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WO2019012161A1 - Procédé pour la préparation de (1h-1,2,4-triazol-1-yl)alcools substitués - Google Patents

Procédé pour la préparation de (1h-1,2,4-triazol-1-yl)alcools substitués Download PDF

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WO2019012161A1
WO2019012161A1 PCT/EP2018/078041 EP2018078041W WO2019012161A1 WO 2019012161 A1 WO2019012161 A1 WO 2019012161A1 EP 2018078041 W EP2018078041 W EP 2018078041W WO 2019012161 A1 WO2019012161 A1 WO 2019012161A1
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alkyl
process according
formula
methyl
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Christoph SCHOTES
Manfred Meyer
Eike Kevin Heilmann
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Bayer AG
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Bayer AG
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    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a process for preparing substituted (lH-l,2,4-triazol-l-yl)alcohols.
  • WO 2017/029179 Al discloses such substituted (lH-l,2,4-triazol-l-yl)alcohols and several routes to synthesize those.
  • One of said routes is referred to in WO 2017/029179 Al as process B and comprises ring-opening of suitable oxirane derivatives by reacting said oxirane derivatives with 1H- 1 ,2,4-triazole in the presence of a base and optionally an organic solvent.
  • process B comprises ring-opening of suitable oxirane derivatives by reacting said oxirane derivatives with 1H- 1 ,2,4-triazole in the presence of a base and optionally an organic solvent.
  • Such procedure provides access to the target (lH-l,2,4-triazol-l-yl)alcohols.
  • further improvement of the process e.g. in terms of yield, purity and/or use of environmental sustainable solvents, is desirable.
  • object of the invention is providing an improved process for the synthesis of substituted ( 1H- 1,2,4- triazol- 1 -yl)alcohols.
  • (lH-l,2,4-triazol-l-yl)alcohols can be synthesized in high yield by reacting suitable oxirane derivatives with lH-l,2,4-triazole in the presence of a base and polyalkylene glycol.
  • subject of this invention is a process for preparing compounds of formula (I)
  • R 1 represents hydrogen, Ci-C6-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl, Cs-Cs-cycloalkyl, C3-C8- cycloalkyl-Ci-C 4 -alkyl or C6-Ci 4 -aryl, wherein the aliphatic moieties, excluding cycloalkyl moieties, of R 1 may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C 4 -alkoxy and Ci-C 4 -halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently from each other from halogen, CN, nitro, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -halogenalkyl, C 1 -C4
  • Y represents a 6-membered aromatic heterocycle selected from
  • R represents hydrogen, Ci-C 2 -halogenalkyl, Ci-C 2 -halogenalkoxy, Ci-C 2 -alkylcarbonyl or halogen; each R represents independently from each other halogen, CN, nitro, Ci-C4-alkyl, C1-C4- halogenalkyl, Ci-C4-alkoxy or Ci-C4-halogenalkoxy; and - - n is an integer and is 0 or 1 ; by reacting lH-l,2,4-triazole and an oxirane of formula (II)
  • R 1 , R 4 , m and Y are defined as in formula (I); in the presence of a base and polyalkylene glycol.
  • the process allows producing compounds of formula (I) in at least partially crystalline form.
  • Formula (I) provides a general definition of the triazole derivatives obtainable by the process according to the invention.
  • Preferred radical definitions for the formulae shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all educts and intermediates, e.g. the oxiranes of formula (II).
  • R 1 preferably represents hydrogen, Ci-C4-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl, cyclopropyl or Ce-Cio- aryl, wherein the aliphatic moieties, excluding the cycloalkyl moieties, of R 1 may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C4-alkoxy and Ci-C4-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently of one another from halogen, CN, nitro, Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-halogenalkyl, C1-C4- halogenalkoxy, and wherein the cycloalkyl and/or C6-Cio-aryl moieties
  • R 1 more preferably represents hydrogen, Ci-C 4 -alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl, cyclopropyl or phenyl, wherein the aliphatic moieties, excluding the cycloalkyl moieties, of R 1 may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C4-alkoxy and Ci-C4-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently of one another from halogen, CN, nitro, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -halogenalkyl, C 1 -C 4 - halogenalkoxy, and wherein the cycloalkyl and/or phenyl moieties of R 1
  • R 1 more preferably represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, allyl, CH 2 C ⁇ C-CH 3 or CH 2 C ⁇ CH, wherein the aliphatic groups R 1 may carry 1 , 2, 3 or up to the maximum possible number of identical or different groups R a which independently of one another are selected from halogen, CN, nitro, phenyl, Ci-C4-alkoxy and Ci-C4-halogenalkoxy, wherein the phenyl may be substituted by 1, 2, 3, 4 or 5 substituents selected independently of one another from halogen, CN, nitro, Ci-C 4 -alkyl, Ci-C4-alkoxy, Ci-C4-halogenalkyl, Ci-C4-halogenalkoxy.
  • R 1 more preferably represents hydrogen or non-substituted methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, CF 3 , benzyl, allyl, CH 2 C ⁇ C-CH 3 or CH 2 C ⁇ CH.
  • R 1 more preferably represents hydrogen, methyl or ethyl.
  • R 1 more preferably represents hydrogen or methyl.
  • R 1 most preferably represents methyl
  • Each R 4 preferably represents independently from each other methyl, ethyl, n-propyl, iso-propyl, CF 3 , OCF3, Br, CI, pentafluoro ⁇ 6 -sulfanyl, cyclopropyl, 1 -halogencyclopropyl, l-Ci-C 4 -alkylcyclopropyl, C 2 -C6-alkenyl, C 2 -C6-halogenalkenyl, C 2 -C6-alkynyl, C 2 -C6-halogenalkynyl, Ci-C 4 -alkylsulfanyl, Ci-C 4 -halogenalkylsulfanyl, Ci-C 4 -alkylsulfonyl, phenylsulfonyl, Ci-C 4 -alkyl-S0 2 NH-, phenyl- S0 2 NH-, formyl, aziridinyl, pyrrol
  • R 4b represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl, preferably hydrogen or methyl.
  • Each R 4 more preferably represents independently from each other CF 3 , OCF 3 , Br, CI or pentafluoro- 6-sulfanyl. Each R 4 most preferably represents independently from each other Br or CI.
  • R 4 is located in the 2- and/or 4-position of the phenyl moiety of formula (I).
  • R 4 is located in the 4-position of the phenyl moiety of formula (I).
  • m preferably is 1, 2 or 3.
  • m more preferably is 1 or 2.
  • m most preferably is 1.
  • Y preferably represents a 6-membered aromatic heterocycle selected from wherein Y is connected to the O via the bonds identified with "U” and Y is connected to the CR 1 moiety via the bonds identified with “V” and wherein R, R 3 and n are defined as mentioned above for formula (I).
  • Y more preferably represents a 6-membered aromatic heterocycle selected from
  • Y more preferably represents a 6-membered aromatic heterocycle selected from
  • Y most preferably represents wherein Y is connected to the O via the bonds identified with "U” and Y is connected to the CR 1 moiety via the bonds identified with "V” and wherein R, R 3 and n are defined as mentioned above for formula (I).
  • R preferably represents hydrogen, Ci-C2-halogenalkyl or halogen.
  • R more preferably represents hydrogen, Ci-halogenalkyl, F or CI.
  • R more preferably represents Ci-halogenalkyl, F or CI.
  • R more preferably represents CF3 or CI.
  • R most preferably represents CF3.
  • Each R 3 preferably represents independently from each other F, CI, Br, CN, nitro, methyl, CF 3 , methoxy or OCF3.
  • n preferably is 0.
  • R 1 represents methyl
  • R 4 represents Br or CI; m is 1 ; and - -
  • Ci-C6-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-dimethyl
  • Ci-C4-alkyl such as methyl, ethyl, n-, isopropyl, n-, iso-, sec-, tert-butyl.
  • the definition Ci-C 2 -alkyl comprises methyl and ethyl.
  • the definition halogen comprises fluorine, chlorine, bromine and iodine.
  • Halogen-substituted alkyl - e.g. referred to as halogenalkyl, halogenoalkyl or haloalkyl, e.g. C1-C4- halogenalkyl or Ci-C 2 -halogenalkyl - represents, for example, Ci-C4-alkyl or Ci-C 2 -alkyl as defined above substituted by one or more halogen substituents which can be the same or different.
  • C 1 -C4- halogenalkyl 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-l -methylethyl, 2- fluoro- 1 , 1 -dimethylethyl, 2-fluoro- 1 -fluoromethyl- 1 -methylethyl, 2-fluoro
  • Ci-C 2 -halogenalkyl 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.
  • Ci-C4-alkyl represents, for example, Ci-C4-alkyl as defined above substituted by one or more fluorine substituent(s).
  • Preferably mono- or multiple fluorinated Ci-C4-alkyl represents fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1 -fluoro- l-methylethyl, 2-fluoro- l , l-dimethylethyl, 2-fluoro- l - fluoromethyl- 1 -methylethyl, 2-fluoro- l, l -di(fluoromethyl)-ethyl, l -methyl-3-trifluoromethylbutyl, 3- methyl- 1 -trifluoromethylbutyl.
  • 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.
  • aryl comprises aromatic, mono-, bi- or tricyclic ring, for example phenyl, naphthyl, anthracenyl (anthryl), phenanthracenyl (phenanthryl).
  • the process according to the invention is performed in the presence of polyalkylene glycol.
  • the polyalkylene glycol is selected from polyalkylene glycols of formula (III)
  • R 2 represents C2-C4-alkylene, and o is an integer from 2 to 200; - - and mixtures thereof.
  • R 2 preferably represents ethylene, n-propylene or tetramethylene, more preferably represents ethylene.
  • 0 preferably is an integer from 2 to 150, more preferably from 2 to 100, even more preferred 2 to 50, 3 to 40, 4 to 30, 4 to 20, or 4 to 15, most preferred 4 to 10. It is possible to use just one particular polyalkylene glycol, however, also mixtures of different polyalkylene glycols differing in R 2 and/or o can be used. Preferably, the polyalkylene glycols used differ only in o, i.e. the number of repeating units.
  • the polyalkylene glycol is selected from tetraethylene glycol and the polyethylene glycol commercially available as PEG 400.
  • the latter is a mixture of compounds of formula (III), wherein R 2 is ethylene and the average number of repeating units is about 8.2 to 9.1, resulting in an average molecular weight M n of about 380 to 420 g/mol (gel permeation chromatography (GPC), polystyrol standard).
  • the polyalkylene glycol is present in an amount of at least 2 % by weight based on the total weight of the reaction mixture, more preferred in an amount of 3 to 80 % by weight, even more preferred in an amount of 4 to 20 % by weight, and most preferred in an amount of 5 to 15 % by weight, each time based on the total weight of the reaction mixture.
  • the given amounts refer to the sum of the amounts of all polyalkylene glycols.
  • n-butanol preferably n-butanol, n-propanol, isopropanol, ethanol, methanol, or mixtures thereof, particularly preferred n-butanol.
  • the volumetric ratio of polyalkylene glycol and Ci-Cio-alcohol is 1 : 1 to 1 : 40, more preferred
  • the given ratios refer to the sum of the volumes of all polyalkylene glycols and the sum of the volumes of all Ci-Cio-alcohols.
  • an additional organic solvent preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, teri-butyl methyl ether, toluene, N- methylpyridione (NMP), dimethylformamide (DMF) and mixtures thereof.
  • NMP N- methylpyridione
  • DMF dimethylformamide
  • no additional organic solvent is present, i.e. besides polyalkylene glycol only Ci-Cio-alcohol is present as organic solvent.
  • the process according to the invention is performed in the presence of a base.
  • 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, n- or i- propoxide
  • the base is selected from Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 , NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably from KOH, K2CO3, CS2CO3 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 lH-l,2,4-triazole and a sodium or potassium base, preferably selected from NaOH, NaH and Na-alcoholates or KOH and K- alcoholates, respectively.
  • the sodium or potassium salt of lH-l,2,4-triazole acts as base and lH-l,2,4-triazole, i.e. lH-l,2,4-triazole and base are partially or fully replaced by the sodium or potassium salt of lH-l,2,4-triazole.
  • the molar ratio of base and oxirane of formula (II) is 0.1 : 1 to 2 : 1, more preferred 0.2 : 1 to 0.6 : 1, and most preferred 0.35 : 1 to 0.45 : 1.
  • the given ratios refer to the sum of the molar amounts of all oxiranes of formula (II) and the sum of the molar amounts of all bases.
  • the lH-l,2,4-triazole and the oxirane of formula (II) are reacted in a molar ratio of 0.8 : 1 to 4 : 1, more preferred 0.9 : 1 to 3 : 1, most preferred 1 : 1 to 2 : 1.
  • the given ratios refer to the sum of the molar amounts of all oxiranes of formula (II).
  • the process is carried out at a temperature of 20°C to 150°C, more preferred 120°C to 150°C, and most preferred 120°C to 140°C.
  • the reaction time 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.
  • the process according to the invention is generally performed under standard pressure (1 arm). However, it is also possible to work under elevated or reduced pressure.
  • the reaction mixture resulting from the process according to the invention 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. lH-l,2,4-triazole is readily available from commercial sources.
  • Oxiranes of formula (II) can be obtained by various routes in analogy to prior art processes known, in particular by process B disclosed in WO 2017/029179 Al .
  • step A) of this process a compound of formula (IV)
  • Pv' represents hydrogen, Ci-C 2 -halogenalkyl, Ci-C 2 -halogenalkoxy, Ci-C 2 -alkylcarbonyl, fluorine chlorine;
  • X represents fluorine or chlorine
  • R' is defined as in formula (IV); with hydrogen chloride in the presence of dinitrogen trioxide or an organic nitrite.
  • gaseous hydrogen chloride is used. This means the hydrogen chloride is added in gaseous state and remains in the gaseous state under the specific reaction conditions.
  • Step A) is preferably conducted at a temperature of from 0 to 30 °C and a pressure of from 0.5 to 2 bar.
  • step A) is carried out in the presence of an solvent, preferably selected from dichloromethane, trichloromethane, tetrachloromethane, 1 ,2-dichloroethane, 1 , 1 , 1 -trichloroethane, 1 , 1 ,2-trichloroethane, cyclohexane, methylcyclohexane, heptane, hexane, trifluoromethylbenzene, 4- chloro-trifluoromethylbenzene, chlorobenzene, 1 ,2-dichlorobenzene, 1 ,3-dichlorobenzene, acetic acid, trifluoroacetic acid, nitrobenzene, tetrahydrofuran, methyltetrahydrofuran, in particular 2- methyltetrahydrofuran, dioxane, acetonitrile, diethylether, cyclopentyl methyl ether, teri
  • the organic nitrite is preferably selected from methyl nitrite, ethyl nitrite, isopropyl nitrite, isobutyl nitrite and teri-butyl nitrite. Preferred is teri-butyl nitrite.
  • R 1 represents Ci-C6-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkynyl, Cs-Cs-cycloalkyl, Cs-Cs-cycloalkyl-Ci-C/r alkyl, phenyl, phenyl-Ci-C4-alkyl, phenyl-C 2 -C4-alkenyl or phenyl-C 2 -C4-alkynyl; and
  • Pv' and X are defined as in formula (IV); is prepared by reacting the compound of formula (IV) in a first step B) with a compound of formula (VII) - -
  • R represents Ci-C6-alkyl or Cs-Cs-cycloalkyl; and Z represents chlorine or bromine; and reacting the resulting product in step C) with an anhydride of formula (VIII)
  • R 1 is defined as in formula (VI).
  • step B) the compound of formula (IV) is reacted with a Grignard reagent.
  • the Grignard reagent is represented by formula (VII).
  • Grignard compounds undergo a solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenck equilibrium.
  • the Schlenck equilibrium for the Grignard reagent according to formula (VII) can be schematically illustrated as follows:
  • R' and R 1 are defined as in formula (VI); and R 4 and m are defined as in formula (I); wherein the reaction of the compound of formula (VI) to the oxirane derivative of formula (Ila) comprises the following steps : step D): reacting the compound of formula (VI) with a phenol derivative of formula (IX)
  • R 4 and m are defined as in formula (I); in the presence of a base to a compound of formula (X)
  • Formulae given above provide a general definition of the compounds involved in the process to obtain oxiranes of formula (Ila).
  • Preferred radical definitions for said formulae regarding R 4 and m are given above and regarding R', R 1 , Z and R" below. These definitions apply to the oxiranes of formula (Ila) and likewise to all educts and intermediates bearing the respective radical(s).
  • R' preferably represents Ci-C2-halogenalkyl or Ci-C 2 -halogenalkoxy.
  • R' more preferably represents Ci-halogenalkyl.
  • R' more preferably represents CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 or OCH 2 F.
  • 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, CF 3 , allyl, CH 2 C ⁇ C-CH 3 or CH 2 C ⁇ CH.
  • 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
  • Z most preferably represents chlorine.
  • R' ' preferably represents G-C 4 -alkyl or C 2 -C6-cycloalkyl.
  • R' ' more preferably represents methyl, ethyl, propyl, isopropyl, butyl or cyclopropyl.
  • R' ' more preferably represents methyl, ethyl, propyl, isopropyl or butyl.
  • R' ' most preferably represents isopropyl.
  • Grignard compounds may be formed, which are represented by formula (IV-Gr) and/or (IV-Br)
  • R', X and Z are defined as outlined above.
  • Grignard compounds generally undergo a solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenck equilibrium.
  • Schlenck equilibrium the so-called Schlenck equilibrium.
  • step B) may work-up for example in order to isolate, concentrate, dilute or purify the Grignard compound or a solution or suspension thereof.
  • step B) and step C) without any treatment like isolation or purification of the reaction product resulting from step B).
  • step B) and step C) without any treatment like isolation or purification of the reaction product resulting from step B).
  • step B) and step C) without any treatment like isolation or purification of the reaction product resulting from step B).
  • step B) it is particularly preferred to add the reaction mixture resulting from step B) to the anhydride of formula (VIII).
  • steps B) and C) are carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene and mixtures thereof, more preferably from tetrahydrofuran, toluene and mixtures thereof.
  • steps B) and C) are carried out at a temperature of -30°C to 50°C, preferably - 10°C to 10°C.
  • the compound of formula (IV) and the compound of formula (VII) are reacted in a molar ratio of 1 : 0.8 to 1 : 1.5, more preferred 1 : 0.9 to 1 : 1.4, more preferred about 1 : 1 to 1 : 1.3, most preferred 1 : 1 to 1 : 1.1.
  • the Grignard reagent of formula (VII) is preferably used as solution in an aprotic solvent, in particular as solution in tetrahydrofuran, particularly preferred as a 1.0 to 3.0 molar solution in tetrahydrofuran.
  • the Grignard reagent of formula (VII) is added as solution in an aprotic solvent, preferably tetrahydrofuran, to a reaction vessel or flask containing the compound of formula (IV) and an aprotic solvent, preferably toluene.
  • an aprotic solvent preferably tetrahydrofuran
  • the molar ratio of compound of formula (IV) and anhydride of formula (VIII) is 1 : 1 to 1 : 2, more preferred 1 : 1.05 to 1 : 1.8, more preferred 1 : 1.1 to 1 : 1.5, most preferred 1 : 1.1 to 1 : 1.3.
  • step B) and step C) are carried out under anhydrous conditions, preferably under argon atmosphere.
  • step C) is conducted in the absence of a copper catalyst, more preferred in the absence of any catalyst. Even more preferred also in step B) no catalyst is present.
  • the reaction mixture resulting from step C) 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.
  • step D The resulting solution of the compound of formula (VI) can be directly used in step D). It is also possible to isolate the compound of formula (VI), preferably by evaporation of the organic solvent, preferably under reduced pressure. The process yields the compounds of formula (VI) in high purity. However, if desired, the compounds of formula (VI) may be further purified by known techniques, for example distillation or chromatography.
  • Step D) 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 Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 , NaOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof, more preferably form NaOMe, KOMe, K 2 CO3, CS 2 CO3 and mixtures thereof.
  • the base is selected from KOMe and K 2 CO3.
  • the phenolate nucleophile can be generated in-situ by use of the abovementioned bases or prepared from the phenol derivative of formula (IX) and the base and possibly isolated prior to the reaction.
  • the generated MeOH is preferably distilled off together with all or a portion of any present solvent.
  • step D) is carried out in the presence of a solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, tert-buiyl methyl ether, methyl isobutyl ketone, methyl ethyl ketone, toluene, dimethylformamide (DMF), 1-propanol, 2-propanol, 1-butanol, polyalkylene glycol, in particular polyethylene glycol (PEG), and mixtures thereof.
  • a solvent preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, tert-buiyl methyl ether, methyl isobutyl ketone, methyl ethyl ketone, toluene, di
  • step D) is carried out in the presence of methyl isobutyl ketone, methyl ethyl ketone, toluene, 1-propanol, 2-propanol, 1-butanol, PEG 400 or mixtures thereof. Most preferably the reaction is carried out in the presence of toluene, 1-propanol, 2-propanol, 1-butanol, PEG 400 or any mixture thereof.
  • step D) 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 (VI).
  • the reagents used in step D) are mixed at room temperature (23 °C). After mixing the reagents, preferably the temperature is increased. Preferably, step D) 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 D) 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 E).
  • the compounds of formula (X) may be further purified by known techniques, for example recrystallization or chromatography.
  • step E) compounds of formula (X) are converted into epoxides of formula (Ila) 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 E).
  • 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 kation.
  • step E) is carried out at a temperature of -30°C to 50°C, preferably - 10°C to 40°C, particularly preferred 20°C to 40°C.
  • Step E) is preferably conducted in the presence of water, dimethylsulfide or a mixture thereof. It is preferably carried out in the presence of a base.
  • the base is selected from Na 2 CC>3, K 2 CO3, Cs 2 C0 3 , NaOH, KOH, KOtBu, NaH and mixtures thereof, more preferably the base is KOH.
  • 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.
  • Resulting organic and aqueous phases are separated, the aqueous phase is extracted with an organic solvent, preferably teri-butyl methyl ether.
  • the resulting solution of the compound of formula (Ila) or the crude product obtained by evaporation of the organic solvent and other volatile components can be directly used in the process according to the invention.
  • the compounds of formula (Ila) may be further purified by known techniques, for example recrystallization or chromatography.
  • the reaction time of each of the steps of the process outlined above 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.
  • the process steps are generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the process according to the invention allows producing compounds of formula (I) in solid form, in particular in at least partially crystalline form. It has now be found that the compound of formula (I) 2- [6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3 -yl] - 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)propan-2- ol occurs in different polymorphic forms (herein also named as polymorphs or crystalline forms).
  • Polymorphism is the ability of a compound to crystallize in different crystalline phases with different arrangements and/or conformations of the molecules in the crystal lattice. Hence, polymorphs are different crystalline forms of the same pure chemical compound. On account of the different arrangement and/or conformation of molecules, polymorphs exhibit different physical, chemical and biological properties. Properties which may be affected include but are not limited solubility, dissolution rate, stability, optical and mechanical properties, etc.
  • the relative stability of a polymorph depends on its free energy, i.e. a more stable polymorph has a lower free energy. Under a defined set of experimental conditions only one polymorph has the lowest free energy.
  • This polymorph is the thermodynamically stable form and all other polymorph(s) is (are) termed metastable form(s).
  • a metastable form is one that is thermodynamically unstable but can nevertheless be prepared, isolated and analyzed as a result of its relatively slow rate of transformation.
  • a solvate is a crystalline molecular compound in which molecules of the solvent of crystallisation are incorporated into the host lattice, consisting of unsolvated molecules.
  • a hydrate is a special case of a solvate, when the incorporated solvent is water.
  • the presence of solvent molecules in the crystal lattice influences the intermolecular interactions and confers unique physical properties to each solvate.
  • a solvate thus has its own characteristic values of internal energy, enthalpy, entropy, Gibbs free energy, and thermodynamic activity.
  • R 1 represents methyl
  • R 4 represents Br; m is 1 ;
  • the polymorphic form A can be obtained by applying specific crystallisation conditions.
  • Crystals of polymorphic form A of suitable size and quality for crystallographic studies are for example obtained by diluting and/or suspending 400 mg 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-
  • 2- [6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol in step a) can essentially be any known form of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH- 1 ,2,4-triazol- 1 -yl)propan-2-ol.
  • the polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol can be characterized by X-ray powder diffractometry on the basis of the respective diffraction diagrams, which are recorded at 25°C and with Cu- ⁇ 1 radiation (1.5406 A).
  • the polymorphic form A displays at least 3, often at least 5, in particular at least 7, more particularly at least 10, and especially all of the reflections quoted in the following as values:
  • the polymorphic form A is in particular characterized by at least the reflections, quoted as 2 ⁇ value ⁇ 0.2°, 14.2 ⁇ 0.2°, 14.9 ⁇ 0.2° and 18.8 ⁇ 0.2°, more particularly by at least the reflections 14.2 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.8 ⁇ 0.2°, 23.3 ⁇ 0.2° and 28.0 ⁇ 0.2°, more particularly by at least the reflections 14.2 ⁇ 0.2°, 14.9 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 26.1 ⁇ 0.2° and 28.0 ⁇ 0.2°, and especially by at least the reflections 14.2 ⁇ 0.2°, 14. 15.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 20.2 ⁇ 0.2°, 22.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 23.8 ⁇ 0.2°, 26.1 ⁇ 0.2° and 28.0 ⁇ 0.2°.
  • the polymorphic form A is further characterized by the X-ray powder diffractogram depicted in Fig. la.
  • the polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol can be characterized by Raman spectroscopy on the basis of the respective spectrum, which are recorded at 25°C and with a laser wavelength of 1064 nm and a resolution of 2 cm .
  • the polymorphic form A displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima:
  • Fig. lb shows the FT Raman spectrum of polymorphic form A of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol.
  • the polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol can be characterized by infrared spectroscopy on the basis of the respective spectrum, which are recorded at 25°C using an universal diamond ATR device and a resolution of 4 cm 4 .
  • the polymorphic form A displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima: - - Table 3: IR bands of polymorphic form A
  • Fig. lc shows the IR spectrum of polymorphic form A of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol.
  • polymorphic form A of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l- (lH- l,2,4-triazol-l-yl)propan-2-ol a polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol-l-yl)propan-2-ol as well as an amorphous form have been identified, which are further characterized in the following.
  • the polymorphic form B can be obtained by applying specific crystallisation conditions. For example, it is obtained by a process comprising the following steps: a) diluting and/or suspending 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4- triazol- 1 -yl)propan-2-ol in a suitable solvent or solvent mixture, selected from ethylacetate, ethylacetate / n- heptane (1 : 10 parts by volume) and methanol; b) heating the same to boiling temperature of the solvent or solvent mixture; and c) cooling the solution or slurry obtained in step b) to a temperature of less than 25°C.
  • a suitable solvent or solvent mixture selected from ethylacetate, ethylacetate / n- heptane (1 : 10 parts by volume) and methanol
  • a suitable solvent or solvent mixture selected from ethy
  • Crystals of polymorphic form B of suitable size and quality for crystallographic studies are for example obtained by diluting and/or suspending 100 mg 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- l-(lH-l,2,4-triazol-l-yl)propan-2-ol in 10 ml methanol, heating the same to boiling temperature, cooling the obtained solution to 25°C whilst adding 100 ml water, storing the resulting suspension at 25°C for 24 hours, before filtration and evaporation of the adsorbed solvent at 25°C. - 5 -
  • 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol in step a) can essentially be any known form of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH- 1 ,2,4-triazol- 1 -yl)propan-2-ol.
  • the polymorphic form B of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- 1 -yl)propan-2-ol can be characterized by X-ray powder diffractometry on the basis of the respective diffraction diagrams, which are recorded at 25°C and with Cu- ⁇ 1 radiation (1.5406 A).
  • the polymorphic form B displays at least 3, often at least 5, in particular at least 7, more particularly at least 10, and especially all of the reflections quoted in the following as values:
  • the polymorphic form B is in particular characterized by at least the reflections, quoted as 2 ⁇ value ⁇ 0.2°, 18.3 ⁇ 0.2°, 24.5 ⁇ 0.2° and 26.8 ⁇ 0.2°, more particularly by at least the reflections 18.3 ⁇ 0.2°, 21.7 ⁇ 0.2°, 21.8 ⁇ 0.2°, 24.5 ⁇ 0.2° and 26.8 ⁇ 0.2°, more particularly by at least the reflections 17.4 ⁇ 0.2°, 18.3 ⁇ 0.2°, 21.7 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 24.5 ⁇ 0.2° and 26.8 ⁇ 0.2°, and especially by at least the reflections 17.0 ⁇ 0.2°, 17.4 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.2 ⁇ 0.2°, 21.7 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 24.5 ⁇ 0.2°, 26.6 ⁇ 0.2° and 26.8 ⁇ 0.2°.
  • the polymorphic form B is further characterized by the X-ray powder diffractogram depicted in Fig. 2a
  • the polymorphic form B of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- l-yl)propan-2-ol can be characterized by Raman spectroscopy on the basis of the respective spectrum, which are recorded at 25°C and with a laser wavelength of 1064 nm and a resolution of 2 cm .
  • the polymorphic form B displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima:
  • Fig. 2b shows the FT Raman spectrum of polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol.
  • the polymorphic form B of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- 1 -yl)propan-2-ol can be characterized by infrared spectroscopy on the basis of the respective spectrum, which are recorded at 25°C using an universal diamond ATR device and a resolution of 4 cm "1 .
  • the polymorphic form B displays at least 3, often at least 5, in particular at least 7, and especially all of the bands quoted in the following as peak maxima:
  • Fig. 2c shows the IR spectrum of polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]- 1 -(1H- 1 ,2,4-triazol- 1 -yl)propan-2-ol.
  • the amorphous form of 2-[6-(4-bromophenoxy)-2-(trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- l- yl)propan-2-ol can be obtained by melting crystals of polymorphic form B of 2-[6-(4-bromophenoxy)-2- (trifluoromethyl)pyridin-3-yl]-l-(lH-l,2,4-triazol- l-yl)propan-2-ol at 150°C and storing the melt at 25°C to let it cool to that temperature.
  • the amorphous form is characterized by the IR spectrum depicted in Fig. 3a
  • 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine (225 g, 0.575 mol, 1 equivalent (in the following equiv)) was added to a mixture of 608 mL of n-butanol and 68 mL of PEG400 (commercially available from Merck under the name Polyethylene glycol 400).
  • 60.6 g of lH-l,2,4-triazole (0.862 mol, 1.5 equiv) and 15.2 g of K2CO3 (0.23 mol, 0.4 equiv) were added and the mixture was heated to 100 °C for 13 h. The solvent was removed under reduced pressure until a viscous light-brown oil remained.
  • the suspension was further cooled down to 10-15 °C, filtered and washed with 800 mL of water.
  • the product was dried under vacuum at 50 °C to obtain 202 g of light-beige crystals of 97.9%a/a HPLC purity (77.6% yield).
  • 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine of 91.7% purity 40 g, 98 mmol, 1 equiv
  • n-butanol and PEG400 commercially available from Merck under the name Polyethylene glycol 400
  • 10.2 g of lH-l,2,4-triazole (147 mmol, 1.5 equiv) and 7.4 g of K 2 CO3 (54 mmol, 0.55 equiv) were added and the mixture was heated to 118-120 °C for 3 h.
  • the solvent was removed under reduced pressure and water was added to further remove the solvent azeotropically.
  • the residue was brought to room temperature, filtered, and washed with water to obtain a crude product of 84%a/a of target compound and 8% of its 4N-isomer.
  • 45 mL of toluene were added to the crude product and the mixture was heated to 70 °C. After cooling to 50 °C, some seeding crystals were added and the mixture was further cooled to 5 °C.
  • the suspension was filtered, washed with mother liquor, cold toluene and with petrol ether and finally dried to obtain 31.7 g of target compound of 95.5%a/a HPLC purity (69.7% yield).
  • 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine of 98% purity 40 g, 105 mmol, 1 equiv
  • n-butanol 40 mL
  • 10.9 g of lH-l,2,4-triazole (157 mmol, 1.5 equiv) and 8 g of K2CO3 (58 mmol, 0.55 equiv) were added and the mixture was heated to 118-120 °C for 3 h. The solvent was removed under reduced pressure and water was added to further remove the solvent azeotropically.
  • 6-(4-bromophenoxy)-3-(2-methyloxiran-2-yl)-2-(trifluoromethyl)pyridine of 94.4% purity 40 g, 100,9 mmol, 1 equiv
  • PEG400 commercially available from Merck under the name Polyethylene glycol 400
  • 10.5 g of lH-l,2,4-triazole (151.4 mmol, 1.5 equiv) and 5.6 g of K2CO3 (40.4 mmol, 0.4 equiv) were added and the mixture was heated to 110-120 °C for 4 h. After cooling the reaction mixture to room temperature, water (1.5 L) was added and the mixture was stirred thoroughly.
  • the precipitated solid was filtered using a suction strainer and remaining smeary residues were triturated with more water until they turned solid, whereupon they were added to the filter cake on the suction strainer. After washing with water and further straining, 73.73 g wet crude product of 92.1%a/a HPLC purity were obtained as beige solid.
  • the material was dissolved in 110 mL of isopropanol at 78 °C, stirred for 10 min and 160 mL of water were added. After stirring at 70 °C for 10 minutes, the mixture was let cool down to room temperature overnight. The suspension was filtered and the product was dried to obtain 35 g of off- white crystals of 97.6%a/a HPLC purity (76.4% yield). This shows that using PEG as sole solvent provides the target compound in high yield and purity even in the absence of a co-solvent.
  • X-Ray diffraction patterns were recorded at room temperature using XRD -diffractometers X ert PRO (PANalytical) and STOE STADI-P (radiation Cu K alpha 1, wavelength 1.5406 A). All X-Ray reflections are quoted as °2 ⁇ (theta) values (peak maxima) with a resolution of ⁇ 0.2°.
  • Raman spectra were recorded at room temperature using FT-Raman-spectrophotometers (model RFS 100 and MultiRam) from Bruker. Resolution was 2 cm . Measurements were performed in glass vials or aluminium discs.
  • IR-ATR-spectra were recorded at room temperature using a FT-IR-spectrophotometer one with universal diamond ATR device from Perkin-Elmer. Resolution was 4 cm .

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Abstract

La présente invention concerne un procédé de préparation de (1H-1,2,4-triazol-1-yl)alcools substitués de formule (I), dans laquelle R1, R4, m et Y sont tels que définis dans la description, par réaction de 1H-1,2,4-triazole et d'oxirane de formule (II), en présence d'une base et de polyalkylèneglycol. L'invention concerne également des formes cristallines particulières de 2-[6-(4-bromophénoxy)-2-(trifluorométhyl)pyridin-3-yl]-1-(1H -1,2,4-triazol-1-yl)propan-2-ol, un composé disponible selon ledit procédé.
PCT/EP2018/078041 2017-10-18 2018-10-15 Procédé pour la préparation de (1h-1,2,4-triazol-1-yl)alcools substitués Ceased WO2019012161A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017029179A1 (fr) 2015-08-14 2017-02-23 Bayer Cropscience Aktiengesellschaft Dérivés de triazole, leurs intermédiaires et leur utilisation comme fongicides

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017029179A1 (fr) 2015-08-14 2017-02-23 Bayer Cropscience Aktiengesellschaft Dérivés de triazole, leurs intermédiaires et leur utilisation comme fongicides

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* Cited by examiner, † Cited by third party
Title
MILTON ORCHIN, JOURNAL OF CHEMICAL EDUCATION, vol. 66, no. 7, 1999, pages 586 - 588

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