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WO2025163139A1 - Procédé de préparation de dérivés d'oxadiazole microbiocides - Google Patents

Procédé de préparation de dérivés d'oxadiazole microbiocides

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Publication number
WO2025163139A1
WO2025163139A1 PCT/EP2025/052520 EP2025052520W WO2025163139A1 WO 2025163139 A1 WO2025163139 A1 WO 2025163139A1 EP 2025052520 W EP2025052520 W EP 2025052520W WO 2025163139 A1 WO2025163139 A1 WO 2025163139A1
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WIPO (PCT)
Prior art keywords
formula
phenyl
alkyl
base
methyl
Prior art date
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Pending
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PCT/EP2025/052520
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English (en)
Inventor
Patrick ISENEGGER
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Syngenta Crop Protection AG Switzerland
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Syngenta Crop Protection AG Switzerland
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Publication of WO2025163139A1 publication Critical patent/WO2025163139A1/fr
Pending legal-status Critical Current
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of substituted oxadiazole derivatives of formula (I), which can be obtained through reaction of amidoximes of formula (II) in the presence of an organic guanidine base.
  • Substituted oxadiazole derivatives are versatile intermediates, which can be converted to substituted 3-aryl-5- trifluoro-1 ,2,4-oxadiazoles, that are known to be useful for controlling phytopathogenic fungi, for example, from WO2015/185485, WO2017/055473 A1 , WO2017/211649, WO2017/178245, WO2018/177894,
  • WO2019/020501 and WO2019/020451 describe the formation of 1 ,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetic halide in the presence of an organic solvent or in substance. All synthetic examples disclose the use of at least 2 equivalents of trifluoroacetic halide, which leads to the formation of at least one equivalent of free trifluoroacetic acid (TFA) as a side product, along with hydrogen halides, which requires special reaction equipment to avoid corrosion.
  • TFA free trifluoroacetic acid
  • WO2020/212513 describes the formation of 1 ,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetates in the presence of metal alkoxylates.
  • Metal alkoxylates are non-recyclable bases, and further restrict the solvents that can be employed for this conversion.
  • WO2021/156174 describes the formation of 1 ,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetates in the presence of a base. All synthetic examples disclose the use of at least 2 equivalents of trifluoroacetate, based on the amount of amidoxime, in the presence of sodium methylate as a base. Sodium methylate is a non-recyclable base, and further restricts the solvents that can be employed for this conversion.
  • WO2021/156175 describes the formation of 1 ,2,4-oxadiazole derivatives by reacting amidoximes with trifluoroacetates in the presence of a base, such as metal alkoxylates. All synthetic examples disclose the use of 5 equivalents of trifluoroacetate, based on the amount of amidoxime, in the presence of sodium methylate as a base. Sodium methylate is a non-recyclable base, and further restricts the solvents that can be employed for this conversion.
  • the current invention provides an industrial large-scale, environmentally friendly, and cost-efficient production process, which employs readily available, non-toxic, recyclable and cheap reagents.
  • the reaction process may be performed with a low excess of acylating reagent based on the amidoxime starting material and such leads to less waste products. Furthermore, fast conversion is achieved, at moderate reaction temperatures with high yields of the required 3-aryl-1 ,2,4-oxadiazole-derivatives.
  • the organic solvent that can be used is not restricted due to the nature of the base used.
  • R 2 is selected from Ci-C2-haloalkyl
  • R 3 is selected from hydrogen, Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, or cyclopropyl;
  • R 4 is selected from Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, Cs-Ce-cycloalkyl, Ci-C2-alkoxy-Ci-C3-alkyl, or phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen;
  • R 5 is selected from hydrogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or Ci-C4-alkoxy-Ci-C2-alkoxy; and W is selected from O, or S; said process comprising the reaction of an amidoxime compound of formula (II)
  • R 1 , R 3 , R 4 and R 5 are as defined for compounds of formula (I), with a haloacetic ester of formula (III) wherein R 2 is as defined for compounds of formula (I), and R 6 is selected from Ci-Ci2-alkyl, C2-Cs-alkenyl, Ci- Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; in the presence of at least one base, wherein said process is characterized in that said at least one base is selected from a guanidine-base.
  • the process of the present invention may be performed with a low excess of acylating reagent based on the amidoxime starting material and such leads to less waste products. Furthermore, fast conversion is achieved, at moderate reaction temperatures with high yields of the required 3-aryl-1 ,2,4-oxadiazole-derivatives. Further for the process of the present invention the organic solvent that can be used is not restricted due to the nature of the base used, and the base is non-toxic, and recyclable, and such provides an environmentally friendly, and cost-efficient industrial large-scale production process.
  • halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine, or bromine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl, and haloalkoxy.
  • thiol means a -SH group.
  • cyano means a -CN group.
  • hydroxyl or “hydroxy” means an -OH group.
  • carboxylic acid means a -COOH group.
  • Ci-Cn-alkyl refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the carbon atoms having 1 to n carbon atoms, for example, any one of the radicals 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 -
  • C2-Cn-alkenyl refers to a straight or branched alkenyl chain moiety having from two to n carbon atoms and one or two double bonds, for example, ethenyl, prop-1 -enyl, but-2-enyl.
  • Cs-Cn-cycloalkyl refers to three (3) to n membered cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Ci-Cn-alkoxy refers to a straight-chain or branched saturated alkyl radical having one (1 ) to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1 -methylethoxy, n-butoxy, 1 -methylpropoxy, 2-methyl propoxy and 1 ,1 -dimethylethoxy.
  • Ci-Cn-alkoxy Ci-C n alkoxy refers to a radical of the formula R a -O-Rb- wherein R a is a Ci-C n alkyl radical as generally defined above, and Rb is a Ci-C n alkoxy radical as generally defined above.
  • Ci-C n -haloalkyl refers to a straight-chain or branched saturated alkyl radical attached via any of the carbon atoms having 1 to n carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by fluorine, chlorine, bromine and/or iodine, i.e., for example, any one of 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-difluoroe
  • Ci-C n -haloalkoxy refers to a Ci-Cn-alkoxyl radical substituted with one or more halo atoms which may be the same or different.
  • controlling refers to reducing the number of pests, eliminating pests and/or preventing further pest damage such that damage to a plant or to a plant derived product is reduced.
  • pest refers to insects, and molluscs that are found in agriculture, horticulture, forestry, the storage of products of vegetable origin (such as fruit, grain, and timber); and those pests associated with the damage of man-made structures.
  • the term pest encompasses all stages in the life cycle of the pest.
  • the term "effective amount” refers to the amount of the compound, or a salt thereof, which, upon single or multiple applications provides the desired effect.
  • room temperature or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15° C to about 35° C.
  • rt can refer to a temperature of about 20° C to about 30° C.
  • the compounds of formula (I) can be used in the agricultural sector and related fields of use, e.g., as versatile intermediates, or as active ingredients for controlling plant pests or on non-living materials for the control of spoilage microorganisms or organisms potentially harmful to man.
  • the compounds of formula (I) are useful as versatile intermediates for the preparation of 3-aryl-1 ,2,4-oxadiazole-derivatives, which show a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi, particularly phytopathogenic fungi especially Phakopsora pachyrhizi, Corynespora cassiicola, or Diaporthe spp., like Diaporthe miriciae, also known as Diaporthe ueckeri or Diaporthe ueckerae.
  • the compounds of formula (I) have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi.
  • the compounds of formula (I) are particularly suitable for use as a fungicide.
  • the compounds of formula (I) are suitable for control of diseases caused by phytopathogenic fungi especially Phakopsora pachyrhizi, causal agent of Asian soybean rust, and to a method of controlling diseases on useful plants, especially soybeans.
  • the compounds of formula (I) are suitable for control of diseases caused by phytopathogenic fungi especially phytopathogenic microorganism Corynespora cassiicola, and to a method of controlling diseases on useful plants, for example on soybean or cotton.
  • the compounds of formula (I) are suitable for controlling Phakopsora pachyrhizi in genetically modified plants.
  • the genetically modified plants are soybean plants. More preferably said genetically modified soybean plants are Bt soybean plants, even more preferably Bt soybean plants selected from Intacta RR2 PRO®, or Conkesta Enlist E3®.
  • the compounds of formula (I) are suitable for control of the phytopathogenic microorganism Corynespora cassiicola, in genetically modified plants, for example on soybean or cotton.
  • the genetically modified plants are soybean plants. More preferably said genetically modified soybean plants are Bt soybean plants, even more preferably Bt soybean plants selected from Intacta RR2 PRO®, or Conkesta Enlist E3®.
  • fungicide as used herein means a compound that controls, modifies, or prevents the growth of fungi. According to this particular aspect of the invention, the use may exclude methods for the treatment of the human or animal body by surgery or therapy.
  • compound of formula (III) in the process for preparation of compounds of formula (I), is a haloacetic ester of formula (II) wherein R 2 is as defined for compounds of formula (I), and R 6 is Ci-Ci2-alkyl, vinyl or benzyl.
  • R 2 is trifluoromethyl, or difluoromethyl; and R 6 is Ci-C4-alkyl.
  • R 2 is trifluoromethyl, or difluoromethyl; and R 6 is methyl, ethyl or butyl.
  • R 2 is trifluoromethyl
  • R 6 is methyl, ethyl or butyl.
  • the compound of formula (III) is selected from methyl trifluoroacetate, ethyl trifluoroacetate, or butyl trifluoroacetate.
  • the amount of haloacetic ester of formula (III) in the process for the preparation of compound of formula (I) according to the present invention, can be from 1 .0 to 3.0 eq., from 1 .0 to 2.0 eq., from 1 .0 to 1 .5 eq., from 1 .0 to 1 .25 eq., from 1 .0 to 1.1 eq., or from 1 .0 to 1 .05 eq., based on the number of moles (mol) of amidoxime compound of formula (II).
  • the molar ratio of haloacetic ester of formula (III), to amidoxime compound of formula (II) can be from 3:1 to 1 :1 , or from 2.5:1 to 1 :1 or from 2:1 to 1 :1 or from 1 .5:1 to 1 :1 , or from 1 .25:1 to 1 :1 , or from 1 .1 :1 to 1 :1 , or from 1.05:1 to 1 :1.
  • the process in the process for the preparation of compound of formula (I) according to the present invention, is carried out in the presence of at least one base, wherein said base is a guanidine-base.
  • the guanidine-base in the process for the preparation of compound of formula (I) according to the present invention, is not identical with a compound of formula (I), (II), (III), or an inert organic solvent as defined herein.
  • Guanidines have been known to chemists for over 150 years now (Strecker, A. Liebigs Ann. Chem. 1861 , 118, 151) and are well recognized primarily 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 useful reagents and catalysts in organic synthesis (I, P. Selig (Ed , Topics in Heterocycl. Chem., Springer, 2017, vol. 50).
  • guanidines act as very strong nucleophilic base, and given their most interesting potential, it is quite surprising that the use of guanidines for the process of the present invention acting as nucleophilic base has not been reported up to now.
  • the guanidine-bases suitable for preparation of compounds of 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's base), 1 ,1 ,2,3-tetramethylguanidine, guanidine carbonate (Diguanidinium 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-tetramethylgu
  • the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of at least one base, wherein said base is a guanidine base, wherein said guanidine base is 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 (diguanidinium 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-1 H-imidazo[1 ,2-a]imidazole, 1 ,5,
  • the process for the preparation of a compound of 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.
  • the process for the preparation of a compound of formula (I) is carried out in the presence of 1 ,1 ,3,3-tetramethylguanidine, 2-tert-buty 1-1 ,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.
  • the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 1 ,1 ,3,3- tetramethylguanidine.
  • the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 1 ,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD).
  • the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 2-tert- butyl-1 ,1 ,3,3-tetramethylguanidine.
  • the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) is carried out in the presence of 7-methyl- 1 ,5,7-triazabicyclo[4.4.0]dec-5-ene.
  • the amount of said guanidine-base in the process for the preparation of compound of formula (I) according to the present invention, can be from 0.05 to 3.0 eq., from 0.1 to 2.5 eq., from 0.1 to 2.0 eq., from 0.1 to 1.5 eq., from 0.1 to 1.25 eq., based on the number of moles (mol) of amidoxime compound of formula (II).
  • the molar ratio of said guanidine-base to amidoxime of formula (II) can be from 3:1 to 0.1 :1 , or from 1 .25 :1 to 0.2:1 , preferably from 1.25:1 to 0.2:1 , or from 1.25:1 to 0.25:1 , or from 0.02:1 to 0.2:1.
  • the process for the preparation of compound of formula (I) can be carried out in the presence of an additional base, wherein said additional base is selected from an inorganic base or an organic base, and wherein said additional base is not a guanidine base.
  • suitable second bases include inorganic bases and organic bases.
  • Example of suitable inorganic bases are for example, but not limited to alkali metal and alkaline earth metal phosphates; alkali metal and alkaline earth metal formats; 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.
  • the inorganic base is selected from alkali metal carbonates or alkali metal acetates, or any combination thereof. Particular preferred are sodium carbonate, potassium carbonate, or sodium acetate.
  • alkali metal refers to the elements in group 1 of the Periodic Table, preferably to lithium (Li), sodium (Na), or potassium (K).
  • organic bases are for example, but no limited to tertiary amines, substituted or nonsubstituted pyridine, bicyclic amines, alkali metal Ci-Csalkoxylates, and mixtures thereof.
  • the organic base is selected from trimethylamine, triethylamine, tributylamine, diisopropylethylamine, pyridine, N,N- dimethylaminopyridine, 2,4,6-collidine, 2,6-lutidine, 2-picoline, 3-picoline, 4-picoline, 5- ethyl-2-methyl-pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or mixtures thereof.
  • said organic base is selected from triethylamine.
  • the process for the preparation of compound of formula (I) can be carried out in the presence of an acid.
  • Example of suitable acids are for example, but not limited to organic acids or inorganic acids.
  • Suitable organic acids are for example, but no limited to acetic acid, citric acid, formic acid, benzoic acid, lactic acid, trifluoracetic acid, propionic acid, and any combination thereof.
  • acetic acid citric acid
  • formic acid formic acid
  • benzoic acid lactic acid
  • trifluoracetic acid propionic acid
  • the acid is selected from acetic acid, citric acid or trifluoroacetic acid.
  • the preparation of compounds of formula (I) by reaction of a compound of formula (II) with compounds of formula (III) in the presence of at least one base, wherein said base is a guanidine-base can be carried out in the presence of an inert organic solvent, or mixtures of such solvents.
  • inert organic solvent refers to an organic solvent, which does not enter into any appreciable reaction with either the reactants or the products under the reaction conditions of the process of this invention.
  • organic solvent that can be used for the process of the present invention is one that will be suitable of dissolving compounds of formula (II) and miscible with the base being used.
  • a person of skill in the art will recognize that there are a number of organic solvents which meet these specifications.
  • Suitable organic solvents are, but not limited to polar protic solvent, polar aprotic solvent, or a nonpolar solvent.
  • polar protic solvents include, but are not limited to, methanol, ethanol, /-propanol, n-butanol, terf- butanol, or 2-pentanol.
  • polar aprotic solvents include, but are not limited to, acetone, acetonitrile, dimethyl sulfoxide (DMSO), dichloromethane (DCM), dimethyl carbonate, A/,A/-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).
  • NMP N-methyl-2- pyrrolidone
  • THF tetrahydrofuran
  • Me-THF 2-methyltetrahydrofuran
  • tetramethylene sulfone sulfolane
  • nonpolar solvents are, but not limited to, hydrocarbon solvents, like alkanes and aromatic solvents, for example pentane, hexane, methylcyclohexane, toluene and xylene; ether solvents, for example 1 ,4- dioxane, diethyl ether, or chloroform.
  • hydrocarbon solvents like alkanes and aromatic solvents, for example pentane, hexane, methylcyclohexane, toluene and xylene
  • ether solvents for example 1 ,4- dioxane, diethyl ether, or chloroform.
  • the organic solvent may be selected from 2-butanol, n-butanol, ethanol, i-butanol, 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.
  • the process of the present invention can be carried out under atmospheric pressure or under elevated or reduced pressure. Typically, the atmospheric and elevated pressure is employed. In a preferred embodiment the process of the present invention can be carried out at pressure ranges typically from 0.8 atmospheres (atm) to 80 atm, preferably form 1 .0 atm to 20 atm, in particular from 1 .0 to 7 atm.
  • the temperature used in the process of the present invention can vary widely and is preferably from -30 to 150°C, more preferably from -10 to 120°C, or even more preferably from 0 to 100°C, 20 to 80°C, or 25 to 75°C.
  • Typical reaction times are in the range of from 1 to 20 hours, preferably from 1 to 15 hours, or more preferably from 1 to 10 hours, or from 1 to 5 hours.
  • R 1 is wherein the staggered line denotes the connection to the phenyl-group.
  • R 1 is wherein the staggered line denotes the connection to the phenyl-group.
  • R 1 is wherein the staggered line denotes the connection to the phenyl-group.
  • R 2 is selected from Ci-C2-haloalkyl.
  • R 2 is CF3, or CF2CI.
  • R 2 is CF3.
  • R 2 is CF2CI.
  • R 3 is selected from hydrogen, Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, or cyclopropyl.
  • R 3 is hydrogen, methyl, ethyl, methoxy, ethoxy, or cyclopropyl.
  • R 4 is selected from Ci-Cs-alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, C3-C6- cycloalkyl, Ci-C 2 -alkoxy-Ci-C3-alkyl, or phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen.
  • R 4 is methyl, ethyl, methoxy, ethoxy, cyclopropyl, 1 -methoxyethyl, or 2-fluoro-phenyl.
  • R 5 is selected from hydrogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or C1-C4- alkoxy-Ci-C 2 -alkoxy.
  • R 5 is hydrogen, Ci-Cs-alkoxy, or Ci-Cs-haloalkoxy. More preferably R 5 is hydrogen, methoxy, ethoxy, or methoxy-ethoxy.
  • W is selected from O, or S. In one embodiment of the invention, W is O. In another embodiment of the invention, W is S.
  • R 6 is selected from Ci-Ci 2 -alkyl, C 2 -C6-alkenyl, Ci-Cs-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl.
  • R 6 is Ci-Ci 2 -alkyl, vinyl or benzyl. More preferably, R 6 is methyl, ethyl, /-propyl, n-butyl, tert-butyl, vinyl or benzyl. Even more preferably, R 6 is methyl, ethyl, n-butyl, or terf-butyl.
  • the present invention accordingly, makes available a compound of formula (I) having R 1 , R 2 , R 3 , R 4 , R 5 and W, as defined above in all combinations / each permutation.
  • Embodiments according to the invention are provided as set out below.
  • the present invention relates to a process for the preparation of compounds of formula (I) wherein
  • R 2 is selected from Ci-C2-haloalkyl
  • R 3 is selected from hydrogen, Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, or cyclopropyl;
  • R 4 is selected from Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, Cs-Ce-cycloalkyl, Ci-C2-alkoxy-Ci-C3-alkyl, or phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen;
  • R 5 is selected from hydrogen, Ci-C4-alkoxy, Ci-C4-haloalkoxy, or Ci-C4-alkoxy-Ci-C2-alkoxy; and W is selected from O, or S; said process comprising the reaction of an amidoxime compound of formula (II) wherein R 2 is as defined for compounds of formula (I), and R 6 is selected from Ci-Ci2-alkyl, C2-Cs-alkenyl, C1- Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; in the presence of at least one base, wherein said base is a guanidine-base, and wherein said guanidine-base is selected from 1, 7,3,3-tetramethylguanidine, 2-tert-butyl-1 ,1 ,3,3-tetramethylguanidine,
  • R 2 is CF 3 , or CF 2 CI
  • R 3 is hydrogen, methyl, ethyl, methoxy, ethoxy, or cyclopropyl
  • R 4 is methyl, ethyl, methoxy, ethoxy, cyclopropyl, 1 -methoxyethyl, or 2-fluoro-phenyl;
  • R 5 is hydrogen, methoxy, ethoxy, or methoxy-ethoxy
  • R 6 is Ci-Ci 2 -alkyl, C 2 -C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine- base, and wherein said guanidine-base is selected from 7, 7,3,3-tetramethylguanidine, 2-terf-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.
  • the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning
  • R 2 is CF 3 ;
  • R 3 is hydrogen, or Ci-C 2 -alkoxy
  • R 4 is Cs-Ce-cycloalkyl, or Ci-C 2 -alkoxy-Ci-C3-alkyl
  • R 6 is Ci-Ci 2 -alkyl, C 2 -C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine- base, and wherein said guanidine-base is selected from 1, 7,3,3-tetramethylguanidine, 2-fert-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.
  • the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning
  • R 2 is CF 3 ;
  • R 3 is hydrogen, or methoxy
  • R 4 is cyclopropyl, or 1 -methoxyethyl
  • R 6 is methyl, ethyl, /-propyl, n-butyl, tert-butyl, vinyl or benzyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine- base, and wherein said guanidine-base is selected from 1, 7,3,3-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.
  • the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning
  • R 2 is CF 3 ;
  • R 3 is methyl, or 2-fluorophenyl
  • R 4 is hydrogen
  • R 6 is Ci-Ci2-alkyl, C2-Cs-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine- base, and wherein said guanidine-base is selected from 7, 7,3,3-tetramethylguanidine, 2-terf-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.
  • the present invention relates to a process for the preparation of compounds of formula (I), from compounds of formula (II) and formula (III), wherein the variables in compounds of formula (I), (II), (III) have the following meaning
  • R 2 is CF 3 , or CF2CI
  • R 3 is hydrogen, cyclopropyl, or Ci-C2-alkoxy
  • R 4 is Ci-Cs-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, Cs-Ce-cycloalkyl, or Ci-C2-alkoxy-Ci-C3-alkyl;
  • R 6 is Ci-Ci2-alkyl, C2-Cs-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine- base, and wherein said guanidine-base is selected from 1, 7,3,3-tetramethylguanidine, 2-fert-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.
  • R 2 is CF 3 , or CF2CI
  • R 5 is hydrogen, methoxy, ethoxy, or methoxy-ethoxy
  • R 6 is Ci-Ci2-alkyl, C2-Cs-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine- base, and wherein said guanidine-base is selected from 7, 7,3,3-tetramethylguanidine, 2-terf-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.
  • R 2 is CF3
  • R 6 is Ci-Ci2-alkyl, C2-C6-alkenyl, Ci-Ce-haloalkyl, phenyl, or benzyl, wherein said phenyl and benzyl are unsubstituted or substituted by 1 or 2 substituents individually selected from halogen, or Ci-C4-alkyl; wherein said process is carried out in the presence of at least one base, wherein said base is a guanidine- base, and wherein said guanidine-base is selected from 1, 7,3,3-tetramethylguanidine, 2-fert-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.
  • the compound of formula (I) is selected from N-methoxy-N-[[4-[5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide according to structure (l-A)
  • compound of formula (I) is N-methoxy-N-[[4-[5-(trifluoromethyl)-
  • compound of formula (I) is N,2-dimethoxy-N-[[4-[5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]propanamide according to structure (l-B).
  • compound of formula (I) is N-(2-fluorophenyl)-4-[5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzamide according to structure (l-H).
  • compound of formula (I) is N-methyl-4-[5-(trifluoromethyl)-
  • the compound of formula (I) is ethyl 1-[[4-[5-(trifluoromethyl)-
  • the compound of formula (I) is 4-(2-methoxyethoxy)-2-[[4-[5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]pyridazin-3-one according to structure (l-E).
  • the compound of formula (I) is ethyl 1-[[4-[5- [chloro(difluoro)methyl]-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]pyrazole-4-carboxylate according to structure (l-F).
  • the compound of formula (I) is 5,5-dimethyl-2-[[4-[5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]phenyl]methyl]isoxazolidin-3-one according to structure (l-G).
  • the compound of formula (I) is 3-(p-tolyl)-5-(trifluoromethyl)-
  • a compound of formula (I), wherein R 1 is methyl is converted to a valuable chemical product or other intermediate. Accordingly, in one embodiment, compounds of formula (I) wherein R 1 is methyl, can be further chlorinated to obtain a compound of formula (l-a), and wherein R 2 is as defined as for compounds of formula (I)
  • methyl-group (R 1 ) of compounds of formula (I) can be converted to a trichloromethyl-group as disclosed in WO2019/020451 A1 and references cited therein.
  • the present invention also relates to intermediates of any of formulae (V) and (VI) which are formed in the process of the invention from the step of reacting a compound of formula (II) with a compound of formula (III) in the presence of a guanidine base (Scheme 1 ).
  • the intermediates so obtained may be characterized by any suitable analytical techniques such as NMR and IR spectroscopy.
  • the compound of formula (III) reacts with a guanidine-base to the corresponding acetamide of formula (V), and then the acyl-moiety is transferred to the compound of formula (II) under formation of intermediate of formula (VI).
  • the guanidine-base may act as acyl- transfer reagent.
  • R 7 , R 8 , R 9 , R 10 are independently selected from hydrogen, or methyl and R 2 is Ci-C2-haloalkyl.
  • R 7 , R 8 , R 9 , R 10 are independently selected from hydrogen, or methyl and R 2 is trifluoromethyl, or difluoromethyl.
  • the compounds of formula (I) according to the invention may be prepared using the synthetic techniques described both above and below. Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. Free radicals represent methyl groups. 1 H NMR and 19 F NMR measurements were recorded on a Bruker 400MHz spectrometer (or as indicated), chemical shifts are given in ppm relevant to a TMS ( 1 H) and CFCI3 ( 19 F) standard. Spectra measured in deuterated solvents as indicated.
  • Example P1 Preparation of N-methoxy-N- r5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yllphenyl1methyl1- cyclopropanecarboxamide with ethyl trifluoroacetate (Compound P-1 , Table P)
  • a screening vial is at room temperature charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N- methoxy-cyclopropanecarboxamide (amidoxime) (94%, 280 mg, 1 mmol) and butyl acetate (2 mL) to obtain a suspension.
  • ethyl trifluoroacetate 99%, 287 mg, 2 mmol
  • TMG 99%, 144 mg, 1.25 mmol
  • Example P2 Preparation of N-methoxy-N-IT4-r5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yllphenyl1-methyl1- cyclopropanecarboxamide with methyl trifluoroacetate (Compound P-1 , Table P)
  • a screening vial is at room temperature charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N- methoxy-cyclopropanecarboxamide (amidoxime) (94%, 280 mg, 1 mmol) and butyl acetate (2 mL) to obtain a suspension.
  • methyl trifluoroacetate 99%, 259 mg, 2 mmol
  • TMG 99%, 144 mg, 1.25 mmol
  • Example P3 Preparation of N-methoxy-N- r5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yllphenyl1methyl1- cyclopropanecarboxamide with ethyl trifluoroacetate (Compound P-1 , Table P)
  • a screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy- cyclopropanecarboxamide (98%, 4 mmol, 1.07 g), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1 .21 g), and the resulting suspension is stirred for 2 min at 50°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 50°C.
  • a screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N,2-dimethoxy- propanamide (97%, 4 mmol, 1 .16 g), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1 .21 g), and the resulting suspension is stirred for 2 min at 50°C followed by addition of TMG (99%, 4.4 mmol, 511.9 mg) and this reaction mixture is stirred for 4 hrs at 50°C.
  • a screening vial (20 mL) is charged with N'-hydroxybenzamidine (98%, 4 mmol, 555.7 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1 .21 g), and the resulting suspension is stirred for 2 min. at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 60°C.
  • Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1 ,3,5- trimethoxybenzene as internal standard. Chemical yield 92% (product in aqueous and organic layer). Isolated yield (product in organic layer): 91 %.
  • a screening vial (20 mL) is charged with methyl 4-[N'-hydroxycarbamimidoyl]benzoate (97%, 4 mmol, 800.8 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1 ,3,5-trimethoxybenzene as internal standard. Chemical yield 89% (product in aqueous and organic layer). Isolated yield (product in organic layer): 88%
  • Example P9 Preparation of 4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl1benzonitrile (Compound P-7, Table P)
  • a screening vial (20 mL) is charged with 4-cyano-N-hydroxybenzimidamide, (97%, 4 mmol, 664.6 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1 .21 g), and the resulting suspension is stirred for 2 minutes at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 60°C.
  • a screening vial (20 mL) is charged with 4-bromo-N'-hydroxy-benzamidine (98%, 4 mmol, 878.0 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1 .21 g), and the resulting suspension is stirred for 2 minutes at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layers are separated and both layers are analyzed by quantitative NMR analysis using 1 ,3,5-trimethoxybenzene as internal standard. Chemical yield 94% (product in aqueous and organic layer). Isolated yield (product in organic layer): 90%
  • a screening vial (20 mL) is charged with 4-chloro-N'-hydroxy-benzamidine (97%, 4 mmol, 703.5 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1 .21 g), and the resulting suspension is stirred for 2 minutes at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layer are separated and both layers are analyzed by quantitative NMR analysis using 1 ,3,5-trimethoxybenzene as internal standard. Chemical yield 93% (product in aqueous and organic layer). Isolated yield (product in organic layer): 92%
  • a screening vial (20 mL) is charged with 4-(N-hydroxycarbamirnidoyl)-N-methyl-benzarnide (95%, 4 mmol, 813.5 mg), BuOAc (2 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. Water (1 g) is added, the layers are separated at 50°C and both layers are analyzed by quantitative NMR analysis using 1 , 3, 5-tri methoxybenzene as internal standard. Chemical yield 94% (product in aqueous and organic layer). Isolated yield (product in organic layer): 90%
  • a screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy- cyclopropanecarboxamide (98%, 4 mmol, 1.07 g), BuOAc (3 mL) and ethyl trifluoroacetate (98%, 8.4 mmol, 1 .06 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hours at 60°C.
  • a screening vial (20 mL) is charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy- cyclopropanecarboxamide (98%, 4 mmol, 1.07 g), BuOAc (2 mL) and ethyl chlorodifluoroacetate (97%, 8.4 mmol, 1 .37 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hours at 60°C.
  • a screening vial (20 mL) is charged with N-(2-fluorophenyl)-4-[(Z)-N-hydroxycarbamimidoyl]benzamide (95%, 4 mmol, 1 150.6 mg), BuOAc (4 mL) and ethyl trifluoroacetate (99%, 8.4 mmol, 1.21 g), and the resulting suspension is stirred for 2 min at 60°C followed by addition of TMG (99%, 4.4 mmol, 511 .9 mg) and this reaction mixture is stirred for 4 hrs at 60°C. The reaction mixture is cooled to rt, and the final product is filtered and analyzed by quantitative NMR analysis using 1 ,3,5-trimethoxybenzene as internal standard. Chemical yield 97% (product in aqueous and organic layer). Isolated yield 90% (product in organic layer).
  • a screening vial is at rt charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N-methoxy- cyclopropanecarboxamide (4 mmol, amidoxime) and butyl acetate (0.5 mL/mmol amidoxime) to obtain a suspension.
  • ethyl trifluoroacetate 2.1 eq. based on amidoxime
  • TMG 1.1 eq. based on amidoxime
  • a screening vial is at room temperature charged with N-[[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]-N- methoxy-cyclopropanecarboxamide (4 mmol, amidoxime) and solvent to obtain a suspension.
  • ethyl trifluoroacetate (2 to 2.2 eq. based on amidoxime)
  • 1 ,1 ,3,3-tetramethylguanidine 1.1 to 1.25 eq. based on amidoxime
  • the resulting reaction mixture is stirred at 30 to 75°C (see examples) for 4 to 5 hrs (homogenous after 10 min).
  • Table B2 Solvent Screening with 2.1 eq. ethyl trifluoroacetate, 1.1 eq. TMG, 0.75 mL solvent/mmol amidoxime
  • Table B3 Solvent Screening with 2.2 eq. ethyl trifluoroacetate, 1 .25 eq. TMG, 2 mL solvent/mmol amidoxime b]: determined by quantitative HPLC analysis, [c]: determined by quantitative NMR analysis of reaction mixture using 1,2,3-trimethoxybenzene as internal standard
  • Table B4 Solvent Screening with 45 mmol amidoxime 2.1 eq. ethyl trifluoroacetate, 1.1 eq. TMG, 0.5 mL solvent/mol amidoxime, 60°C
  • the organic solvent that can be used is not restricted due to the nature of the base used.
  • the above results show that high yields of the required oxadiazole derivatives were achieved by using TMG as a base at moderate reaction temperatures in various solvents.

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Abstract

La présente invention concerne, entre autres, un procédé de préparation de dérivés d'oxadiazole substitués de formule (I), qui peuvent être obtenus par réaction d'amidoximes de formule (II) en présence d'une base guanidine organique, les substituants étant tels que définis dans les revendications. La présente invention concerne en outre des composés intermédiaires utilisés dans ledit procédé, et des procédés de production desdits composés intermédiaires.
PCT/EP2025/052520 2024-02-02 2025-01-31 Procédé de préparation de dérivés d'oxadiazole microbiocides Pending WO2025163139A1 (fr)

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