WO2016086722A1 - Procédé de préparation de composé isoxazole et d'intermédiaire associé - Google Patents

Procédé de préparation de composé isoxazole et d'intermédiaire associé Download PDF

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WO2016086722A1
WO2016086722A1 PCT/CN2015/091889 CN2015091889W WO2016086722A1 WO 2016086722 A1 WO2016086722 A1 WO 2016086722A1 CN 2015091889 W CN2015091889 W CN 2015091889W WO 2016086722 A1 WO2016086722 A1 WO 2016086722A1
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compound
base
group
molar ratio
sodium
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PCT/CN2015/091889
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Chinese (zh)
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苏叶华
史界平
陆建鑫
张天浩
蔡国平
虞小华
陈邦池
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浙江省诸暨合力化学对外贸易有限公司
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Publication of WO2016086722A1 publication Critical patent/WO2016086722A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing an isoxazole compound and an intermediate thereof.
  • Isoxazoles are an important class of organic compounds that are widely used in the fields of medicine and pesticides.
  • isoxaflutole is a new herbicide developed by Bayer and is widely used in corn and sugar cane fields to control grass weeds and broadleaf weeds.
  • CN1069267, CN1057524, CN1135210 disclose a preparation method of isoxaflutole, which is prepared by using 2-nitro-4-trifluoromethylbenzoic acid (a) as a raw material and methyl esterification to obtain 2-nitro- Methyl 4-trifluoromethylbenzoate (b), intermediate (b) is reacted with sodium methanethiolate to give methyl 2-methylthio-4-trifluoromethylbenzoate (c), intermediate (c Condensation with cyclopropyl ketone under basic conditions to give 3-cyclopropyl-1-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione (d), The intermediate (d) is reacted with triethyl orthoformate and acetic anhydride to carry out the olefinic etherification reaction, and then reacted with hydroxylamine hydrochloride and sodium acetate to obtain 5-cyclopropyl-4-(2-methylthio-4
  • the main preparation method of the starting material of the process is the hydrolysis of 4-trifluoromethyl-2-nitrophenyl cyanide.
  • No. 4,868,333 discloses the hydrolysis of 4-trifluoromethyl-2-nitrophenyl cyanide with hydrobromic acid above 100 ° C to give 4-trifluoromethyl-2-nitrobenzoic acid.
  • CN101575308 discloses the hydrolysis of 4-trifluoromethyl-2-nitrobenzonitrile with sodium hydroxide at 140 ° C in an ethylene glycol solvent to give 4-trifluoromethyl-2-nitrol in good yield. benzoic acid.
  • the object of the present invention is to overcome the deficiencies of the prior art and provide a preparation method of an isoxazole compound and an intermediate thereof which are easy to obtain raw materials, high in yield, high in purity, low in waste, low in cost, and simple in post-treatment.
  • a method for preparing an isoxazole compound comprising the steps of:
  • Step A in a solvent and in the presence of a base, the compound (I) and the compound (II) are reacted at a certain temperature, and then continue to react with an oxidizing agent to obtain an intermediate compound (III);
  • Step B the compound (III) is reacted with an acid chloride reagent, and then reacted with an alcohol at a certain temperature to obtain a compound (IV), or the compound (III) is reacted with an alkylating agent under a base at a certain temperature to obtain a compound ( IV);
  • Step C in a solvent, the compound (IV) and the sulfide (V) are reacted at a certain temperature to obtain a compound (VI);
  • Step D in a solvent and in the presence of a base, the compound (VI) and methyl ketone (VII) condensation reaction at a certain temperature to obtain a compound (VIII);
  • Step E in the solvent, the compound (VIII) and the orthoformate (IX) and the acid anhydride are subjected to an ene etherification reaction at a certain temperature, and then continue to be cyclized with a hydroxylamine hydrochloride in the presence of an acid binding agent at a certain temperature. Reaction to give compound (X);
  • Step F in a solvent, the compound (X) and hydrogen peroxide are reacted at a certain temperature to obtain a product isoxazole compound (XI), which is represented by the following reaction formula:
  • L is halogen, sulfonyl or sulfinyl
  • R is alkoxy, amino, alkylamino, alkyl, aryl or hydrogen
  • Rf is C1-C6 fluoroalkyl
  • R 1 is methyl or Ethyl
  • R 2 is a C1-C6 alkyl group or a C6-C10 aryl group
  • R 3 is a C1-C6 alkyl group or a C6-C10 aryl group
  • R 4 is a methyl group or an ethyl group
  • M is an alkali metal.
  • the L is preferably fluorine, chlorine or bromine; the R is preferably a methoxy group, an ethoxy group or an amino group; the Rf is preferably a trifluoromethyl group; and the R 2 is preferably a methyl group; R 3 is preferably a cyclopropyl group; said R 4 is preferably an ethyl group; M is preferably sodium or potassium; and the oxidizing agent described in step A is preferably oxygen, ozone, peroxyacid, sodium hypochlorite, chlorine, bromine or hydrogen peroxide.
  • the base described in the step A is preferably an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal hydroxide, an alkali metal acetate, an alkali metal formate or an alkali metal organic alkoxide. , quaternary ammonium base, quaternary phosphonium base or organic amine.
  • the solvent described in the step A is preferably one or more of DMF, NMP, DMSO, THF, ethanol, methanol, acetonitrile, water, and the base described in the step A is further preferably sodium carbonate, potassium carbonate, sodium hydroxide or hydrogen.
  • the molar ratio of the base and the compound (I) described in the step A is preferably 1-3:1, the compound (II)
  • the molar ratio to the compound (I) is preferably 1-2:1
  • the reaction temperature described in the step A is preferably -10-60 ° C
  • the oxidizing agent described in the step A is further preferably hydrogen peroxide, the oxidizing agent and the compound described in the step A.
  • the molar ratio of (I) is preferably from 2 to 8:1; the acyl chloride reagent described in step B is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or trichlorochloride.
  • the molar ratio of oxyphosphorus, acid chloride reagent to compound (III) is preferably 1-5:1
  • the alcohol described in step B is preferably methanol or ethanol
  • the reaction temperature of the acid chloride and alcohol described in step B is preferably 0-80.
  • the alkylating agent described in the step B is preferably dimethyl sulfate, diethyl sulfate, methyl iodide or ethyl iodide, and the molar ratio of the alkylating agent to the compound (III) is preferably 1-3.
  • the base described in the step B is preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine, and the molar ratio of the base to the compound (III) in the step B is preferably 1-2:1.
  • the alkylation reaction temperature described in the step B is preferably 10-50 ° C; the solvent described in the step C is preferably DMF, DMSO or NMP, and the sulfide (V) and the compound (IV) described in the step C
  • the molar ratio is preferably 1-3:1
  • the reaction temperature of the step C is preferably 0-50 ° C;
  • the solvent described in the step D is preferably DMSO, DMF, NMP, methyl tert-butyl ether, THF, toluene.
  • One or more of the bases described in step D are preferably sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium t-butoxide, potassium t-butoxide, sodium hydrogen or LDA.
  • the molar ratio of the base to the compound (VI) in the step D is preferably 1-3:1, and the molar ratio of the methyl ketone (VII) to the compound (VI) in the step D is preferably 1-3:1.
  • the reaction temperature in the step D is preferably 10-80 ° C;
  • the solvent described in the step E is preferably acetic anhydride, acetic acid, formic acid, methanol, ethanol or isopropanol, and the orthoformate (IX) described in the step E is preferably.
  • the molar ratio of the orthoformate (IX) to the compound (VIII) in the step E is preferably 1-3:1, the olefin etherification reaction described in the step E is triethyl orthoformate or trimethyl orthoformate.
  • the temperature is preferably 80-140 ° C
  • the molar ratio of hydroxylamine hydrochloride to compound (VIII) in step E is preferably 1-2:1
  • the acid binding agent described in step E is preferably sodium acetate, potassium acetate, sodium carbonate or Potassium carbonate
  • step E The molar ratio of the acid binding agent to the compound (VIII) is preferably from 0.5 to 2:1
  • the cyclization reaction temperature described in the step E is preferably from 0 to 50 ° C
  • the solvent described in the step F is preferably acetic acid or sulfuric acid
  • step F The molar ratio of the hydrogen peroxide to the compound (X) is preferably from 2 to 6:1, and the reaction temperature in the step F is preferably from 10 to 70 °C.
  • L is a halogen, a sulfonyl group or a sulfinyl group
  • R is an alkoxy group, an amino group, an alkylamino group, an alkyl group, an aryl group or a hydrogen group
  • Rf is a C1-C6 fluoroalkyl group.
  • the X is preferably fluorine, chlorine or bromine, and the R is preferably a methoxy group, an ethoxy group or an amino group, and the Rf is preferably a trifluoromethyl group.
  • the base is preferably an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal hydroxide, an alkali metal acetate, an alkali metal formate, an alkali metal organic alkoxide, or a quaternary ammonium.
  • the oxidizing agent is preferably oxygen, ozone, peroxyacid, sodium hypochlorite, chlorine, bromine or hydrogen peroxide, and the oxidizing agent is further preferably hydrogen peroxide.
  • the solvent is preferably one or more of DMF, NMP, DMSO, THF, ethanol, methanol, acetonitrile, and water
  • the base is further preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or ethanol.
  • Sodium, sodium methoxide, triethylamine or pyridine the molar ratio of the base to the compound (I) is preferably 1-3:1, and the molar ratio of the compound (II) to the compound (I) is preferably 1- 2:1
  • the reaction temperature is preferably -10 to 60 ° C
  • the molar ratio of the oxidizing agent to the compound (I) is preferably 2 to 8:1.
  • Step A in a solvent and in the presence of a base, the compound (I) and the compound (II) are reacted at a certain temperature, and then continue to react with an oxidizing agent to obtain an intermediate compound (III);
  • Step B the compound (III) is reacted with an acid chloride reagent, and then reacted with an alcohol at a certain temperature to obtain a compound (IV), or the compound (III) is reacted with an alkylating agent under a base at a certain temperature to obtain a compound ( IV);
  • Step C in a solvent, compound (IV) is reacted with sulfide (V) at a certain temperature to obtain compound (VI), which is represented by the following reaction formula:
  • L is halogen, sulfonyl or sulfinyl
  • R is alkoxy, amino, alkylamino, alkyl, aryl or hydrogen
  • Rf is C1-C6 fluoroalkyl
  • R 1 is methyl or Ethyl
  • R 2 is a C1-C6 alkyl group or a C6-C10 aryl group
  • M is an alkali metal.
  • the L is preferably fluorine, chlorine or bromine; the R is preferably a methoxy group, an ethoxy group or an amino group; the Rf is preferably a trifluoromethyl group; and the R 2 is preferably a methyl group;
  • the base described in step A is preferably an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal hydroxide, an alkali metal acetate, an alkali metal formate,
  • the alkali metal organic alkoxide, quaternary ammonium base, quaternary phosphonium base or organic amine, the oxidizing agent described in the step A is preferably oxygen, ozone or hydrogen peroxide.
  • the solvent described in the step A is preferably one or more of DMF, NMP, DMSO, THF, ethanol, methanol, acetonitrile, water, and the base described in the step A is further preferably sodium carbonate, potassium carbonate, sodium hydroxide or hydrogen.
  • the molar ratio of the base and the compound (I) described in the step A is preferably 1-3:1, and the compound (II) and the compound (I)
  • the molar ratio is preferably 1-2:1, the reaction temperature described in the step A is preferably -10-60 ° C, the oxidizing agent described in the step A is further preferably hydrogen peroxide, and the molar ratio of the oxidizing agent and the compound (I) described in the step A
  • it is 2-8:1;
  • the acid chlorinating reagent described in step B is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride, acid chloride reagent
  • the molar ratio to the compound (III) is preferably 1-5:1, and the alcohol described in the step B is
  • the reaction temperature of the acid chloride and the alcohol described in the step B is preferably 0-80 ° C, and the alkylating agent described in the step B is preferably dimethyl sulfate, diethyl sulfate, methyl iodide or ethyl iodide.
  • the molar ratio of the alkylating agent to the compound (III) is preferably 1-3:1, and the base described in the step B is preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine, step B
  • the molar ratio of the base to the compound (III) is preferably 1-2:1, the alkylation reaction temperature described in the step B is preferably 10-50 ° C; the solvent described in the step C is preferably DMF, DMSO or NMP.
  • the molar ratio of the sulfide (V) to the compound (IV) in the step C is preferably 1-3:1, and the reaction temperature in the step C is preferably 0-50 °C.
  • a method for preparing an isoxazole compound comprising the steps of:
  • Step A in a solvent and in the presence of a base, the compound (I) and the compound (II) are reacted at a certain temperature, and then continue to react with an oxidizing agent to obtain an intermediate compound (III);
  • Step B the compound (III) is reacted with an acid chloride reagent, and then reacted with an alcohol at a certain temperature to obtain a compound (IV), or the compound (III) is reacted with an alkylating agent under a base at a certain temperature to obtain a compound ( IV);
  • Step C in a solvent, the compound (IV) and the sulfide (V) are reacted at a certain temperature to obtain a compound (VI);
  • Step D in a solvent and in the presence of a base, the compound (VI) and methyl ketone (VII) condensation reaction at a certain temperature to obtain a compound (VIII);
  • Step E in the solvent, the compound (VIII) and the orthoformate (IX) and the acid anhydride are subjected to an ene etherification reaction at a certain temperature, and then continue to be cyclized with a hydroxylamine hydrochloride in the presence of an acid binding agent at a certain temperature. Reaction to give compound (X);
  • Step F in a solvent, the compound (X) and hydrogen peroxide are reacted at a certain temperature to obtain a product isoxazole compound (XI), which is represented by the following reaction formula:
  • L is halogen, sulfonyl or sulfinyl
  • R is alkoxy, amino, alkylamino, alkyl, aryl or hydrogen
  • Rf is C1-C6 fluoroalkyl
  • R 1 is methyl or Ethyl
  • R 2 is a C1-C6 alkyl group or a C6-C10 aryl group
  • R 3 is a C1-C6 alkyl group or a C6-C10 aryl group
  • R 4 is a methyl group or an ethyl group
  • M is an alkali metal.
  • the L is preferably fluorine, chlorine or bromine; the R is preferably a methoxy group, an ethoxy group or an amino group; the Rf is preferably a trifluoromethyl group; and the R 2 is preferably a methyl group; R 3 is preferably a cyclopropyl group; said R 4 is preferably an ethyl group; M is preferably sodium or potassium; and the oxidizing agent described in step A is preferably oxygen, ozone, peroxyacid, sodium hypochlorite, chlorine, bromine or hydrogen peroxide.
  • the base described in the step A is preferably an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal hydroxide, an alkali metal acetate, an alkali metal formate or an alkali metal organic alkoxide. , quaternary ammonium base, quaternary phosphonium base or organic amine.
  • the solvent described in the step A is preferably one or more of DMF, NMP, DMSO, THF, ethanol, methanol, acetonitrile, water, and the base described in the step A is further preferably sodium carbonate, potassium carbonate, sodium hydroxide or hydrogen.
  • the molar ratio of the base and the compound (I) described in the step A is preferably 1-3:1, and the compound (II) and the compound (I)
  • the molar ratio is preferably 1-2:1, the reaction temperature described in the step A is preferably -10-60 ° C, the oxidizing agent described in the step A is further preferably hydrogen peroxide, and the molar ratio of the oxidizing agent and the compound (I) described in the step A Preferably, it is 2-8:1;
  • the acid chlorinating reagent described in step B is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride, acid chloride reagent
  • the molar ratio to the compound (III) is preferably 1-5:1, the alcohol described in the step B is preferably
  • the alkylating agent is preferably dimethyl sulfate, diethyl sulfate, methyl iodide or ethyl iodide, and the molar ratio of the alkylating agent to the compound (III)
  • the base is preferably 1-3:1
  • the base described in the step B is preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine
  • the molar ratio of the base to the compound (III) described in the step B is preferably 1-2:1
  • the alkylation reaction temperature described in step B is preferably 10-50 ° C
  • the solvent described in step C is preferably DMF, DMSO or NMP
  • the molar ratio of IV) is preferably 1-3:1, the reaction temperature of step C is preferably 0-50 ° C;
  • the solvent described in step D is preferably DMSO, DMF, NMP, methyl
  • the molar ratio of the base to the compound (VI) in the step D is preferably 1-3:1, and the molar ratio of the methyl ketone (VII) to the compound (VI) in the step D is preferably 1-3.
  • the reaction temperature described in step D is preferably 10-80 ° C;
  • the solvent described in step E is preferably acetic anhydride, acetic acid, formic acid, methanol, ethanol or isopropanol,
  • the orthoformate described in step E ( IX) is preferably triethyl orthoformate
  • the molar ratio of the orthoformate (IX) to the compound (VIII) in the step E is preferably 1-3:1, and the olefin etherification reaction temperature in the step E is preferably 80-140 ° C.
  • the molar ratio of hydroxylamine hydrochloride to compound (VIII) in step E is preferably 1-2:1, and the acid binding agent described in step E is preferably sodium acetate, potassium acetate, sodium carbonate or potassium carbonate, as described in step E.
  • the molar ratio of the acid binding agent to the compound (VIII) is preferably from 0.5 to 2:1, the cyclization reaction temperature described in the step E is preferably from 0 to 50 ° C; the solvent described in the step F is preferably acetic acid or sulfuric acid, step F
  • the molar ratio of the hydrogen peroxide to the compound (X) is preferably from 2 to 6:1, and the reaction temperature in the step F is preferably from 10 to 70 °C.
  • L is a halogen, a sulfonyl group or a sulfinyl group
  • R is an alkoxy group, an amino group, an alkylamino group, an alkyl group, an aryl group or a hydrogen group
  • Rf is a C1-C6 fluoroalkyl group.
  • the L is preferably fluorine, chlorine or bromine, and the R is preferably a methoxy group, an ethoxy group or an amino group, and the Rf is preferably a trifluoromethyl group.
  • the base is preferably an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal hydroxide, an alkali metal acetate, an alkali metal formate, an alkali metal organic alkoxide, or a quaternary ammonium.
  • the oxidizing agent is preferably oxygen, ozone, peroxyacid, sodium hypochlorite, chlorine, bromine or hydrogen peroxide, and the oxidizing agent is further preferably hydrogen peroxide.
  • the solvent is preferably one or more of DMF, NMP, DMSO, THF, ethanol, methanol, acetonitrile, and water
  • the base is further preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or ethanol.
  • Sodium, sodium methoxide, triethylamine or pyridine the molar ratio of the base to the compound (I) is preferably 1-3:1, and the molar ratio of the compound (II) to the compound (I) is preferably 1- 2:1
  • the reaction temperature is preferably -10 to 60 ° C
  • the molar ratio of the oxidizing agent to the compound (I) is preferably 2 to 8:1.
  • Step A in a solvent and in the presence of a base, the compound (I) and the compound (II) are reacted at a certain temperature, and then continue to react with an oxidizing agent to obtain an intermediate compound (III);
  • Step B the compound (III) is reacted with an acid chloride reagent, and then reacted with an alcohol at a certain temperature to obtain a compound (IV), or the compound (III) is reacted with an alkylating agent under a base at a certain temperature to obtain a compound ( IV);
  • Step C in a solvent, compound (IV) is reacted with sulfide (V) at a certain temperature to obtain compound (VI), which is represented by the following reaction formula:
  • L is halogen, sulfonyl or sulfinyl
  • R is alkoxy, amino, alkylamino, alkyl, aryl or hydrogen
  • Rf is C1-C6 fluoroalkyl
  • R 1 is methyl or Ethyl
  • R 2 is a C1-C6 alkyl group or a C6-C10 aryl group
  • M is an alkali metal.
  • the L is preferably fluorine, chlorine or bromine; the R is preferably a methoxy group, an ethoxy group or an amino group; the Rf is preferably a trifluoromethyl group; and the R 2 is preferably a methyl group;
  • the base described in step A is preferably an alkali metal carbonate, an alkali metal hydroxide, an alkaline earth metal carbonate, an alkaline earth metal hydroxide, an alkali metal acetate, an alkali metal formate,
  • the alkali metal organic alkoxide, quaternary ammonium base, quaternary phosphonium base or organic amine, the oxidizing agent described in the step A is preferably oxygen, ozone or hydrogen peroxide.
  • the solvent described in the step A is preferably one or more of DMF, NMP, DMSO, THF, ethanol, methanol, acetonitrile, water, and the base described in the step A is further preferably sodium carbonate, potassium carbonate, sodium hydroxide or hydrogen.
  • the molar ratio of the base and the compound (I) described in the step A is preferably 1-3:1, and the compound (II) and the compound (I)
  • the molar ratio is preferably 1-2:1, the reaction temperature described in the step A is preferably -10-60 ° C, the oxidizing agent described in the step A is further preferably hydrogen peroxide, and the molar ratio of the oxidizing agent and the compound (I) described in the step A Preferably, it is 2-8:1;
  • the acid chlorinating reagent described in step B is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride, acid chloride reagent
  • the molar ratio to the compound (III) is preferably 1-5:1, the alcohol described in the step B is preferably
  • the alkylating agent is preferably dimethyl sulfate, diethyl sulfate, methyl iodide or ethyl iodide, the alkylating agent and the compound (III)
  • the base is preferably 1-3:1
  • the base described in the step B is preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or triethylamine
  • the molar ratio of the base to the compound (III) described in the step B is preferably 1-2:1
  • the alkylation reaction temperature described in step B is preferably 10-50 ° C
  • the solvent described in step C is preferably DMF, DMSO or NMP
  • the sulfide (V) and the compound described in step C ( The molar ratio of IV) is preferably from 1 to 3:1
  • the reaction temperature in the step C is preferably from 0 to 50 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé isoxazole et d'un intermédiaire associé, ledit procédé comprenant les étapes suivantes : un composé (I), utilisé comme produit de départ, est soumis à une réaction de substitution avec un composé (II) en présence d'une base, et ensuite à une réaction d'oxydation pour préparer un acide intermédiaire (III); l'acide intermédiaire (III) est soumis à une estérification méthylique pour obtenir un intermédiaire (IV); l'intermédiaire (IV) est soumis à une thionation pour obtenir un intermédiaire (VI); l'intermédiaire (VI) est soumis à une condensation avec une cyclopropyl-méthanone dans des conditions basiques pour obtenir un intermédiaire (VIII); l'intermédiaire (VIII) est soumis à une réaction d'éthérification d'alcène avec de l'ortho-formiate et cyclisé avec du chlorhydrate d'hydroxylamine pour obtenir un intermédiaire (X); le méthylthio de l'intermédiaire (X) est oxydé par du peroxyde d'hydrogène pour obtenir le composé isoxazole (XI). Le produit de départ utilisé dans le procédé de la présente préparation est facilement disponible, et le procédé de préparation présente des propriétés élevées de productivité et de pureté, produit moins de déchets industriels en termes d'eaux, de gaz et de résidus, et peut être mis en œuvre à faible coût et présente une bonne valeur industrielle.
PCT/CN2015/091889 2014-12-02 2015-10-14 Procédé de préparation de composé isoxazole et d'intermédiaire associé WO2016086722A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410720121.3 2014-12-02
CN201410720121.3A CN105712944B (zh) 2014-12-02 2014-12-02 一种异噁唑类化合物及其中间体的制备方法

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