WO2012053659A1 - Procédé de production d'un époxyalcool - Google Patents

Procédé de production d'un époxyalcool Download PDF

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WO2012053659A1
WO2012053659A1 PCT/JP2011/074601 JP2011074601W WO2012053659A1 WO 2012053659 A1 WO2012053659 A1 WO 2012053659A1 JP 2011074601 W JP2011074601 W JP 2011074601W WO 2012053659 A1 WO2012053659 A1 WO 2012053659A1
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group
formula
compound
difluorophenyl
methyl
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PCT/JP2011/074601
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English (en)
Japanese (ja)
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村岡　秀郎
信宏 荒井
正 水野
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住友化学株式会社
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Priority to CN201180050550.9A priority Critical patent/CN103180305B/zh
Publication of WO2012053659A1 publication Critical patent/WO2012053659A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/32—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a method for producing an epoxy alcohol compound.
  • Epoxy alcohol compounds such as 3- (2 ′, 4′-difluorophenyl) -3,4-epoxy-2-butanol and (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2
  • Triazole compounds such as-[(1H-1,2,4-triazol-1-yl) methyl] oxirane are known to be useful as intermediates for production of, for example, antifungal agents (eg, US Pat. No. 5,807,854, EP 698606, WO 2007/062542).
  • US 2008/081921 discloses a reaction mixture containing 3- (2 ′, 4′-difluorophenyl) -3,4-epoxy-2-butanol, which is an epoxy alcohol compound, and hydrochloric acid. Is obtained at a temperature of 25 ° C. or lower to obtain 3- (2 ′, 4′-difluorophenyl) -3,4-epoxy-2-butanol ([0059] to [0063]).
  • the epoxy alcohol compound may be obtained as an isomer mixture with its structural isomer.
  • the present invention relates to formula (3) (In the formula, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Ar represents an aromatic group or a methyl group substituted with an aromatic group.) And an epoxy alcohol compound (compound (3)) represented by the formula (3 ′) and its structural isomer (In the formula, R and Ar are as defined above.) An isomer mixture containing an epoxy alcohol compound represented by the formula (compound (3 ′)) is mixed with an acid at 30 ° C. to 70 ° C., and an epoxy alcohol compound represented by the formula (3) is obtained from the resulting mixture.
  • the present invention relates to a method for producing an epoxy alcohol compound represented by (3).
  • the alkyl group having 1 to 6 carbon atoms represented by R includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and an isopentyl group.
  • a linear or cyclic alkyl group such as neopentyl group, hexyl group and cyclohexyl group, preferably an alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, etc. More preferably, a methyl group is mentioned.
  • examples of the aromatic group represented by Ar include an optionally substituted aromatic carbocyclic group having 6 to 12 carbon atoms such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • an aromatic heterocyclic group having 3 to 12 carbon atoms such as 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 2-pyridyl group, 2-quinolyl group and the like.
  • substituents include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom), an alkyl group having 1 to 6 carbon atoms, and a trifluoromethyl group.
  • aromatic carbocyclic group which may be substituted include phenyl group, 1-naphthyl group, 2-naphthyl group, 2-tolyl group, 3-tolyl group, 4-tolyl group and 2,4-xylyl.
  • trifluoromethylphenyl group especially 2- (trifluoromethyl) phenyl group, 3- (trifluoro) Oromechiru) phenyl group, 4- (trifluoromethyl) phenyl group
  • 2,4-difluorophenyl group 2,5-difluorophenyl group is more preferable.
  • examples of the aromatic group of the methyl group substituted with the aromatic group represented by Ar include the same examples as the aromatic group represented by Ar.
  • methyl group substituted with the aromatic group represented by Ar include a benzyl group and a furfuryl group.
  • examples of the halogen atom represented by X include a chlorine atom, a bromine atom, and an iodine atom, and among them, an iodine atom is preferable.
  • examples of the leaving group represented by Y include halogen atoms such as chlorine atom, bromine atom and iodine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, and p-toluenesulfonyl.
  • Examples thereof include sulfonyloxy groups such as an oxy group and a p-trifluoromethanesulfonyloxy group.
  • the leaving group is preferably a sulfonyloxy group, more preferably a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a p-toluenesulfonyloxy group.
  • a methanesulfonyloxy group is preferable.
  • an isomer mixture containing compound (3) and its structural isomer, compound (3 ′) is, for example, an ylide prepared from halogenated trimethyloxosulfonium or halogenated trimethylsulfonium and a base and the formula ( 1) (In the formula, R and Ar are as defined above.) It can manufacture by making keto alcohol compound (compound (1)) shown by these react.
  • Compound (1) can be obtained by a known method such as the method described in US2003 / 236419.
  • an alkyl lactate is reacted with a dialkylamine to obtain a lactate dialkylamide, which is reacted with ethyl vinyl ether to protect the hydroxyl group with a 1-ethoxyethyl group, and then 2,4- It can be obtained by reacting an aromatic grinder reagent such as difluorophenyl magnesium halide.
  • Compound (1) may be an optically active form or a racemic form.
  • the optically active substance may be of any optical purity. Specific examples of the compound (1) include 2 ′, 4′-difluoro-2-hydroxypropiophenone, 2 ′, 5′-difluoro-2-hydroxypropiophenone, 2 ′, 4 ′, 6′-tri.
  • Fluoro-2-hydroxypropiophenone, 2 '-(trifluoromethyl) -2-hydroxypropiophenone, 3'-(trifluoromethyl) -2-hydroxypropiophenone and 4 '-(trifluoromethyl)- 2-hydroxypropiophenone is mentioned.
  • the halogenated trimethyloxosulfonium include trimethyloxosulfonium chloride, trimethyloxosulfonium bromide and trimethyloxosulfonium iodide, and among them trimethyloxosulfonium iodide is preferable.
  • Examples of the halogenated trimethylsulfonium include trimethylsulfonium chloride, trimethylsulfonium bromide, and trimethylsulfonium iodide. Among them, trimethylsulfonium iodide is preferable.
  • Examples of the base used for the preparation of ylide include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, sodium carbonate and potassium carbonate.
  • metal hydrides such as sodium hydride and lithium hydride
  • metal alkoxides such as sodium methoxide, sodium ethoxide, sodium butoxide, potassium butoxide, etc.
  • sodium hydroxide, sodium hydride, and lithium hydride are mentioned, More preferably, sodium hydride is mentioned.
  • the reaction of halogenated trimethyloxosulfonium or ylide prepared from halogenated trimethylsulfonium and a base with compound (1) is preferably carried out in a solvent.
  • ether solvents such as tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diethylene glycol dimethyl ether (diglyme), ethylene glycol dimethyl ether, 1,3-dioxolane, 2-methyltetrahydrofuran, and N, N-dimethyl.
  • Amide solvents such as formamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidinone, nitrile solvents such as acetonitrile and propionitrile, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-2-imidazolidinone and hexamethyl And phosphoric acid amides, preferably tetrahydrofuran, N, N-dimethylformamide and dimethyl sulfoxide, more preferably dimethyl sulfoxide and Hydrofuran and the like.
  • the ylide is prepared, for example, by a method in which halogenated trimethyloxosulfonium or halogenated trimethylsulfonium is mixed with a solvent, and then a base is added dropwise or dividedly to the mixture.
  • the preparation temperature of ylide varies depending on the solvent and base used, but is preferably 0 ° C. to 30 ° C., more preferably 8 ° C. to 15 ° C.
  • the preparation time of ylide varies depending on the solvent, base and the like used, but is preferably 1 to 24 hours.
  • the reaction between ylide and compound (1) is, for example, a method of adding compound (1) to ylide prepared by the above-mentioned method, or adding ylide to compound (1) or a mixture of compound (1) and a solvent. It can be done by a method.
  • the temperature at which compound (1) or ylide is added is preferably ⁇ 10 ° C. to 10 ° C., more preferably 0 ° C. to 5 ° C. in terms of the stability of compound (1) and compound (3) obtained by the reaction.
  • the time required for the addition is preferably 3 to 15 hours, more preferably 4 to 10 hours.
  • the reaction temperature between the ylide and the compound (1) is preferably ⁇ 10 ° C. to 10 ° C., more preferably 0 ° C.
  • the reaction time is preferably 1 to 8 hours, more preferably 1 to 5 hours.
  • Specific examples of the compound (3) include 3- (2 ′, 4′-difluorophenyl) -3,4-epoxy-2-butanol, 3- (2 ′, 5′-difluorophenyl) -3,4- Epoxy-2-butanol, 3- (2 ′, 4 ′, 6′-difluorophenyl) -3,4-epoxy-2-butanol, 3- (2 ′-(trifluoromethyl) phenyl) -3,4- Epoxy-2-butanol, 3- (3 ′-(trifluoromethyl) phenyl) -3,4-epoxy-2-butanol and 3- (4 ′-(trifluoromethyl) phenyl) -3,4-epoxy 2-butanol is mentioned.
  • an isomer mixture containing compound (3) and compound (3 ′) is mixed with an acid at a temperature selected from the range of 30 ° C. to 70 ° C.
  • structural isomers contained in the isomer mixture can be selectively decomposed.
  • the acid used include mineral acids such as hydrochloric acid and sulfuric acid, and carboxylic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, citric acid, and phthalic acid, preferably hydrochloric acid, succinic acid, citric acid, and the like.
  • a phthalic acid is mentioned, More preferably, a citric acid and a phthalic acid are mentioned.
  • An acid may be used independently and may mix and use 2 or more types of acids.
  • the amount of the acid to be used varies depending on the ratio of the compound (3) and the compound (3 ′) contained in the isomer mixture, but for example 0.1 to 2 mol, preferably 0 2 to 0.7 mol, more preferably 0.3 to 0.5 mol.
  • the acid is preferably used as an aqueous solution.
  • the amount of water used is, for example, 0.5 to 15 mL, preferably 1 to 10 mL, more preferably 1 to 8 mL with respect to 1 g of compound (3) contained in the isomer mixture.
  • This process is, for example, (A) A method of adjusting an isomer mixture containing the compound (3) and the compound (3 ′) to 30 ° C. to 70 ° C., and adding an acid or an aqueous solution thereof, (B) A method of adjusting an acid or an aqueous solution thereof to 30 ° C. to 70 ° C., and adding an isomer mixture containing the compound (3) and the compound (3 ′) thereto, (C) a method of adding an acid or an aqueous solution thereof to an isomer mixture containing the compound (3) and the compound (3 ′), and adjusting the resulting mixture to 30 ° C.
  • organic solvents include methylene chloride, 1,2-dichloroethane, monochlorobenzene, 1,2-dichlorobenzene, 2-chlorotoluene, 3-chlorotoluene, 4-chlorotoluene, 2-chloro-m-xylene.
  • Hydrocarbon solvents are preferred, aromatic hydrocarbon solvents are more preferred, and toluene is particularly preferred.
  • the amount of the organic solvent to be used is, for example, 0.5 to 10 mL, preferably 1 to 8 mL, more preferably 1 to 5 mL with respect to 1 g of compound (3) contained in the isomer mixture.
  • the mixing temperature in this step is 30 ° C. to 70 ° C., preferably 40 ° C. to 50 ° C. By setting the temperature at 30 ° C. to 70 ° C., the decomposition of the compound (3) can be suppressed and the compound (3 ′) can be selectively decomposed.
  • the reaction time varies depending on the type and amount of the acid used, the reaction temperature, etc., but is, for example, 0.5 to 24 hours, preferably 1 to 15 hours, and more preferably 3 to 10 hours.
  • Compound (3 ′) is mixed with an acid in the above-described step to give a compound of formula (4) (In the formula, R and Ar are as defined above. X represents a halogen atom.)
  • the present invention comprises the step of obtaining the compound (3) from the mixture obtained in the above-described steps, the compound (3) and the compound (3 ′) obtained from the reaction of the ylide and the compound (1).
  • the mixture obtained in the above step contains compound (3) and compound (4).
  • distillation can be performed under normal pressure conditions or under reduced pressure conditions, and is preferably performed under reduced pressure conditions from the viewpoint of the stability of the compound (3).
  • the temperature in the distillation varies depending on the compound (3) and the like, but is 20 to 200 ° C., preferably 60 to 160 ° C., for example, from the viewpoint of recovering the high purity compound (3) and the stability of the compound (3). More preferably, it is 80 to 140 ° C.
  • the time required for distillation varies depending on the type, amount and temperature of the compound (3), but is, for example, 0.5 to 24 hours, preferably 1 to 15 hours, and more preferably 3 to 10 hours.
  • the compound (3) thus obtained can be obtained, for example, by the method shown below according to the formula (5) (In the formula, R and Ar are as defined above.) It can convert into the triazole compound (compound (5)) shown by these.
  • Examples of the leaving group represented by Y include a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, and a benzenesulfonyloxy group.
  • the method described in (a) will be described in more detail.
  • the leaving group represented by Y is a sulfonyloxy group, for example, by reacting compound (3) with a sulfonylating agent in the presence of an amine such as triethylamine, the compound ( 3) can be converted to compound (6).
  • the sulfonylating agent examples include methanesulfonyl chloride, p-toluenesulfonyl chloride, and trifluoromethanesulfonic anhydride, and preferably include methanesulfonyl chloride and trifluoromethanesulfonic anhydride.
  • the amount of the sulfonylating agent to be used is preferably 0.8 to 1.8 mol, more preferably 0.9 to 1.2 mol, per 1 mol of compound (3).
  • Such a reaction is preferably carried out in the presence of a hydrocarbon solvent such as toluene.
  • Conversion of compound (3) to compound (6) can be performed, for example, by a method of mixing compound (3) and amine in a hydrocarbon solvent and adding a sulfonylating agent to the resulting mixture.
  • the addition temperature and reaction temperature of the sulfonylating agent are preferably ⁇ 20 ° C. to 40 ° C., more preferably 0 ° C. to 20 ° C.
  • the time required for the addition and reaction of the sulfonylating agent varies depending on the addition temperature and reaction temperature, but is preferably 0.5 to 5 hours, more preferably 1 to 3 hours.
  • the reaction between compound (6) and 1,2,4-triazole is preferably carried out in the presence of a base.
  • Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; Examples include alkaline earth metal carbonates such as calcium carbonate; metal hydroxides such as sodium hydride and lithium hydride; metal alkoxides such as sodium methoxide, sodium ethoxide, sodium butoxide, and potassium butoxide.
  • sodium hydroxide, sodium methoxide, sodium hydride, and lithium hydride are mentioned, More preferably, sodium hydroxide, sodium methoxide, and sodium hydride are mentioned.
  • the reaction between compound (6) and 1,2,4-triazole is preferably carried out in a solvent.
  • the solvent include ether solvents such as tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diethylene glycol dimethyl ether (diglyme), ethylene glycol dimethyl ether, 1,3-dioxolane, and 2-methyltetrahydrofuran; carbonization such as toluene and xylene.
  • Hydrogen-based solvents N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric acid amide, etc.
  • Aprotic polar solvents nitrile solvents such as acetonitrile and propionitrile
  • alcohol solvents such as methanol.
  • toluene, N, N-dimethylformamide, dimethyl sulfoxide and methanol are mentioned, More preferably, toluene, N, N-dimethylformamide and dimethyl sulfoxide are mentioned.
  • the temperature at which compound (6) reacts with 1,2,4-triazole varies depending on the type and boiling point of the solvent used in the reaction, the type and amount of base used, etc., but is, for example, 20 to 100 ° C., preferably 30 C. to 70.degree. C., more preferably 40 to 50.degree.
  • the reaction time varies depending on the reaction temperature and the like, but is, for example, 0.5 to 24 hours, preferably 1 to 15 hours, and more preferably 3 to 10 hours.
  • the reaction mixture obtained by the method described in (a) above is mixed with water and / or hydrochloric acid and subjected to extraction treatment, washing treatment, drying treatment, concentration treatment, crystallization treatment, solid-liquid separation treatment, etc.
  • the compound (5) can be isolated by By adopting the crystallization treatment and the solid-liquid separation treatment, an excellent quality compound (5) can be obtained.
  • the crystallization treatment is performed, for example, by adjusting the temperature of the concentrated mixture obtained by the concentration treatment to a predetermined temperature, adding seed crystals to the concentrated mixture, and stirring the resulting mixture.
  • a hydrocarbon solvent such as heptane may be added before and / or after the addition of the seed crystal.
  • the solid-liquid separation process is performed, for example, by a method of filtering the solid-liquid mixture obtained by the crystallization process.
  • the solid obtained by filtration may be subjected to washing treatment and drying treatment.
  • Compound (5) may be any optically active substance or a mixture of two or more thereof (for example, a racemate, an enantiomeric mixture, or a diastereomeric mixture). Specific examples of the compound (5) include (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl.
  • Compound (5) can be derived into a compound useful as an antifungal agent, for example, according to the method described in US Pat. No. 5,807,854, EP698606, WO2007 / 062542, and the like.
  • Example 1 Preparation of isomer mixture containing compound (3) and compound (3 ') Dimethyl sulfoxide (615 mL), tetrahydrofuran (259 mL), trimethyloxosulfonium iodide (158.4 g) were mixed, and the resulting mixture was heated to about 11 ° C. Cooled and temperature controlled. Thereto was added dropwise a mixture of 22.9 g of sodium hydride (about 60% mineral oil dispersion) and 46.0 g of liquid paraffin, and the mixture was kept warm and stirred until hydrogen bubbling ceased to prepare an ylide.
  • Dimethyl sulfoxide (615 mL), tetrahydrofuran (259 mL), trimethyloxosulfonium iodide (158.4 g) were mixed, and the resulting mixture was heated to about 11 ° C. Cooled and temperature controlled. Thereto was added dropwise a mixture of 22.9 g of sodium hydride (about 60% mineral oil dis
  • reaction mixture was added dropwise to a solution prepared by mixing 47.4 g of citric acid monohydrate, 875 mL of water and 410 mL of toluene, and the mixture was stirred at 40-45 ° C. for about 8 hours to give compound (3 ′ 1- (2,4-difluorophenyl) -1- (2-methyl-2-oxiranyl) methanol is decomposed to 1- (2,4-difluorophenyl) -1- (2-methyl-2- Oxiranyl) methanol was converted to 3- (2,4-difluorophenyl) -2-methyl-2-iodomethyloxirane, which is compound (4).
  • the mixture obtained above was cooled to around room temperature, and extracted with 410 mL and 205 mL of toluene, respectively.
  • the toluene layers obtained by extraction were combined, and the combined toluene layers were washed with weak alkaline water prepared by dissolving 2.3 g of sodium bicarbonate in 410 mL of water, and then washed twice with 410 mL of ion-exchanged water.
  • the washed toluene layer was concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-2, which is compound (3).
  • Example 4 Production of Compound (5) Using (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-2-butanol obtained in Example 3, (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-2-butanol was carried out in the same manner as in Example 2 except that the scale was changed to 17 g scale, and (2R, 3S) -2- (2 , 4-Difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane was obtained (yield: 39.4%).
  • Example 6 Production of Compound (5) Using (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-2-butanol obtained in Example 5, (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-2-butanol was carried out in the same manner as in Example 2 except that the scale was changed to 17 g scale, and (2R, 3S) -2- (2 , 4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane (8.8 g) was obtained (yield: 41.4%).
  • Example 8 Production of Compound (5) Using (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-2-butanol obtained in Example 7, (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-2-butanol was carried out in the same manner as in Example 2 except that the scale was changed to 17 g scale, and (2R, 3S) -2- (2 , 4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane was obtained (yield: 44.3%).
  • Example 10 Production of Compound (6) 20.0 g of (2R, 3R) -3- (2,5-difluorophenyl) -3,4-epoxy-2-butanol obtained in Example 9 (0.
  • Example 11 Production of compound (3) 47.4 g of citric acid monohydrate and 875 mL of water were replaced with 11.7 g of 35% hydrochloric acid and 436 mL of water, and (R) -1- (2,5-difluorophenyl ) -2-Hydroxy-1-propanone Performed in the same manner as in Example 9 except that the scale was changed to 46.6 g, and (2R, 3R) -3- (2,5-difluorophenyl) -3,4-epoxy- 21.1 g of 2-butanol was obtained (yield: 62.1%). Its purity (HPLC area percentage) was 79.5%.
  • Example 12 Production of Compound (5) Using (2R, 3R) -3- (2,5-difluorophenyl) -3,4-epoxy-2-butanol obtained in Example 11, (2R, 3R) -3- (2,5-difluorophenyl) -3,4-epoxy-2-butanol was carried out in the same manner as in Example 10 except that the scale was changed to 20 g, and (2R, 3S) -2- (2 , 5-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane was obtained (yield: 43.4%).
  • Example 13 Production of compound (3) 47.4 g of citric acid monohydrate and 875 mL of water were replaced with 11.25 g of phthalic acid and 263 mL of water, and (R) -1- (2,5-difluorophenyl) (2R, 3R) -3- (2,5-difluorophenyl) -3,4-epoxy-2-equivalent to Example 9 except that 2-hydroxy-1-propanone was changed to 30 g scale. 19.7 g of butanol was obtained (yield: 63.2%). Its purity (HPLC area percentage) was 76.5%.
  • sodium hydride about 60% mineral oil dispersion
  • Example 15 Isolation of compound (4)
  • compound (3) (2R, 3R) -3- (2,4-difluorophenyl) -3,4-epoxy-
  • 2-butanol was obtained by distillation, the distillation residue was purified by silica gel column chromatography and then crystallized to give 3- (2,4-difluorophenyl) -2-methyl- which is compound (4).
  • 2-Iodomethyloxirane was isolated.
  • the isolated 3- (2,4-difluorophenyl) -2-methyl-2-iodomethyloxirane was used as an analytical standard in Example 1 and the like described above.
  • epoxy alcohol compounds such as 3- (2 ', 4'-difluorophenyl) -3,4-epoxy-2-butanol are useful as intermediates for producing antifungal agents, for example.
  • the present invention is useful as a method for producing an epoxy alcohol compound.

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

Abstract

La présente invention concerne un époxyalcool de formule (3) (où R représente un atome d'hydrogène ou un groupement alkyle comportant entre 1 et 6 atomes de carbone, et Ar représente un groupement aromatique ou un groupement méthyle substitué par un groupement aromatique) qui est aisément produit en mélangeant un mélange d'isomères contenant l'époxyalcool de formule (3) et l'un de ses isomères structuraux, à savoir un époxyalcool de formule (3') (où R et Ar répondent aux définitions décrites ci-avant), un acide à une température comprise entre 30 °C et 70 °C, et en obtenant un époxyalcool de formule (3) à partir du mélange résultant.
PCT/JP2011/074601 2010-10-22 2011-10-19 Procédé de production d'un époxyalcool WO2012053659A1 (fr)

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CN201180050550.9A CN103180305B (zh) 2010-10-22 2011-10-19 环氧基醇化合物的制造方法

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JP2010237119A JP5716349B2 (ja) 2010-10-22 2010-10-22 エポキシアルコール化合物の取得方法、並びにエポキシアルコール化合物及びトリアゾール化合物の製造方法
JP2010-237119 2010-10-22

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WO2019031240A1 (fr) 2017-08-10 2019-02-14 住友化学株式会社 Procédé pour produire un composé de type époxy-alcool
JPWO2019031240A1 (ja) * 2017-08-10 2020-07-02 住友化学株式会社 エポキシアルコール化合物の製造方法
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EP3666762A4 (fr) * 2017-08-10 2021-04-07 Sumitomo Chemical Company, Limited Procédé pour produire un composé de type époxy-alcool
JP7060019B2 (ja) 2017-08-10 2022-04-26 住友化学株式会社 エポキシアルコール化合物の製造方法

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