WO2020025574A1 - Procédé de préparation de 6-(haloalkyl)-2-halo-5-acylpyridines et d'intermédiaires pour ce procédé - Google Patents

Procédé de préparation de 6-(haloalkyl)-2-halo-5-acylpyridines et d'intermédiaires pour ce procédé Download PDF

Info

Publication number
WO2020025574A1
WO2020025574A1 PCT/EP2019/070426 EP2019070426W WO2020025574A1 WO 2020025574 A1 WO2020025574 A1 WO 2020025574A1 EP 2019070426 W EP2019070426 W EP 2019070426W WO 2020025574 A1 WO2020025574 A1 WO 2020025574A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
process according
alkyl
haloalkyl
Prior art date
Application number
PCT/EP2019/070426
Other languages
English (en)
Inventor
Florian ERVER
Dirk Eckart Brohm
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2020025574A1 publication Critical patent/WO2020025574A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for preparing 6-(haloalkyl)-2-halo-5-acylpyridines, and optionally further reacting such pyridines to triazole derivatives. It further relates to a process for preparing certain hydroxypyridine derivatives which are useful educts in said process for preparing 6-(haloalkyl)-2- halo-5-acylpyridines.
  • 6-(haloalkyl)-2-halo-5-acylpyridines are known to be valuable intermediates in the synthesis of compounds useful in the field of crop protection.
  • WO 2017/029179 Al discloses fungicidal triazole compounds and several routes to synthesize those.
  • One of said routes is referred to in WO 2017/029179 Al as process B and comprises synthesis of 6-(haloalkyl)-2-halo-5-acylpyridines which are converted in several steps to triazole derivatives.
  • 6-(haloalkyl)-2-halo-5-acylpyridines are formed by converting dihalogenated pyridine derivatives into Grignard compounds and subsequently reacting such Grignard compounds with acyl chlorides to the desired compounds.
  • object of the invention is provision of an process for the synthesis of 6-(haloalkyl)-2-halo-5- acylpyridines that avoids the drawbacks of the known method.
  • 6-(haloalkyl)-2-halo-5-acylpyridines can be synthesized in high yield starting from certain 2-hydroxynicotinic acid derivatives or the respective carbonitriles. This process avoids the need of employing dihalogenated pyridine derivatives and the drawbacks associated therewith.
  • subject of this invention is a process for preparing a compound of formula (I)
  • R represents Ci-C2-alkyl or Ci-C2-haloalkyl
  • R 1 represents Ci-C 6 -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cx-Cx-cycloalkyl, Cs-Cs-cycloalkyl-Ci-C t - alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C2-C4-alkenyl or phenyl-C2-C4-alkynyl
  • X represents chlorine or bromine
  • R A represents -CN or -COOH; and R is defined as in formula (I); is reacted in a first step A) with a a dehydroxyhalogenation agent selected from COCL, diphosgene, triphosgene, cyanuric chloride, SO Cl 2 , SO 2 CI 2 , PCI 3 , PCI 5 , POCI 3 , PBr 3 , SOBr 2 and S02Br2, to arrive at a compound of formula (III)
  • a dehydroxyhalogenation agent selected from COCL, diphosgene, triphosgene, cyanuric chloride, SO Cl 2 , SO 2 CI 2 , PCI 3 , PCI 5 , POCI 3 , PBr 3 , SOBr 2 and S02Br2
  • R B represents -CN or -COX; and X and R are defined as in formula (I); and the compound of formula (III) is reacted in step B) with a compound of formula (IV) ⁇ M 1 (IV), wherein
  • M 1 represents Li or MgY, wherein Y represents chlorine or bromine; and R 1 is defined as in formula (I).
  • Formula (I) provides a general definition of the pyridines obtainable by the process according to the invention.
  • Preferred radical definitions for formula (I) shown above and below are given below. These definitions apply to compounds of formula (I) and likewise to all educts, intermediates and products bearing the respective radical(s).
  • R preferably represents Ci-C 2 -haloalkyl.
  • R more preferably represents Ci-haloalkyl.
  • R more preferably represents CF 3 , CHF 2 or CFLF.
  • R most preferably represents CF 3 .
  • R 1 preferably represents Ci-C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cyclopropyl, phenyl, benzyl, phenylethenyl or phenylethinyl.
  • R 1 more preferably represents methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, allyl, CFhCoC- CH 3 or CH 2 CoCH.
  • R 1 more preferably represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl.
  • R 1 more preferably represents methyl or ethyl.
  • R 1 most preferably represents methyl
  • X most preferably represents chlorine.
  • Formulae (II) and (III) provide a general definition of the educt and product of step B) of the process according to the invention. Preferred radical definitions those formulae shown above and below are given below.
  • R A preferably represents -COOH.
  • R B preferably represents -COX.
  • Formula (IV) provides a general definition of the organometallic compounds used in step B) of the process according to the invention. Preferred radical definitions for formula (IV) shown above and below are given below.
  • M 1 preferably represents MgY, wherein Y represents chlorine or bromine, preferably bromine.
  • M 1 preferably represents Li.
  • step B) compounds of formula (III) are reacted with a organometallic reagent of formula (IV).
  • the organometallic reagent is a Grignard reagent represented by formula (IV’) R ⁇ MgY (IV’), wherein
  • Y represents chlorine or bromine, preferably bromine; and R 1 is defined as in formula (I).
  • Grignard compounds undergo a solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenk equilibrium.
  • the Schlenk equilibrium for the Grignard reagent according to formula (IV’) can be schematically illustrated as follows:
  • solvent molecules in particular ethers such as diethylether or THF, which are commonly used for reactions with Grignard reagents, can add to the magnesium of the Grignard reagent thereby forming etherates.
  • formula (IV’) encompasses not only the structures as depicted, but also the structures resulting from the Schlenk equilibrium as well as the respective solvent adducts.
  • radical definitions and explanations given above in general terms or stated within preferred ranges can also be combined with one another as desired, i.e. including between the particular ranges and preferred ranges. They apply both to the end products and correspondingly to precursors and intermediates. In addition, individual definitions may not apply. Preference is given to those cases in which each of the radicals have the abovementioned preferred definitions.
  • a dehydroxyhalogenation agent selected from COCL, diphosgene, triphosgene, cyanuric chloride, SOCL, SO2CI2, PCL, PCL, or POCI3, to arrive at a compound of formula (Ilia)
  • M 1 represents Li or MgY, wherein Y represents chlorine or bromine, preferably bromine.
  • Y represents chlorine or bromine, preferably bromine.
  • Ci-C 6 -alkyl comprises the largest range defined here for an alkyl radical. Specifically, this definition comprises the meanings methyl, ethyl, n-, isopropyl, n-, iso-, sec-, tert-butyl, and also in each case all isomeric pentyls and hexyls, such as methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2- dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, 1 -methylpentyl, 2- methylpentyl, 3 -methylpentyl, 4-methylpentyl, 1 ,2-
  • Ci-C4-alkyl such as methyl, ethyl, n-, isopropyl, n-, iso-, sec-, tert-butyl.
  • Ci-C2-alkyl comprises methyl and ethyl.
  • halogen comprises fluorine, chlorine, bromine and iodine. Halogen-substitution is generally indicated by the prefix halo, halogen or halogeno.
  • Halogen-substituted alkyl - e.g. referred to as halogenalkyl, halogenoalkyl or haloalkyl, e.g. C1-C4- haloalkyl or Ci-C2-haloalkyl - represents, for example, Ci-C4-alkyl or Ci-C2-alkyl as defined above substituted by one or more halogen substituents which can be the same or different.
  • C1-C4- haloalkyl represents chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2- dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1,1-difluoroethyl, pentafluoroethyl, 1 -fluoro- 1 -methylethyl, 2- fluoro- 1 , 1 -dimethylethyl, 2-fluoro- 1 -fluoromethyl- 1 -methylethyl, 2-
  • Ci-C2-haloalkyl represents chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2- fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1,1-difluoroethyl, pentafluoroethyl.
  • C2-C6-alkenyl comprises the largest range defined here for an alkenyl radical. Specifically, this definition comprises the meanings ethenyl, n-, isopropenyl, n-, iso-, sec-, tert-butenyl, and also in each case all isomeric pentenyls, hexenyls, 1 -methyl- 1-propenyl, 1 -ethyl- 1 -butenyl.
  • Halogen-substituted alkenyl - referred to as C2-C6-haloalkenyl - represents, for example, C2-C6-alkenyl as defined above substituted by one or more halogen substituents which can be the same or different.
  • C2-C6-alkynyl comprises the largest range defined here for an alkynyl radical. Specifically, this definition comprises the meanings ethynyl, n-, isopropynyl, n-, iso-, sec-, tert-butynyl, and also in each case all isomeric pentynyls, hexynyls.
  • Halogen-substituted alkynyl - referred to as C2-C6-haloalkynyl - represents, for example, C2-C6-alkynyl as defined above substituted by one or more halogen substituents which can be the same or different.
  • Cs-Cs-cycloalkyl comprises monocyclic saturated hydrocarbyl groups having 3 to 8 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • step A) of the process according to the present invention a compound of formula (II) is reacted with a dehydroxyhalogenation agent, selected from COCI2, diphosgene, triphosgene, cyanuric chloride, SOCI2, SO2CI2, PCh, PC1 5 , POCh, PBr 3 , SOBr 2 and S0 2 Br 2 .
  • a dehydroxyhalogenation agent selected from COCI2, diphosgene, triphosgene, cyanuric chloride, SOCI2, SO2CI2, PCh, PC1 5 , POCh, PBr 3 , SOBr 2 and S0 2 Br 2 .
  • the dehydroxyhalogenation agent is selected from POCI3, COCfr, diphosgene and triphosgene, more preferably from POCI3, COCfr and triphosgene.
  • Step A) can be conducted in presence or absence of a formamide catalyst.
  • the formamide catalyst is preferably selected from /V, /V- D i m ct by 1 fo rm amide, /V, /V- D i c t h y 1 fo r m a m i dc , NN- Diisopropylformamide, /V, /V- D i - n - b u t y 1 fo r m a m i d c and mixtures thereof, more preferably the formamide catalyst is /V, /V- D i m c t by 1 fo r m a m i d c or /V, /V- D i - n - bu ty 1 fo rm am i dc .
  • the amount of formamide catalyst in step A) of the process according to the invention is preferably 0.1 to 10 mole %, more preferably 0.5 to 8 mole %, more preferably 1 to 6 mole %, most preferably 1.5 to 6 mole %, each based on the molar amount of compound of formula (II).
  • step A) is carried out in the presence of an aprotic solvent, preferably selected from alkylbenzenes, chlorobenzenes, anisole, butyronitrile and mixtures thereof, more preferably selected from toluene, xylenes, mesitylene, chlorobenzene, butyronitrile and mixtures thereof, most preferred in the presence of toluene, xylenes and/or butyronitrile.
  • an aprotic solvent preferably selected from alkylbenzenes, chlorobenzenes, anisole, butyronitrile and mixtures thereof, more preferably selected from toluene, xylenes, mesitylene, chlorobenzene, butyronitrile and mixtures thereof, most preferred in the presence of toluene, xylenes and/or butyronitrile.
  • step A) is carried out at a temperature of 20°C to l50°C, preferably 50°C to l45°C.
  • the compound of formula (II) and the dehydroxyhalogenation agent are reacted in a molar ratio of 1 : 1.5 to 1 : 30, preferably 1 : 2 to 1 : 20, more preferred 1 : 2.2 to 1 : 19, even more preferred 1 : 2.5 to 1 : 4.5.
  • 1 equivalent of diphosgene or triphosgene correspond to 2 equivalents or 3 equivalents of phosgene as active chlorinating agent, respectively.
  • any reference to a molar amount of a compound or a molar ratio of two reactants is based on the total amount of the compound and reactants, respectively. Therefore, in case a mixture of a particular compound or reactant is present, the molar amount and molar ratio is based on the total amount of all members of this mixture. For example, if a mixture of two or more dehydroxyhalogenation agents is present in step A), the molar ratio is to be calculated based on the total amount of all present dehydroxyhalogenation agents. This applies mutatis mutandis for any reference to an amount by weight or volume and any weight or volume ratios.
  • Step A) may be performed in the presence of a base.
  • a base preferably include alkali metal or alkaline earth metal acetates, for example sodium acetate, potassium acetate or calcium acetate, and also basic organic nitrogen compounds, for example trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N- dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2-methyl-, 3 -methyl-, 4-methyl-, 2,4-dimethyl-, 2,6- dimethyl-, 3,4-dimethyl- and 3,5-dimethylpyridine, 5-ethyl-2-methylpyridine, 4-dimethylaminopyridine, N-methylpiperidine, l,4-diazabicyclo[2.2.2]-o
  • the base is selected from basic organic nitrogen compounds, in particular trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, 1,4- diazabicyclo[2.2.2]-octane (DABCO), l,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or 1,8- diazabicyclo[5.4.0]-undec-7-ene (DBU) and mixtures thereof, more preferably from trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, and mixtures thereof.
  • the base is triethylamine or ethyl
  • step A) is performed under elevated pressure (> 1 atm), preferably at a pressure of 1.2 to 10 bar, more preferred 1.4 to 8 bar, most preferred 1.5 to 5 bar.
  • the preferred and particular preferred dehydroxyhalogenation agent is selected as outlined above.
  • no base is added.
  • the dehydroxyhalogenation agent used in step A) is selected from COCh (phosgene), diphosgene and triphosgene and step A) is performed under standard pressure (1 atm).
  • step A) comprises steps Al) and A2), wherein in the first step Al) the compound of formula (II) is reacted with a first dehydroxyhalogenation agent, and the resulting product is reacted in subsequent step A2) with a second dehydroxyhalogenation agent.
  • This embodiment is particularly preferred, if R A in formula (II) represents -COOH.
  • the first dehydroxyhalogenation agent used in step Al) is preferably selected from POCI3, COCfr, diphosgene, triphosgene and mixtures thereof, more preferably from POCI3 , COCfr and triphosgene.
  • the second dehydroxyhalogenation agent used in step A2) is preferably selected from SOCfr, SO2CI2 and mixtures thereof, more preferably the second dehydroxyhalogenation agent is SOCfr.
  • step Al) is carried out in the presence of an aprotic solvent, preferably selected from alkylbenzenes, chlorobenzenes, anisole, butyronitrile and mixtures thereof, more preferably selected from toluene, xylenes, mesitylene, chlorobenzene, butyronitrile and mixtures thereof, most preferred in the presence of toluene, xylenes, and/or butyronitrile.
  • an aprotic solvent preferably selected from alkylbenzenes, chlorobenzenes, anisole, butyronitrile and mixtures thereof, more preferably selected from toluene, xylenes, mesitylene, chlorobenzene, butyronitrile and mixtures thereof, most preferred in the presence of toluene, xylenes, and/or butyronitrile.
  • step Al) is carried out at a temperature of 20°C to 150°C, preferably 50°C to 145°C, more preferred 100°C to 145°C.
  • the molar ratio of compound of formula (II) and the dehydroxyhalogenation agent in step Al) is 1 : 1.5 to 1 : 20, preferably 1 : 2 to 1 : 15, more preferred 1 : 2 to 1 : 10, most preferred 1 : 2.2 to 1 : 10.
  • 1 equivalent of diphosgene or triphosgene correspond to 2 equivalents or 3 equivalents of phosgene as active chlorinating agent, respectively.
  • step Al) is carried out in the presence of a base. Description of bases in general and preferred bases given above for step A) apply also for step Al).
  • step A2) is preferably carried out in the presence of an aprotic solvent, preferably selected from alkylbenzenes, chlorobenzenes, anisole, butyronitrile and mixtures thereof, more preferably selected from toluene, xylenes, mesitylene, chlorobenzene, butyronitrile and mixtures thereof, most preferred in the presence of toluene, xylenes, and/or butyronitrile.
  • an aprotic solvent preferably selected from alkylbenzenes, chlorobenzenes, anisole, butyronitrile and mixtures thereof, more preferably selected from toluene, xylenes, mesitylene, chlorobenzene, butyronitrile and mixtures thereof, most preferred in the presence of toluene, xylenes, and/or butyronitrile.
  • step A2 More preferably, the same kind of solvent that is present in step Al), if any, is also used in step A2).
  • step A2) is carried out at a temperature of 20°C to 150°C, preferably 50°C to 120°C, more preferred 70°C to 100°C.
  • the dehydroxyhalogenation agent is present in a molar amount to arrive at a molar ratio of compound of formula (II) to dehydroxyhalogenation agent of 1 : 0.1 to 1 : 15, preferably 1 : 0.15 to 1 : 14, more preferred 1 : 0.15 to 1 : 13, more preferred 1 : 0.2 to 1 : 12, most preferred 1 : 0.2 to 1 : 1 1.
  • step A2) is carried out without addition of a base.
  • step A2) is performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • Both, step Al) and step A2) can be conducted in presence or absence of a formamide catalyst.
  • the amount of formamide catalyst in each of steps Al) and A2) of the process according to the invention is preferably 0.1 to 10 mole %, more preferably 0.5 to 8 mole %, more preferably 1 to 6 mole %, most preferably 1.5 to 6 mole %, each based on the molar amount of compound of formula (II).
  • reaction mixture resulting from step Al) can be directly used in step A2) without isolation or purification of the reaction product resulting from step Al).
  • the reaction mixture resulting from step Al) is worked-up by procedures generally known in the art before using it in step A2).
  • the reaction mixture is treated with water, an aqueous hydrogen chloride solution, an aqueous sodium chloride solution, an aqueous sodium sulfate solution and/or a saturated aqueous ammonium chloride solution.
  • the pH of the resulting mixture is subsequently adjusted to 8-12 by addition of a base, preferably alkali metal hydroxide, more preferred sodium hydroxide, an organic solvent, preferably selected from n-pentane, n-hexane, n-heptane, ethyl acetate and mixtures thereof, is added and the resulting organic and aqueous phases are separated.
  • the aqueous phase is preferably adjusted to pH 1 -4, preferably 1-2, by addition of an acid, preferably hydrochloric acid, to initiate precipitation of the desired compound.
  • the resulting suspension is cooled to -10 to 10°C, preferably 0 to 5°C to foster further precipitation and crystallization.
  • the resulting precipitate is preferably isolated by filtration and optionally further purified e.g. by washing with water. Finally, the resulting solid may be dried.
  • reaction mixture resulting from step A) or step A2) can be directly used in step B) without isolation or purification of the resulting compound of formula (III).
  • step B) of the process according to the invention is as pure as possible in order to maximize efficiency of this step.
  • the reaction mixture resulting from step A) or A2) is worked-up by procedures generally known in the art.
  • the reaction mixture is purified by evaporation of volatile components, in particular excess dehydroxyhalogenation agent, preferably under reduced pressure.
  • step B) is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, aromatic hydrocarbons, chlorinated aromatic hydrocarbons and mixtures thereof, more preferably selected from tetrahydrofuran, methyltetrahydrofuran, alkylbenzenes, chlorobenzenes and mixtures thereof, more preferably selected from tetrahydrofuran, methyltetrahydrofuran, toluene, xylenes, mesitylene, chlorobenzene and mixtures thereof, more preferably selected from tetrahydrofuran, methyltetrahydrofuran, toluene and mixtures thereof, most preferably selected from tetrahydrofuran, methyltetrahydrofuran and mixtures thereof.
  • an aprotic solvent preferably selected from tetrahydrofuran, methyltetrahydrofuran, aromatic hydrocarbons, chlorinated aromatic hydro
  • the aprotic solvent present in step B) comprises tetrahydrofuran and/or methyltetrahydrofuran.
  • the weight ratio of amount of tetrahydrofuran and methyltetrahydrofuran to amount of aromatic hydrocarbons and/or chlorinated aromatic hydrocarbons is preferably at least 4 : 1, more preferred at least 5 : 1, most preferred at least 10 : 1.
  • methyltetrahydrofuran is 2-methyltetrahydrofuran.
  • step B) is carried out at a temperature of -30°C to 50°C, preferably - l0°C to l0°C.
  • the organometallic compound of formula (IV) is present in a molar amount to arrive at a molar ratio of compound of formula (II) and compound of formula (IV) from 1 : 1 to 1 : 2, preferably 1 : 1 to 1 : 1.8, more preferred 1 : 1 to 1 : 1.5, more preferred 1 : 1 to 1 : 1.3, most preferred 1 : 1 to 1 : 1.15.
  • the organometallic compound of formula (IV) is preferably used as solution in an aprotic solvent, in particular as solution in tetrahydrofuran and/or methyltetrahydrofuran, particularly preferred as a 1.0 to 4.0 molar solution in tetrahydrofuran and/or methyltetrahydrofuran.
  • the organometallic compound of formula (IV) is added as solution in an aprotic solvent, preferably tetrahydrofuran and/or methyltetrahydrofuran, to a reaction vessel or flask containing the compound of formula (III) and an aprotic solvent, for example tetrahydrofuran, methyltetrahydrofuran, toluene and mixtures thereof.
  • an aprotic solvent preferably tetrahydrofuran and/or methyltetrahydrofuran
  • organometallic compound of formula (IV) it is preferred to add the organometallic compound of formula (IV) to the compound of formula (III) under a particular dosage regime.
  • the organometallic compound of formula (IV) is added continuously at a constant dosage rate of 10 to 20 mole-%, based on the total molar amount of compound of formula (IV) to be added, per hour.
  • the dosage rate is reduced over time.
  • 50 to 60 mole-% of the organometallic compound of formula (IV) to be added is continuously added at a dosage rate of 50 to 60 mole-% per hour, followed by continuous addition of 20 to 30 mole-% of the organometallic compound of formula (IV) to be added at a dosage rate of 21 to 30 mole-% per hour and, finally, continuous addition of the remaining amount of organometallic compound of formula (IV) to be added at a dosage rate of 10 to 20 mole-% per hour, wherein any reference to mole-% is based on the total molar amount of compound of formula (IV) to be added.
  • step B) is carried out under anhydrous conditions, preferably under inert atmosphere, e.g. argon or nitrogen atmosphere.
  • inert atmosphere e.g. argon or nitrogen atmosphere.
  • step B) is conducted in the presence of a copper(I) or iron(III) catalyst, preferably a copper(I) (pseudo)halogenide or iron(III)l,3-dionate, more preferably iron(acetoacetate)3, iron(2, 2,6,6- tetramethyl-3,5-heptanedionato)3, iron(trifluoroacetylacetonate)3, CuCN, Cul, CuBr or CuCl, most preferably CuCl.
  • a copper(I) or iron(III) catalyst preferably a copper(I) (pseudo)halogenide or iron(III)l,3-dionate, more preferably iron(acetoacetate)3, iron(2, 2,6,6- tetramethyl-3,5-heptanedionato)3, iron(trifluoroacetylacetonate)3, CuCN, Cul, CuBr or CuCl, most preferably CuCl.
  • reaction mixture resulting from step B) is worked-up by procedures generally known in the art. After completion of the reaction, the reaction mixture is quenched by addition of water and/or aqueous hydrochloric acid and/or saturated aqueous ammonium chloride solution. Preferably, organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably toluene, and combined organic phases are washed, preferably with a saturated aqueous NaCl solution, and dried, preferably by azeotropic distillation.
  • the resulting solution of the compound of formula (I) can be directly used in step E) of the process according to the invention outlined below.
  • the process according to the invention yields the compounds of formula (I) in sufficient purity.
  • the compounds of formula (I) may be further purified by known techniques, for example distillation or chromatography.
  • the compounds of formula (I) are purified by distillation before use thereof in step E).
  • the dehydroxyhalogenation agents used in step A) of the process according to the invention as well as the organometallic compounds of formula (IV) used in step B) are well-known compounds being commercially available or readily available by established synthesis routes.
  • the compound of formula (II) is prepared by reacting a compound of formula (V)
  • R is defined as in formula (II);
  • R 2 represents wherein
  • R 3 represents Ci-C4-alkyl; and the corrugated line indicates the linking position of R 2 to the remainder of the compound of formula (V); in a first step C) with a compound of formula (VI) wherein
  • R 4 represents ethynyl, 1 -haloethenyl or 1 ,2-dihaloethanyl; and R 5 represents Ci-C4-alkyl; in the presence of M 2 OR 6 , wherein M 2 represents Li, Na or K; and
  • R 6 represents Ci-C4-alkyl
  • the invention also relates to this process for preparing a compound of formula (II).
  • R is defined as in formulae (II) and, hence, as in formula (I).
  • the preferred, more preferred and most preferred definitions given with regard to formula (I) apply mutatis mutandis.
  • R 2 preferably represents , wherein
  • R 3 represents Ci-C4-alkyl; and the corrugated line indicates the linking position of R 2 to the remainder of the compound of formula (V);
  • R 3 preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl or tert. -butyl, more preferably methyl, ethyl or n-propyl, most preferably methyl or ethyl.
  • R 2 most preferably represents C(0)OCH 3 or C(0)0CH 2 CH 3 .
  • R 4 preferably represents ethynyl, l-chloroethen-l-yl or l,2-dichloroethan-l-yl, more preferably 1,2- dichloroethan- 1 -yl.
  • R 5 preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl or tert. -butyl, more preferably methyl, ethyl or n-propyl, most preferably methyl or ethyl.
  • step C compounds of formulae (V) and (VI) are reacted in the presence of an alcoholate M 2 OR 6 .
  • the alkoholate M 2 OR 6 is selected from L1OCH 3 , NaOCIfr, KOCH 3 , L1OCH 2 CH 3 , NaOCPhCPb, KOCH 2 CH 3 and mixtures thereof, more preferably from L1OCH 3 , NaOCPb, KOCH 3 , NaOCPhCPb and mixtures thereof.
  • the alkoholate M 2 OR 6 is selected from NaOCkb and NaOCH 2 CH 3 .
  • step C) is carried out in the presence of a Ci-C4-alcohol or a mixture thereof, preferably methanol, ethanol, iso-propanol or a mixture thereof, more preferred methanol, ethanol or a mixture thereof.
  • a Ci-C4-alcohol or a mixture thereof preferably methanol, ethanol, iso-propanol or a mixture thereof, more preferred methanol, ethanol or a mixture thereof.
  • the alcohol corresponds to the present alcoholate, i.e. the alcohol is methanol in case a methanolate is used, the alcohol is ethanol in case a ethanolate is used and so on.
  • the Ci-C4-alcohol is present in an amount of 1 to 90 % by weight, based on the total weight of the reaction mixture. More preferably, the Ci-C4-alcohol is present in an amount of 2 to 80 % by weight, more preferably 5 to 80 % by weight, more preferably 5 to 70 % by weight, more preferably 10 to 70 % by weight, more preferably 20 to 70 % by weight, most preferably 25 to 70 % by weight.
  • Step C) is preferably conducted at a temperature of from 0 to 30 °C, preferably 5 to 30 °C, more preferred 10 to 25 °C and ambient pressure, preferably a pressure of from 0.5 to 2 bar.
  • step C) the compound of formula (V) and the compound of formula (VI) are reacted in a molar ratio of 2 : 1 to 1 : 2, preferably 1.5 : 1 to 1 : 1.5, more preferably 1 : 1 to 1 : 1.5.
  • the molar ratio of compound of formula (V) and the alkoholate M 2 OR 6 is 1 : 1 to 1 : 10, preferably 1 : 1.5 to 1 : 8, more preferably 1 : 2 to 1 : 6, most preferably 1 : 2 to 1 : 5.
  • step C) The reaction mixture resulting from step C) can be directly used in step D), i.e. step C) and step D) can be conducted without isolation or purification of the reaction product resulting from step C). Such procedure is preferred.
  • the reaction mixture resulting from step C) can also be worked-up by procedures generally known in the art.
  • the reaction mixture is filtered to remove any precipitate formed during the reaction.
  • the filtrate is concentrated under reduced pressure, optionally washed, preferably with water and/or a saturated aqueous NaCl solution, optionally dried, preferably over magnesium sulfate, and optionally filtered again.
  • the resulting crude product can be used in step D) of the process according to the invention.
  • the crude product may be further purified by known techniques, for example recrystallization or chromatography.
  • step D it is not necessary to perform step D).
  • R 2 represents -CN it is not necessary to perform step D.
  • step C Such compound of formula (II) resulting from step C) can be directly or after worked-up and optional purification used in step A) of the process according to the invention.
  • step C) the product resulting from step C) is treated in step D) of the process according to the invention with water in the presence of a base.
  • the base used in step D) is preferably selected from alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, n- butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide or potassium methoxide, ethoxide,
  • the base is selected from Na2CC>3, K 2 CO 3 , CS 2 CO 3 , LiOH, NaOH, KOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof, more preferably from LiOH, NaOH, KOH and mixtures thereof.
  • Particular preferred is the base NaOH.
  • step D) the base is used in such amount to arrive at a molar ratio of the base and the compound of formula (VI) is 1 : 1 to 10 : 1, preferably 1 : 1 to 8 : 1, more preferably 1.5 : 1 to 5 : 1, most preferably 2 : 1 to 4 : 1.
  • the amount of water present in step D) can vary in wide limits. However, preferably water is employed in such amount that at least 1 mole water per mole of compound of formula (VI) is present, more preferably at least 2 moles, more preferably at least 5 moles, more preferably at least 10 moles. Particularly preferred, water is used as reaction medium.
  • base is dissolved in water and the resulting alkaline aqueous solution is added. Additional water may be added, if desired.
  • Step D) is preferably conducted at a temperature of from 20 to 100 °C, preferably 30 to 90 °C, more preferred 40 to 80 °C, most preferred 50 to 70 °C.
  • the reaction mixture resulting from step D) can be worked-up by procedures generally known in the art.
  • the reaction mixture is distilled in vacuum in order to remove the organic solvent.
  • the solid is filtered, optionally washed, preferably with water, and dried, preferably under vacuum.
  • the process according to the invention yields the compounds of formula (II) in high purity.
  • the compounds of formula (II) may be further purified by known techniques, for example recrystallisation or chromatography.
  • R and R 2 are defined as in formula (V); with ammonia, an ammonium salt or a mixtures thereof.
  • the compounds of formula (VII) are well-known compounds being commercially available or readily obtainable by established synthesis routes.
  • the compound of formula (VII) is reacted with ammonia, an ammonium salt or a mixture thereof, wherein the ammonium salt is selected from ammonium halogenides and ammonium carboxylates, preferably ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium formate, ammonium acetate and mixtures thereof, more preferred ammonium chloride, ammonium bromide, ammonium formate, ammonium acetate and mixtures thereof, more preferred ammonium formate, ammonium acetate and mixtures thereof. Most preferred the compound of formula (VII) is reacted with ammonium acetate.
  • the compound of formula (VII) and the nitrogen source selected from ammonia, ammonium salt and mixtures thereof is applied in a molar ratio of 1 : 0.8 to 1 : 5, preferably 1 : 1 to 1 : 5, more preferably 1 : 1 to 1 : 4, more preferably 1 : 1 to 1 : 3, most preferably 1 : 1 to 1 : 2.
  • the reaction of compound of formula (VII) and the nitrogen source selected from ammonia, ammonium salt and mixtures thereof is conducted at a temperature of from 20 to 100 °C, preferably 30 to 90 °C, more preferred 40 to 80 °C, most preferred 50 to 70 °C.
  • reaction of compound of formula (VII) and the nitrogen source selected from ammonia, ammonium salt and mixtures thereof may be conducted in the presence of an organic solvent and/or water. However, preferably this reaction is conducted without addition of any organic solvent and/or water.
  • reaction mixture resulting from the reaction of compound of formula (VII) and the nitrogen source selected from ammonia, ammonium salt and mixtures thereof may be directly used in step C) of the process according to the invention.
  • the reaction mixture can be worked-up by procedures generally known in the art, for example by phase separation and/or distillation in order to purify and/or isolate the resulting compound of formula (V).
  • compounds of formula (I) are valuable intermediates in the synthesis of compounds useful in the field of crop protection, in particular the triazole compounds disclosed in WO 2017/029179 Al.
  • the present invention refers to a process, wherein a compound of formula (I) is synthesized as outlined above and is further reacted to a triazole derivative of formula (VIII)
  • R and R 1 are defined as in formula (I);
  • R 7 represents halogen, CN, nitro, Ci-C4-alkyl, Ci-C rhaloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, C 1 -C 4 - alkylcarbonyl, hydroxy-substituted Ci-C4-alkyl or pentafluoro ⁇ 6 -sulfanyl; and m is an integer and is 0, 1, 2, 3, 4 or 5; characterized in that the reaction of the compound of formula (I) to the triazole derivative of formula (VIII) comprises the following steps: step E): reacting the compound of formula (I) with a phenol derivative of formula (IX)
  • R 7 and m are defined as in formula (VIII); in the presence of a base to a compound of formula (X)
  • step G reacting the compound of formula (XI) with 1H- 1,2,4-triazole in the presence of a base to the triazole derivative of formula (VIII).
  • R 7 preferably represents halogen, CN, nitro, Ci-C4-alkyl, Ci-C rhaloalkyl, Ci-C4-alkoxy, C1-C4- haloalkoxy or pentafluoro ⁇ 6 -sulfanyl.
  • R 7 more preferably represents CF 3 , OCF 3 , Br, Cl or pentafluoro ⁇ 6 -sulfanyl.
  • R 7 more preferably represents CF3, OCF3, Br, Cl or pentafluoro ⁇ 6 -sulfanyl in the 4-position of the phenyl moiety.
  • R 7 most preferably represents Br or Cl, preferably in the 4-position of the phenyl moiety m preferably is 1. 2 or 3. m more preferably is 1 or 2. m most preferably is 1.
  • Step E) is carried out in the presence of a base.
  • a base preferably include alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide or potassium meth
  • the base is selected from Na2CC>3, K 2 CO 3 , CS 2 CO 3 , KOH, NaOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof, more preferably from KOH, NaOMe, KOMe, K 2 CO 3 , CS 2 CO 3 and mixtures thereof.
  • the base is selected from KOH, KOMe and mixtures thereof.
  • a phenolate nucleophile can be generated in situ from the phenol derivative of formula (IX) by use of the abovementioned bases or prepared separately from the phenol derivative of formula (IX) and the base and possibly isolated prior to the reaction.
  • KOH, NaOMe or KOMe are used as preferred bases to achieve this, the generated water or MeOH is usually distilled off together with all or a portion of any present solvent.
  • step E) is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopropyl methyl ether, /er/-butyl methyl ether, methyl isobutyl ketone, methyl ethyl ketone, toluene, dimethylformamide (DMF) and mixtures thereof. More preferably step E) is carried out in the presence of methyl isobutyl ketone, methyl ethyl ketone, toluene or mixtures thereof. Most preferably the reaction is carried out in the presence of toluene.
  • an aprotic solvent preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopropyl methyl ether, /er/-butyl
  • step E) is carried out in the presence of a catalyst, preferably l,4-diazabicyclo[2.2.2]-octane (DABCO).
  • a catalyst preferably l,4-diazabicyclo[2.2.2]-octane (DABCO).
  • DABCO l,4-diazabicyclo[2.2.2]-octane
  • the catalyst is present in an amount of from 1 to 20 mol%, based on the amount of compound of formula (I).
  • the reagents used in step E) are mixed at room temperature (23 °C). After mixing the reagents, preferably the temperature is increased. Preferably, step E) is carried out at an elevated temperature from 30°C to 150°C, preferably 50°C to 100°C.
  • the reaction mixture resulting from step E) can be worked-up by procedures generally known in the art.
  • the reaction mixture is quenched by addition of water and/or saturated aqueous ammonium chloride solution, the resulting organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably toluene, and the combined organic phases are washed, preferably with a saturated aqueous NaCl solution, dried, preferably over magnesium sulfate, and filtered.
  • the resulting solution of the compound of formula (X) or the crude product obtained by evaporation of the organic solvent can be directly used in step F) of the process according to the invention.
  • the compounds of formula (X) may be further purified by known techniques, for example recrystallization or chromatography.
  • step F) compounds of formula (X) are converted into epoxides of formula (XI) by reaction with a trimethylsulfoxonium halide, a trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate, preferably trimethylsulfoxonium chloride, trimethylsulfonium chloride, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate.
  • trimethylsulfoxonium halide, trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate separately before using it in step F).
  • said reagents in situ e.g. trimethylsulfonium methylsulfate from a mixture of dimethylsulfide and dimethylsulfate, preferably in the presence of a base such as sodium hydroxide or potassium hydroxide.
  • the trimethylsulfoxonium halide, trimethylsulfonium halide, trimethylsulfoxonium methylsulfate or trimethylsulfonium methylsulfate is preferably used in an amount of 1.1 to 2.5, in particular 1.2 to 2, more preferred 1.3 to 1.6 mole equivalents per 1 mole of compound of formula (X).
  • trimethylsulfonium methylsulfate is used.
  • an aqueous solution of trimethylsulfonium methylsulfate is used, preferably an aqueous solution containing 38 to 40 wt%, preferably 38 to 39.5 wt%, more preferred 38 to 39.0 wt% of trimethylsulfonium cation.
  • step F) is carried out at a temperature of -30°C to 50°C, preferably -l0°C to 40°C, particularly preferred 20°C to 40°C.
  • Step F) is preferably conducted in the presence of water, dimethylsulfide or a mixture thereof.
  • the base is selected from Na 2 CC> 3 , K 2 CO 3 , CS 2 CO 3 , NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably the base is KOH.
  • the reaction mixture resulting from step F) can be worked-up by procedures generally known in the art.
  • the reaction mixture is quenched by addition of water.
  • resulting organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably /c/7-butyl methyl ether.
  • the resulting solution of the compound of formula (XI) or the crude product obtained by evaporation of the organic solvent and other volatile components can be directly used in step G) of the process according to the invention.
  • the compounds of formula (XI) may be further purified by known techniques, for example recrystallization or chromatography.
  • Step G) is carried out in the presence of a base.
  • a base preferably include alkali metal or alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate, potassium carbonate or calcium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride, potassium hydride or calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide, ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide or potassium meth
  • the base is selected from Na2CC>3, K 2 CO 3 , CS 2 CO 3 , NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably from KOH, K 2 CO 3 , CS 2 CO 3 and mixtures thereof.
  • a sodium or potassium salt of 1H- 1,2, 4-triazole is used as base.
  • Said sodium or potassium salt can be prepared by reacting 1H- 1,2, 4-triazole and a sodium or potassium base, preferably selected from NaOH, NaH and Na-alcoholates or KOH and K-alcoholates, respectively.
  • step G) is carried out in the presence of an organic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopropyl methyl ether, /c/7- butyl methyl ether, toluene, n-butanol, n-propanol, isopropanol, ethanol, methanol, N- methylpyrrolidinone (NMP), dimethylformamide (DMF) and mixtures thereof, more preferably in the presence of n-butanol.
  • an organic solvent preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopropyl methyl ether, /c/7- butyl methyl ether, toluene, n-butanol, n-propanol, isopropanol
  • step G) is carried out at a temperature of 20°C to l50°C, preferably l20°C to l50°C, particularly preferred l20°C to l40°C.
  • the reaction mixture resulting from step G) can be worked-up by procedures generally known in the art.
  • a suitable organic solvent like ethyl acetate.
  • Water is added and the pH (room temperature) is adjusted to about 6 by introduction of a strong acid like concentrated aqueous hydrochloric acid.
  • the aqueous phase is extracted with a suitable organic solvent like ethyl acetate, and the combined organic phases are dried, preferably over magnesium sulfate.
  • the organic solvent is removed and the resulting crude product further purified by known techniques, for example recrystallization or chromatography.
  • the reaction time of each of the steps of the process according to the invention varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • process steps according to the invention are generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the amount of any solvent present in any process step according to the invention can vary within wide limits, e.g. from 1 to 99 % by weight, based on the total weight of the respective reaction mixture.
  • the amount of any solvent present in any process step according to the invention is from 1 to 95 % by weight, more preferably from 2 to 90 % by weight, more preferably from 3 to 85 % by weight, more preferably from 4 to 85 % by weight, more preferably from 5 to 80 % by weight, more preferably from 10 to 80 % by weight, more preferably from 15 to 70 % by weight, more preferably from 20 to 70 % by weight, each based on the total weight of the respective reaction mixture.
  • the invention further relates to compounds of formula (II”)
  • R represents Ci-C2-haloalkyl.
  • the invention also relates to compounds of formula (II )
  • R’ represents ethyl or Ci-C2-haloalkyl
  • R’ represents Ci-C 2 -haloalkyl, preferably CF 3 , CHF 2 or CH 2 F, more preferred CF 3 ; and X represents chlorine or bromine.
  • R’ represents Ci-C 2 -haloalkyl, preferably CF 3 , CHF 2 or CH 2 F, more preferred CF 3 ; and X represents chlorine.
  • R represents Ci-C2-alkyl or Ci-C2-haloalkyl
  • R represents Ci-C 2 -haloalkyl, preferably CF 3 , CHF 2 or CFhF, more preferred CF 3 ; and X represents bromine.
  • the brown suspension was stirred for further 1 h at 22 °C until a HPLC measurement indicated complete conversion of starting materials.
  • the reaction solution was then treated with aqueous HC1 (20 w%) until pH 7 was reached.
  • From the reaction mixture 44 g ethanol were distilled off at 80 °C and replaced by 30 mL of deionized water.
  • the dark-brown solution was cooled to 22 °C and 20 mL deionized water were added. Cooling to 15 °C led to phase separation.
  • the lower organic phase was separated, dissolved in 24 mL ethanol and the resulting solids were filtered off.
  • the brown filtrate was then treated with deionized water at 2 °C to form a brown suspension.
  • Example 2 Preparation of ethyl 6-hvdroxy-2-(trifluoromethyl)nicotinate from ethyl 3-amino-4.4.4- trifluorocrotonate and ethyl propiolate (step C) of the process according to the invention)
  • the resulting yellow suspension was stirred for further 0.5 h at this temperature until a HPLC measurement indicated complete conversion of starting materials.
  • the suspension was heated to 65-70 °C internal temperature and 400 g of methanol were distilled off. Subsequently, 438.8 g of aqueous sodium hydroxide (20 w%, 2.19 mol, 2.06 eq) were dosed slowly to the reaction solution at 70 °C within 1.5 h to result in a yellow suspension. From this mixture another 283 g of methanol were distilled off. Then 150 mL of deionized water were added and the suspension was cooled to 0-10 °C.
  • Example 7 Preparation of 2-chloro-6-ftrifluoromethylfnicotinic acid from 6-hvdroxy-2- (trifluoromethvfinicotinic acid (step All of the process according to the invention )
  • the aqueous phase was extracted with 1 x 100 mL xylenes.
  • the combined organic phases were then extracted with a basic solution comprising 0.5 L of deionized water and 74.86 g of solid sodium hydroxide under vigorous stirring at 50 °C for 1 hour at a pH of 12-13.
  • the aqueous phase was then cooled to 5-10 °C and 187.0 g of aqueous sulfuric acid (48 % by weight) were dosed to it within 0.5 hours to reach a pH of 1-2 and a temperature of 38 °C.
  • the resulting suspension was then stirred for 1 hour at 5-10 °C to furnish crystallization.
  • Example 8 Preparation of l-(6-chloro-2-(trifluoromethyl)-3-pyridyl)ethanone from 2-chloro-6- (trifluoromethyl)nicotinic acid (steps A2) and B) of the process according to the invention)
  • the reaction mixture was dosed onto 220 mL of hydrochlorid acid (10 % by weight in water).
  • the organic phase was washed with 1 x 100 and 1 x 80 mL aqueous ammonium chloride (15 % by weight in water) and once with 100 mL hydrochloric acid (10 % by weight in water).
  • the organic phase was then subjected to distillation at 40 °C down to a vacuum of 5 mbar to leave 191.6 g (80 % by weight purity, 0.69 mol, 86 % yield) of a red fluid oil.
  • reaction mixture was then cooled down to 0°C and washed with 200 ml water at 0°C.
  • the aqueous phase was extracted with 100 ml butyronitrile and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to 200 ml.
  • To the resulting dark brown solution 12.6 g (106 mmol) thionyl chloride was added and the mixture was heated to l00°C. After 3 h the same amount of thionyl chloride was added again und the mixture was further stirred at l00°C for another 3 h.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de composés de formule (I) (I), dans laquelle R représente alkyle en C1-C2 ou haloalkyle en C1-C2, R1 représente alkyle en C1-C6, alcényle en C2-C6, alcynyle en C2-C6, cycloalkyle en C3-C8, C3-C8-cycloalkyle-C1-C4-alkyle, phényle, phényle-C1-C4-alkyle, phényle-C2-C4-alcényle ou phényle-C2-C4-alcényle, et X représente chlore ou brome, en faisant réagir un composé de formule (II) (II), dans laquelle RA représente -CN ou –COOH et R est défini comme dans la formule (I), dans une première étape A) avec un agent de déhydroxyhalogénation choisi parmi COCl2, diphosgène, triphosgène, chlorure cyanurique, SOCl2, SO2Cl2, PCl3, PCl5, POCl3, PBr3, SOBr2 et SO2Br2, pour obtenir un composé de formule (III) (III), dans laquelle RB représente -CN ou – COX, et X et R sont tels que définis dans la formule (I), et le composé de formule (III) est mis à réagir à l'étape B) avec un composé de formule (IV) R1M1(lV), - 41 - dans laquelle M1 représente Li ou MgY, Y étant du chlore ou du brome, et R1 est défini comme dans la formule (I), et éventuellement faire réagir le composé de formule (I) avec un dérivé de triazole de formule (VIII) (VIII). L'invention concerne en outre un procédé de préparation du composé de formule (II) et des composés particuliers de formule (II) et (III).
PCT/EP2019/070426 2018-08-03 2019-07-30 Procédé de préparation de 6-(haloalkyl)-2-halo-5-acylpyridines et d'intermédiaires pour ce procédé WO2020025574A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18187203.7 2018-08-03
EP18187203 2018-08-03

Publications (1)

Publication Number Publication Date
WO2020025574A1 true WO2020025574A1 (fr) 2020-02-06

Family

ID=63144868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/070426 WO2020025574A1 (fr) 2018-08-03 2019-07-30 Procédé de préparation de 6-(haloalkyl)-2-halo-5-acylpyridines et d'intermédiaires pour ce procédé

Country Status (2)

Country Link
TW (1) TW202019883A (fr)
WO (1) WO2020025574A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022087373A1 (fr) * 2020-10-23 2022-04-28 Vertellus Holdings Llc Procédés de fabrication de dérivés d'acide nicotinique

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020016345A1 (en) 1998-09-15 2002-02-07 Andrew Edmunds Pyridine ketones useful as herbicides
WO2004029026A1 (fr) 2002-09-27 2004-04-08 Glaxo Group Limited Derives de pyridine modulateurs du recepteur cb2
WO2005073192A1 (fr) 2004-02-02 2005-08-11 Astrazeneca Ab Piperidines utilisees comme modulateurs des chimiokines (ccr)
WO2008085119A1 (fr) * 2007-01-12 2008-07-17 Astrazeneca Ab Nouveaux analogues de la pyridine viii 518
WO2009058921A1 (fr) 2007-10-31 2009-05-07 Smithkline Beecham Corporation Antagonistes de ccr5 en tant qu'agents thérapeutiques
WO2013097773A1 (fr) * 2011-12-30 2013-07-04 Centaurus Biopharma Co., Ltd. Nouveaux dérivés d'arylalcène et utilisation de ceux-ci en tant que modulateurs sélectifs de récepteur d'œstrogène
WO2017029179A1 (fr) 2015-08-14 2017-02-23 Bayer Cropscience Aktiengesellschaft Dérivés de triazole, leurs intermédiaires et leur utilisation comme fongicides
WO2017162521A1 (fr) 2016-03-23 2017-09-28 Syngenta Participations Ag Herbicides
WO2018057588A1 (fr) * 2016-09-21 2018-03-29 Vertex Pharmaceuticals Incorporated Composés furo[3,2-b]pyridine utiles en tant qu'inhibiteurs de la voie de signalisation par-2

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020016345A1 (en) 1998-09-15 2002-02-07 Andrew Edmunds Pyridine ketones useful as herbicides
WO2004029026A1 (fr) 2002-09-27 2004-04-08 Glaxo Group Limited Derives de pyridine modulateurs du recepteur cb2
WO2005073192A1 (fr) 2004-02-02 2005-08-11 Astrazeneca Ab Piperidines utilisees comme modulateurs des chimiokines (ccr)
WO2008085119A1 (fr) * 2007-01-12 2008-07-17 Astrazeneca Ab Nouveaux analogues de la pyridine viii 518
WO2009058921A1 (fr) 2007-10-31 2009-05-07 Smithkline Beecham Corporation Antagonistes de ccr5 en tant qu'agents thérapeutiques
WO2013097773A1 (fr) * 2011-12-30 2013-07-04 Centaurus Biopharma Co., Ltd. Nouveaux dérivés d'arylalcène et utilisation de ceux-ci en tant que modulateurs sélectifs de récepteur d'œstrogène
WO2017029179A1 (fr) 2015-08-14 2017-02-23 Bayer Cropscience Aktiengesellschaft Dérivés de triazole, leurs intermédiaires et leur utilisation comme fongicides
WO2017162521A1 (fr) 2016-03-23 2017-09-28 Syngenta Participations Ag Herbicides
WO2018057588A1 (fr) * 2016-09-21 2018-03-29 Vertex Pharmaceuticals Incorporated Composés furo[3,2-b]pyridine utiles en tant qu'inhibiteurs de la voie de signalisation par-2

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BOGDAN N. D.: "Protein-inorganic array construction: design and synthesis of the building blocks", CHEMISTRY A EUROPEAN JOURNAL, vol. 16, 8 January 2010 (2010-01-08), pages 2170 - 2180, XP002786722 *
JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 9, 2010, pages 3814 - 3830
JOURNAL OF ORGANIC CHEMISTRY, vol. 19, 1954, pages 183 - 191
KAGABU S. ET AL.: "Asymmetric chloronicotinyl insecticide, 1-[1-(6-chloro-3-pyridyl)ethyl]-2-nitroiminoimidazolidine: preparation, resolution and biological activities toward insects and their nerve Preparations", BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY, vol. 67, no. 5, 1 May 2014 (2014-05-01), pages 980 - 988, XP002786723 *
MILTON ORCHIN, JOURNAL OF CHEMICAL EDUCATION, vol. 66, no. 7, 1999, pages 586 - 588

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022087373A1 (fr) * 2020-10-23 2022-04-28 Vertellus Holdings Llc Procédés de fabrication de dérivés d'acide nicotinique

Also Published As

Publication number Publication date
TW202019883A (zh) 2020-06-01

Similar Documents

Publication Publication Date Title
KR101537880B1 (ko) 4-아미노-5-플루오로-3-할로-6-(치환된)피콜리네이트의 제조 방법
CA2609050C (fr) Procede pour produire des 1-alkyl-3-phenyluraciles
KR101547044B1 (ko) 4-아미노-5-플루오로-3-할로-6-(치환된)피콜리네이트의 제조 방법
CA2879530C (fr) Procede de preparation de 4-amino-5-fluoro-3-halo-6-picolinates (substitues)
CA2825389C (fr) Procede de preparation de 4-amino-3-chloro-5-fluoro-6-(substitue)picolinates
EP1858878B1 (fr) Conversion de 2-pyrazolines en pyrazoles a l'aide de brome
WO2020025574A1 (fr) Procédé de préparation de 6-(haloalkyl)-2-halo-5-acylpyridines et d'intermédiaires pour ce procédé
EP1873145B1 (fr) Procede de production d'un derive de l'acide nicotique ou d'un sel de celui-ci
WO2020120284A1 (fr) Préparation de 6-halo-2-(haloalkyl)-3-acylpyridines et intermédiaires correspondants
EP3738959A1 (fr) Préparation de 6-phénoxy-2-(haloalkyl)-3-acylpyridines et de leurs intermédiaires
WO2019048526A1 (fr) Procédé de préparation de 1-[6-halogéno-3-pyridyl]cétones
EP4003964A1 (fr) Procédé et intermédiaires pour la préparation de pyroxasulfone
TW202012372A (zh) 製備２－（氟烷基）菸鹼酸的方法
JP6998957B2 (ja) ３－置換２－ビニルフェニルスルホネート類を製造する方法
WO2019012161A1 (fr) Procédé pour la préparation de (1h-1,2,4-triazol-1-yl)alcools substitués
JP2583791B2 (ja) ハロゲン化エチルベンゼンの製造法
JPH05230010A (ja) パラクロロフェニルカルバミン酸エステルの製造方法
AU2015204348A1 (en) Process for the preparation of 4-amino-3-chloro-5-fluoro-6-(substituted)picolinates

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19746474

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19746474

Country of ref document: EP

Kind code of ref document: A1