WO2016086722A1 - 一种异噁唑类化合物及其中间体的制备方法 - Google Patents

一种异噁唑类化合物及其中间体的制备方法 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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French (fr)
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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/zh

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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 Kinetics & Catalysis (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

本发明公开了一种异噁唑类化合物及其中间体的制备方法。该方法以化合物(I)为原料，在碱存在下与化合物(II)进行取代反应，再经氧化反应制备中间体酸(III)；中间体酸(III)经甲酯化得到中间体(IV)；中间体(IV)经硫代反应得中间体(VI)；中间体(VI)与环丙基甲酮在碱性条件下缩合得到中间体(VIII)；中间体(VIII)与原甲酸酯发生烯醚化反应，与盐酸羟胺环化得中间体(X)；中间体(X)被双氧水氧化甲硫基制备得到异噁唑类化合物(XI)。本发明制备方法所用原料易得，产率高，纯度高，三废少，成本低，具有很好的工业价值。

Description

一种异噁唑类化合物及其中间体的制备方法 技术领域
本发明属于有机合成领域，具体涉及一种异噁唑类化合物及其中间体的合成方法。
背景技术
异噁唑类化合物是一类重要的有机化合物，广泛应用于医药和农药领域。例如，异噁唑草酮是拜耳公司开发的新型除草剂，广泛用于玉米和甘蔗田防除禾本科杂草和阔叶杂草。CN1069267、CN1057524、CN1135210公开了异噁唑草酮的制备方法，其合成工艺是以2-硝基-4-三氟甲基苯甲酸(a)为原料，经过甲酯化得到2-硝基-4-三氟甲基苯甲酸甲酯(b)，中间体(b)与甲硫醇钠反应得到2-甲硫基-4-三氟甲基苯甲酸甲酯(c)，中间体(c)与环丙基甲酮在碱性条件下缩合得到3-环丙基-1-(2-甲硫基-4-三氟甲基苯基)丙-1,3-二酮(d)，中间体(d)和原甲酸三乙酯、乙酸酐下进行烯醚化反应，再与盐酸羟胺、醋酸钠反应得到5-环丙基-4-(2-甲硫基-4-三氟甲基苯基)异噁唑(e)，化合物(e)经双氧水或m-CPBA氧化得到异噁唑草酮(f)。
Figure PCTCN2015091889-appb-000001
该工艺的原料2-硝基-4-三氟甲基苯甲酸(a)主要的制备方法是4-三氟甲基-2-硝基苯氰的水解。US4868333公开了在100℃以上以氢溴酸水解4-三氟甲基-2-硝基苯氰得到4-三氟甲基-2-硝基苯甲酸。CN101575308公开了在乙二醇溶剂中，140℃下以氢氧化钠水解4-三氟甲基-2-硝基苯氰，以较好的收率得到4-三氟甲基-2-硝基苯甲酸。但这两种水解方法所用的原料4-三氟甲基-2-硝基苯腈合成困难，通常是使用***或氰化亚铜等高毒性的氰化试剂和4-三氟甲基-2-硝基卤代苯反应制得(CN102675151，EP0994099，EP0758643，US5705674)。此制备方法不仅收率低，杂质多，并且高毒性氰化试剂的使用导致后处理工艺危险，成本高，三废多。
发明内容
本发明的目的是克服现有技术的不足，提供一种原料易得、产率高、纯度高、三废少、成本低、后处理简单的异噁唑类化合物及其中间体的制备方法。
一种异噁唑类化合物的制备方法，包括如下步骤：
步骤A，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应后，继续与氧化剂反应，得到中间体化合物(III)；
步骤B，化合物(III)与酰氯化试剂反应后，再在一定温度下与醇反应得到化合物(IV)，或化合物(III)在一定温度下与烷基化试剂在碱作用下反应得到化合物(IV)；
步骤C，在溶剂中，化合物(IV)与硫化物(V)在一定温度下反应，得到化合物(VI)；
步骤D，在溶剂中和碱存在下，化合物(VI)和甲基酮(VII)在一定温度下缩合反应，得到化合物(VIII)；
步骤E，在溶剂中，化合物(VIII)和原甲酸酯(IX)与酸酐在一定温度下进行烯醚化反应后，继续与盐酸羟胺在缚酸剂存在下，在一定温度下进行环化反应，得到化合物(X)；
步骤F，在溶剂中，化合物(X)和双氧水在一定温度下反应，得到产物异噁唑类化合物(XI)，用反应式表示如下：
Figure PCTCN2015091889-appb-000002
其中，L为卤素、磺酰基或亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基，R1为甲基或乙基，R2为C1-C6的烷基或C6-C10的芳基，R3为C1-C6的烷基或C6-C10的芳基，R4为甲基或乙基，M为碱金属。
所述的L优选为氟、氯或溴；所述的R优选为甲氧基、乙氧基或氨基；所述的Rf优选为三氟甲基；所述的R2优选为甲基；所述的R3优选为环丙基；所述的R4优选为乙基；M优选为钠或钾；步骤A所述的氧化剂优选为氧气、臭氧、过氧酸、次氯酸钠、氯气、溴或双氧水；步骤A所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺。
步骤A所述的溶剂优选为DMF、NMP、DMSO、THF、乙醇、甲醇、乙腈、水的一种或多种，步骤A所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，步骤A所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II) 与化合物(I)的摩尔比优选为1-2:1，步骤A所述的反应温度优选为-10-60℃，步骤A所述的氧化剂进一步优选为双氧水，步骤A所述的氧化剂和化合物(I)的摩尔比优选为2-8:1；步骤B所述的酰氯化试剂优选为光气、三光气、草酰氯、氯化亚砜、三氯化磷、五氯化磷或三氯氧磷，酰氯化试剂与化合物(III)的摩尔比优选为1-5:1，步骤B所述的醇优选为甲醇或乙醇，步骤B所述的酰氯与醇的反应温度优选为0-80℃，步骤B所述的烷基化试剂优选为硫酸二甲酯、硫酸二乙酯、碘甲烷或碘乙烷，所述的烷基化试剂与化合物(III)的摩尔比优选为1-3:1，步骤B所述的碱优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或三乙胺，步骤B所述的碱与化合物(III)的摩尔比优选为1-2:1，步骤B所述的烷基化反应温度优选为10-50℃；步骤C所述的溶剂优选为DMF、DMSO或NMP，步骤C所述的硫化物(V)与化合物(IV)的摩尔比优选为1-3:1，所述的步骤C反应温度优选为0-50℃；步骤D所述的溶剂优选为DMSO、DMF、NMP、甲基叔丁基醚、THF、甲苯中的一种或多种，步骤D所述的碱优选为甲醇钠、甲醇钾、乙醇钠、乙醇钾、异丙醇钠、异丙醇钾、叔丁醇钠、叔丁醇钾、钠氢或LDA，步骤D所述的碱与化合物(VI)的摩尔比优选为1-3:1，步骤D所述的甲基酮(VII)和化合物(VI)的摩尔比优选为1-3:1，步骤D所述的反应温度优选为10-80℃；步骤E所述的溶剂优选为乙酸酐、乙酸、甲酸、甲醇、乙醇或异丙醇，步骤E所述的原甲酸酯(IX)优选为原甲酸三乙酯或原甲酸三甲酯，步骤E所述的原甲酸酯(IX)与化合物(VIII)的摩尔比优选为1-3:1，步骤E所述的烯醚化反应温度优选为80-140℃，步骤E所述的盐酸羟胺与化合物(VIII)的摩尔比优选为1-2:1，步骤E所述的缚酸剂优选为醋酸钠、醋酸钾、碳酸钠或碳酸钾，步骤E所述的缚酸剂与化合物(VIII)的摩尔比优选为0.5-2:1，步骤E所述的环化反应温度优选为0-50℃；步骤F所述的溶剂优选为醋酸或硫酸，步骤F所述的双氧水与化合物(X)的摩尔比优选为2-6:1，步骤F所述的反应温度优选为10-70℃。
一种2-硝基苯甲酸(III)的制备方法，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应完成后，继续与氧化剂反应，得到化合物(III)，用反应式表述如下：
Figure PCTCN2015091889-appb-000003
其中，L为卤素、磺酰基或亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基。
所述的X优选为氟、氯或溴，所述的R优选为甲氧基、乙氧基或氨基，所述的Rf优选为三氟甲基。所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺。所述 的氧化剂优选为氧气、臭氧、过氧酸、次氯酸钠、氯气、溴或双氧水，所述的氧化剂进一步优选为双氧水。
所述的溶剂优选为DMF、NMP、DMSO、THF、乙醇、甲醇、乙腈、水中的一种或多种，所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，所述的反应温度优选为-10-60℃，所述的氧化剂和化合物(I)的摩尔比优选为2-8:1。
一种2-硫醚基苯甲酸酯(V)的制备方法，包括如下步骤：
步骤A，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应后，继续与氧化剂反应，得到中间体化合物(III)；
步骤B，化合物(III)与酰氯化试剂反应后，再在一定温度下与醇反应得到化合物(IV)，或化合物(III)在一定温度下与烷基化试剂在碱作用下反应得到化合物(IV)；
步骤C，在溶剂中，化合物(IV)与硫化物(V)在一定温度下反应，得到化合物(VI)，用反应式表示如下：
Figure PCTCN2015091889-appb-000004
其中，L为卤素、磺酰基、亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基，R1为甲基或乙基，R2为C1-C6的烷基或C6-C10的芳基，M为碱金属。
所述的L优选为氟、氯或溴；所述的R优选为甲氧基、乙氧基或氨基；所述的Rf优选为三氟甲基；所述的R2优选为甲基；M优选为钠或钾；步骤A所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺，步骤A所述的氧化剂优选为氧气、臭氧或双氧水。
步骤A所述的溶剂优选为DMF、NMP、DMSO、THF、乙醇、甲醇、乙腈、水的一种或多种，步骤A所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，步骤A所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，步骤A所述的反应温度优选为-10-60℃，步骤A所述的氧化剂进一步优选为双氧水，步骤A所述的氧化剂和化合物(I)的摩尔比优选为2-8:1；步骤B所述的酰氯化试剂优选为光气、三光气、草酰氯、氯化亚砜、三氯化磷、五氯化磷或三氯氧磷，酰氯化试剂与化合物(III)的摩尔比优选为1-5：1，步骤B所述的醇优选为甲醇 或乙醇，步骤B所述的酰氯与醇的反应温度优选为0-80℃，步骤B所述的烷基化试剂优选为硫酸二甲酯、硫酸二乙酯、碘甲烷或碘乙烷，所述的烷基化试剂与化合物(III)的摩尔比优选为1-3:1，步骤B所述的碱优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或三乙胺，步骤B所述的碱与化合物(III)的摩尔比优选为1-2:1，步骤B所述的烷基化反应温度优选为10-50℃；步骤C所述的溶剂优选为DMF、DMSO或NMP，步骤C所述的硫化物(V)与化合物(IV)的摩尔比优选为1-3:1，所述的步骤C反应温度优选为0-50℃。
本发明提供的异噁唑类化合物及其中间体的制备方法，具有以下优点：
1、通过易得的原料制备异噁唑类化合物及其中间体，反应条件温和，安全；
2、使用绿色氧化剂，对环境友好，三废少；
3、避免了使用高毒性的氰化物所带进安全和三废问题；
4、总收率高，产品纯度高，成本低，有利于工业化生产。
具体实施方式
一种异噁唑类化合物的制备方法，包括如下步骤：
步骤A，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应后，继续与氧化剂反应，得到中间体化合物(III)；
步骤B，化合物(III)与酰氯化试剂反应后，再在一定温度下与醇反应得到化合物(IV)，或化合物(III)在一定温度下与烷基化试剂在碱作用下反应得到化合物(IV)；
步骤C，在溶剂中，化合物(IV)与硫化物(V)在一定温度下反应，得到化合物(VI)；
步骤D，在溶剂中和碱存在下，化合物(VI)和甲基酮(VII)在一定温度下缩合反应，得到化合物(VIII)；
步骤E，在溶剂中，化合物(VIII)和原甲酸酯(IX)与酸酐在一定温度下进行烯醚化反应后，继续与盐酸羟胺在缚酸剂存在下，在一定温度下进行环化反应，得到化合物(X)；
步骤F，在溶剂中，化合物(X)和双氧水在一定温度下反应，得到产物异噁唑类化合物(XI)，用反应式表示如下：
Figure PCTCN2015091889-appb-000005
其中，L为卤素、磺酰基或亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基，R1为甲基或乙基，R2为C1-C6的烷基或C6-C10的芳基，R3为C1-C6的烷基或C6-C10的芳基，R4为甲基或乙基，M为碱金属。
所述的L优选为氟、氯或溴；所述的R优选为甲氧基、乙氧基或氨基；所述的Rf优选为三氟甲基；所述的R2优选为甲基；所述的R3优选为环丙基；所述的R4优选为乙基；M优选为钠或钾；步骤A所述的氧化剂优选为氧气、臭氧、过氧酸、次氯酸钠、氯气、溴或双氧水；步骤A所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺。
步骤A所述的溶剂优选为DMF、NMP、DMSO、THF、乙醇、甲醇、乙腈、水的一种或多种，步骤A所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，步骤A所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，步骤A所述的反应温度优选为-10-60℃，步骤A所述的氧化剂进一步优选为双氧水，步骤A所述的氧化剂和化合物(I)的摩尔比优选为2-8:1；步骤B所述的酰氯化试剂优选为光气、三光气、草酰氯、氯化亚砜、三氯化磷、五氯化磷或三氯氧磷，酰氯化试剂与化合物(III)的摩尔比优选为1-5:1，步骤B所述的醇优选为甲醇或乙醇，步骤B所述的酰氯与醇的反应温度优选为0-80℃，步骤B所述的烷基化试剂优选为硫酸二甲酯、硫酸二乙酯、碘甲烷或碘乙烷，所述的烷基化试剂与化合物(III)的摩尔比优选为1-3:1，步骤B所述的碱优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或三乙胺，步骤B所述的碱与化合物(III)的摩尔比优选为1-2:1，步骤B所述的烷基化反应温度优选为10-50℃；步骤C所述的溶剂优选为DMF、DMSO或NMP，步骤C所述的硫化物(V)与化合物(IV)的摩尔比优选为1-3:1，所述的步骤C反应温度优选为0-50℃；步骤D所述的溶剂优选为DMSO、DMF、NMP、甲基叔丁基醚、THF、甲苯中的一种或多种，步骤D所述的碱优选为甲醇钠、甲醇钾、乙醇钠、乙醇钾、异丙醇钠、异丙醇钾、叔丁醇钠、叔丁醇钾、钠氢或LDA，步骤D所述的碱与化合物(VI)的摩尔比优选为1-3:1，步骤D所述的甲基酮(VII)和化合物(VI)的摩尔比优选为1-3:1，步骤D所述的反应温度优选为10-80℃；步骤E所述的溶剂优选为乙酸酐、乙酸、甲酸、甲醇、乙醇或异丙醇，步骤E所述的原甲酸酯(IX)优选为原甲酸三乙酯或原甲酸三甲酯，步骤E所述的原甲酸酯(IX)与化合物(VIII)的摩尔比优选为1-3:1，步骤E所述的烯醚化反应温度优选为80-140℃，步骤E所述的盐酸羟胺与化合物(VIII)的摩尔比优选为1-2:1，步骤E所述的缚酸剂优选为醋酸钠、醋酸钾、碳酸钠或碳酸钾，步骤E所述的缚酸剂与化合物(VIII)的摩尔比优选为0.5-2:1，步骤E所述的环化反应温度优选为0-50℃；步骤F所述的溶剂优选为醋酸或硫酸，步骤F所述的双氧水与化合物(X)的摩尔比优选为2-6:1，步骤F所述的反应温度优选为10-70℃。
一种2-硝基苯甲酸(III)的制备方法，在溶剂中及碱存在下，化合物(I)与化合物(II) 在一定温度下反应完成后，继续与氧化剂反应，得到化合物(III)，用反应式表述如下：
Figure PCTCN2015091889-appb-000006
其中，L为卤素、磺酰基或亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基。
所述的L优选为氟、氯或溴，所述的R优选为甲氧基、乙氧基或氨基，所述的Rf优选为三氟甲基。所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺。所述的氧化剂优选为氧气、臭氧、过氧酸、次氯酸钠、氯气、溴或双氧水，所述的氧化剂进一步优选为双氧水。
所述的溶剂优选为DMF、NMP、DMSO、THF、乙醇、甲醇、乙腈、水中的一种或多种，所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，所述的反应温度优选为-10-60℃，所述的氧化剂和化合物(I)的摩尔比优选为2-8:1。
一种2-硫醚基苯甲酸酯(V)的制备方法，包括如下步骤：
步骤A，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应后，继续与氧化剂反应，得到中间体化合物(III)；
步骤B，化合物(III)与酰氯化试剂反应后，再在一定温度下与醇反应得到化合物(IV)，或化合物(III)在一定温度下与烷基化试剂在碱作用下反应得到化合物(IV)；
步骤C，在溶剂中，化合物(IV)与硫化物(V)在一定温度下反应，得到化合物(VI)，用反应式表示如下：
Figure PCTCN2015091889-appb-000007
其中，L为卤素、磺酰基、亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基，R1为甲基或乙基，R2为C1-C6的烷基或C6-C10的芳基，M为碱 金属。
所述的L优选为氟、氯或溴；所述的R优选为甲氧基、乙氧基或氨基；所述的Rf优选为三氟甲基；所述的R2优选为甲基；M优选为钠或钾；步骤A所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺，步骤A所述的氧化剂优选为氧气、臭氧或双氧水。
步骤A所述的溶剂优选为DMF、NMP、DMSO、THF、乙醇、甲醇、乙腈、水的一种或多种，步骤A所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，步骤A所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，步骤A所述的反应温度优选为-10-60℃，步骤A所述的氧化剂进一步优选为双氧水，步骤A所述的氧化剂和化合物(I)的摩尔比优选为2-8:1；步骤B所述的酰氯化试剂优选为光气、三光气、草酰氯、氯化亚砜、三氯化磷、五氯化磷或三氯氧磷，酰氯化试剂与化合物(III)的摩尔比优选为1-5：1，步骤B所述的醇优选为甲醇或乙醇，步骤B所述的酰氯与醇的反应温度优选为0-80℃，步骤B所述的烷基化试剂优选为硫酸二甲酯、硫酸二乙酯、碘甲烷或碘乙烷，所述的烷基化试剂与化合物(III)的摩尔比优选为1-3:1，步骤B所述的碱优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或三乙胺，步骤B所述的碱与化合物(III)的摩尔比优选为1-2:1，步骤B所述的烷基化反应温度优选为10-50℃；步骤C所述的溶剂优选为DMF、DMSO或NMP，步骤C所述的硫化物(V)与化合物(IV)的摩尔比优选为1-3:1，所述的步骤C反应温度优选为0-50℃。
下面的实施例进一步举例说明了本发明的一些特征，但本发明所申请保护的内容和范围并不受下述实施例的限制。
实施例1：4-氯-3-硝基三氟甲苯的制备
在1000mL三颈烧瓶中，加入400g对氯三氟甲苯，在30℃下滴加273g 98％硫酸和190g98％硝酸的混酸，滴加完毕后继续反应4小时，分出有机层，有机层水洗两次，得480g 4-氯-3-硝基三氟甲苯。
实施例2：2-硝基-4-三氟甲基苯甲酸的制备
在装有温度计的1000mL三颈烧瓶中，加入500g DMF，180g碳酸钾，78g氰基乙酸乙酯。加入150g 4-氯-3-硝基三氟甲苯，控制反应物温度在50℃以内，滴加完毕后，继续搅拌反应1小时。滴加230g 35％H2O2，滴加完成后继续反应2小时，淬灭双氧水，脱溶，加水，盐酸酸化，过滤、水洗涤，干燥，得到149g 2-硝基-4-三氟甲基苯甲酸。1H-NMRδppm(DMSO-d6)：14.39(br,1H)，8.46(s,1H)，8.21(d,J＝8.0Hz,1H)，8.09(d,J＝8.0Hz,1H)。
实施例3：2-硝基-4-三氟甲基苯甲酸的制备
在1000mL三颈烧瓶中，加入400mL NMP，128g三乙胺，55g氰基乙酰胺。滴入143g 2- 硝基-4-三氟甲基氯苯，控制反应物温度在30℃，滴加完毕后，继续搅拌反应2小时。滴加162g 40％H2O2，滴加完成后继续反应2小时，淬灭双氧水，脱溶，加水，盐酸酸化，过滤，水洗涤，干燥，得到145g 2-硝基-4-三氟甲基苯甲酸。
实施例4：2-硝基-4-三氟甲基苯甲酸的制备
在1000mL三颈烧瓶中，加入500mL DMSO，40g氢氧化钠，41g氰基乙酰胺。滴入100g2-硝基-4-三氟甲基氟苯，控制反应物温度在10℃，滴加完毕后，继续搅拌反应3小时。淬灭双氧水，脱溶，加入400mL水，降温到10℃，滴加122g 40％H2O2，滴加完成后继续反应3小时，盐酸酸化，过滤，水洗涤，干燥，得到106g 2-硝基-4-三氟甲基苯甲酸。
实施例5：4-三氟甲基-2-硝基苯甲酸甲酯的制备
在250mL圆底烧瓶中，加入30g 4-三氟甲基-2-硝基苯甲酸，升温至80℃，加入100g氯化亚砜，80℃下保温反应4小时，蒸出过量的氯化亚砜，加入100g甲醇，室温搅拌至反应结束，脱溶，得到31g 4-三氟甲基-2-硝基苯甲酸甲酯。1H-NMRδppm(CDCl3)：8.22(s,1H)，7.96(dd,J1＝0.8Hz J2＝6.4Hz,1H)，7.88(d,J＝6.4Hz,1H)，3.97(s,3H)。
实施例6：制备4-三氟甲基-2-硝基苯甲酸甲酯
在500mL圆底烧瓶中，加入50g 4-三氟甲基-2-硝基苯甲酸，加入200g甲苯，室温下滴加27g硫酸二甲酯，升温至50℃反应4小时，降至室温，用饱和碳酸氢钠溶液洗涤，水洗涤，脱溶，得到49g 4-三氟甲基-2-硝基苯甲酸甲酯。
实施例7：4-三氟甲基-2-甲硫基苯甲酸甲酯的制备
在250mL圆底烧瓶中加入16g 4-三氟甲基-2-硝基苯甲酸甲酯和80mL DMF，搅拌下缓慢滴入9g甲硫醇钠，室温反应2小时，过滤，脱溶，固体用甲苯-水溶解，有机相依次用水、饱和NaHCO3水溶液洗2遍，干燥，脱溶，得到15g 4-三氟甲基-2-甲硫基苯甲酸甲酯。1H-NMRδppm(CDCl3)8.09(d,J＝8.0Hz,1H)，7.48(s,1H)，7.39(d,J＝8.0Hz,1H)，3.95(s,3H)，2.50(s,3H)。
实施例8：3-环丙基-1-(2-甲硫基-4-三氟甲基苯基)丙-1,3-二酮的制备
往500mL的烧瓶中加入78g 4-三氟甲基-2-甲硫基苯甲酸甲酯、230g甲苯和33g甲醇钠，加热到回流，滴加32g环丙基甲酮，滴加完成后继续搅拌5小时，冷却，加入盐酸淬灭反应并调至酸性，水洗涤两次，蒸除溶剂，得到90.1g制备3-环丙基-1-(2-甲硫基-4-三氟甲基苯基)丙-1,3-二酮。1H-NMRδppm(CDCl3)：15.91(s,1H),7.56(d,J＝6.4Hz,1H)，7.40(s,1H)，7.34(d,J＝6.4Hz,1H)，6.03(s,1H)，2.44(s,3H)，1.68(m,1H)，1.16(m，2H)，0.96(m，2H)；MS-ESI(m/e)：303[m+1]。
实施例9：5-环丙基-4-(2-甲硫基-4-三氟甲基苯基)异噁唑的制备
往500mL的反应瓶中加入83.8g 3-环丙基-1-(2-甲硫基-4-三氟甲基苯基)丙-1,3二酮，55g原甲酸三乙酯和251g乙酸酐，搅拌溶解，加热到120℃反应2小时，降温，减压精馏脱溶，往残余物中加入20g盐酸羟胺、25g无水乙酸钠和250g乙醇，室温搅拌2小时，抽滤， 减压脱溶，残余物加入甲苯，搅拌溶解，有机相用水洗涤，滤液脱溶得到85.3g 5-环丙基-4-(2-甲硫基-4-三氟甲基苯基)异噁唑。1H-NMRδppm(CDCl3)：8.20(s,1H)，7.60(d,J＝6.4Hz,1H)，7.49(d,J＝6.4Hz,1H)，2.72(m,1H)，2.52(s,3H)，1.36(m，2H)，1.26(m，2H)；MS-ESI(m/e)：328[m+1].
实施例10：异噁唑草酮的制备
往1000mL的玻璃反应瓶中加入92.5g 5-环丙基-4-(2-甲硫基-4-三氟甲基苯基)异噁唑、322g乙酸，搅拌下滴加102g 35％双氧水，控制滴加速度使反应温度维持在30～40℃，滴加完毕，继续反应4小时，淬灭双氧水，减压脱溶，残余物用450g乙酸乙酯溶解，再用水、饱和碳酸氢钠溶液、稀盐酸洗涤，脱溶得91.7g异噁唑草酮。1H-NMRδppm(CDCl3)：8.43(s,1H)，8.15(s，1H)，8.02(dd，J1＝6.4Hz J2＝0.8Hz，1H)，7.63(d，J＝6.4Hz，1H)，3.37(s，3H),2.55(m，1H)，1.38(m，2H)，1.24(m，2H)；MS-ESI(m/e)：360[m+1]。

Claims (10)

  1. 一种异噁唑类化合物的制备方法，其特征在于，包括如下步骤：
    步骤A，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应后，继续与氧化剂反应，得到中间体化合物(III)；
    步骤B，化合物(III)与酰氯化试剂反应后，再在一定温度下与醇反应得到化合物(IV)，或化合物(III)在一定温度下与烷基化试剂在碱作用下反应得到化合物(IV)；
    步骤C，在溶剂中，化合物(IV)与硫化物(V)在一定温度下反应，得到化合物(VI)；
    步骤D，在溶剂中和碱存在下，化合物(VI)和甲基酮(VII)在一定温度下缩合反应，得到化合物(VIII)；
    步骤E，在溶剂中，化合物(VIII)和原甲酸酯(IX)与酸酐在一定温度下进行烯醚化反应后，继续与盐酸羟胺在缚酸剂存在下，在一定温度下进行环化反应，得到化合物(X)；
    步骤F，在溶剂中，化合物(X)和双氧水在一定温度下反应，得到产物异噁唑类化合物(XI)，用反应式表示如下：
    Figure PCTCN2015091889-appb-100001
    其中，L为卤素、磺酰基或亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基，R1为甲基或乙基，R2为C1-C6的烷基或C6-C10的芳基，R3为C1-C6的烷基或C6-C10的芳基，R4为甲基或乙基，M为碱金属。
  2. 根据权利要求1所述的制备方法，其特征在于，所述的L优选为氟、氯或溴；所述的R优选为甲氧基、乙氧基或氨基；所述的Rf优选为三氟甲基；所述的R2优选为甲基；所述的R3优选为环丙基；所述的R4优选为乙基；M优选为钠或钾；步骤A所述的氧化剂优选为氧气、臭氧、过氧酸、次氯酸钠、氯气、溴或双氧水；步骤A所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺。
  3. 根据权利要求1所述的制备方法，其特征在于，步骤A所述的溶剂优选为DMF、NMP、 DMSO、THF、乙醇、甲醇、乙腈、水的一种或多种，步骤A所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，步骤A所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，步骤A所述的反应温度优选为-10-60℃，步骤A所述的氧化剂进一步优选为双氧水，步骤A所述的氧化剂和化合物(I)的摩尔比优选为2-8:1；步骤B所述的酰氯化试剂优选为光气、三光气、草酰氯、氯化亚砜、三氯化磷、五氯化磷或三氯氧磷，酰氯化试剂与化合物(III)的摩尔比优选为1-5:1，步骤B所述的醇优选为甲醇或乙醇，步骤B所述的酰氯与醇的反应温度优选为0-80℃，步骤B所述的烷基化试剂优选为硫酸二甲酯、硫酸二乙酯、碘甲烷或碘乙烷，所述的烷基化试剂与化合物(III)的摩尔比优选为1-3:1，步骤B所述的碱优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或三乙胺，步骤B所述的碱与化合物(III)的摩尔比优选为1-2:1，步骤B所述的烷基化反应温度优选为10-50℃；步骤C所述的溶剂优选为DMF、DMSO或NMP，步骤C所述的硫化物(V)与化合物(IV)的摩尔比优选为1-3:1，所述的步骤C反应温度优选为0-50℃；步骤D所述的溶剂优选为DMSO、DMF、NMP、甲基叔丁基醚、THF、甲苯中的一种或多种，步骤D所述的碱优选为甲醇钠、甲醇钾、乙醇钠、乙醇钾、异丙醇钠、异丙醇钾、叔丁醇钠、叔丁醇钾、钠氢或LDA，步骤D所述的碱与化合物(VI)的摩尔比优选为1-3:1，步骤D所述的甲基酮(VII)和化合物(VI)的摩尔比优选为1-3:1，步骤D所述的反应温度优选为10-80℃；步骤E所述的溶剂优选为乙酸酐、乙酸、甲酸、甲醇、乙醇或异丙醇，步骤E所述的原甲酸酯(IX)优选为原甲酸三乙酯或原甲酸三甲酯，步骤E所述的原甲酸酯(IX)与化合物(VIII)的摩尔比优选为1-3:1，步骤E所述的烯醚化反应温度优选为80-140℃，步骤E所述的盐酸羟胺与化合物(VIII)的摩尔比优选为1-2:1，步骤E所述的缚酸剂优选为醋酸钠、醋酸钾、碳酸钠或碳酸钾，步骤E所述的缚酸剂与化合物(VIII)的摩尔比优选为0.5-2:1，步骤E所述的环化反应温度优选为0-50℃；步骤F所述的溶剂优选为醋酸或硫酸，步骤F所述的双氧水与化合物(X)的摩尔比优选为2-6:1，步骤F所述的反应温度优选为10-70℃。
  4. 一种2-硝基苯甲酸(III)的制备方法，其特征在于，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应完成后，继续与氧化剂反应，得到化合物(III)，用反应式表述如下：
    Figure PCTCN2015091889-appb-100002
    其中，L为卤素、磺酰基或亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢， Rf为C1-C6的氟代烷基。
  5. 根据权利要求4所述的制备方法，其特征在于，所述的L优选为氟、氯或溴，所述的R优选为甲氧基、乙氧基或氨基，所述的Rf优选为三氟甲基，所述的氧化剂优选为氧气、臭氧、过氧酸、次氯酸钠、氯气、溴或双氧水。
  6. 根据权利要求4所述的方法，其特征在于，所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺，所述的氧化剂进一步优选为双氧水。
  7. 根据权利要求4所述的方法，其特征在于，所述的溶剂优选为DMF、NMP、DMSO、THF、乙醇、甲醇、乙腈、水中的一种或多种，所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，所述的反应温度优选为-10-60℃，所述的氧化剂和化合物(I)的摩尔比优选为2-8:1。
  8. 一种2-硫醚基苯甲酸酯(V)的制备方法，其特征在于，包括以下反应步骤：
    步骤A，在溶剂中及碱存在下，化合物(I)与化合物(II)在一定温度下反应后，继续与氧化剂反应，得到中间体化合物(III)；
    步骤B，化合物(III)与酰氯化试剂反应后，再在一定温度下与醇反应得到化合物(IV)，或化合物(III)在一定温度下与烷基化试剂在碱作用下反应得到化合物(IV)；
    步骤C，在溶剂中，化合物(IV)与硫化物(V)在一定温度下反应，得到化合物(VI)，用反应式表示如下：
    Figure PCTCN2015091889-appb-100003
    其中，L为卤素、磺酰基、亚磺酰基，R为烷氧基、氨基、烷胺基、烷基、芳基或氢，Rf为C1-C6的氟代烷基，R1为甲基或乙基，R2为C1-C6的烷基或C6-C10的芳基，M为碱金属。
  9. 根据权利要求8所述的制备方法，其特征在于，所述的L优选为氟、氯或溴；所述的R优选为甲氧基、乙氧基或氨基；所述的Rf优选为三氟甲基；所述的R2优选为甲基；M优选为钠或钾；步骤A所述的氧化剂优选为氧气、臭氧或双氧水；步骤A所述的碱优选为碱金属碳酸盐、碱金属氢氧化物、碱土金属碳酸盐、碱土金属氢氧化物、碱金属醋酸盐、碱金属甲酸盐、碱金属有机醇盐、季铵碱、季膦碱或有机胺。
  10. 根据权利要求8所述的制备方法，其特征在于，步骤A所述的溶剂优选为DMF、NMP、 DMSO、THF、乙醇、甲醇、乙腈、水的一种或多种，步骤A所述的碱进一步优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、乙醇钠、甲醇钠、三乙胺或吡啶，步骤A所述的碱和化合物(I)的摩尔比优选为1-3:1，所述的化合物(II)与化合物(I)的摩尔比优选为1-2:1，步骤A所述的反应温度优选为-10-60℃，步骤A所述的氧化剂进一步优选为双氧水，步骤A所述的氧化剂和化合物(I)的摩尔比优选为2-8:1；步骤B所述的酰氯化试剂优选为光气、三光气、草酰氯、氯化亚砜、三氯化磷、五氯化磷或三氯氧磷，酰氯化试剂与化合物(III)的摩尔比优选为1-5:1，步骤B所述的醇优选为甲醇或乙醇，步骤B所述的酰氯与醇的反应温度优选为0-80℃，步骤B所述的烷基化试剂优选为硫酸二甲酯、硫酸二乙酯、碘甲烷或碘乙烷，所述的烷基化试剂与化合物(III)的摩尔比优选为1-3:1，步骤B所述的碱优选为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾或三乙胺，步骤B所述的碱与化合物(III)的摩尔比优选为1-2:1，步骤B所述的烷基化反应温度优选为10-50℃；步骤C所述的溶剂优选为DMF、DMSO或NMP，步骤C所述的硫化物(V)与化合物(IV)的摩尔比优选为1-3:1，所述的步骤C反应温度优选为0-50℃。
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