It is cyclopropyl or 1-methoxyethyl; and R 6 It is methyl, ethyl, isopropyl, n-butyl, tert-butyl, vinyl, or benzyl.

10. The method according to any one of claims 1 to 7, wherein, R 1 It is -C(=O)N(R) 3 R 4 ); R 2 It's CF3; R 3 It is methyl or 2-fluorophenyl; R 4 It is hydrogen; and R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogens or C1-C4-alkyl.

11. The method according to any one of claims 1 to 7, wherein, R 1 yes The interlacing lines indicate connections to the phenyl group; R 2 It is CF3; and R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogens or C1-C4-alkyl.

12. The method according to any one of claims 1 to 7, wherein, R 1 yes The interlacing lines indicate connections to the phenyl group; R 2 It is CF3 or CF2Cl; R 5 It is hydrogen, methoxy, ethoxy, or methoxy-ethoxy; and R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogens or C1-C4-alkyl.

13. The method according to any one of claims 1 to 7, wherein, R 1 yes The interlacing lines indicate connections to the phenyl group; R 2 It is CF3 or CF2Cl; and R 6 It is C1-C 12 -alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl or benzyl, wherein the phenyl and benzyl are unsubstituted or substituted by one or two substituents independently selected from halogens or C1-C4-alkyl.

14. An intermediate compound having the formula (Va) (Va) Where R 2 It is a C1-C2-haloalkyl group, and wherein R 7 R 8 R 9 R 10 It is independently selected from hydrogen or C1-C4-alkyl.

15. The intermediate compound having the formula (Va) according to claim 14, wherein, R 7 R 8 R 9 R 10 Independently selected from hydrogen or methyl; and R 2 It is trifluoromethyl or difluoromethyl.

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