WO2023054702A1 - Aldehyde compound production method and dihydroisoxazole compound production method - Google Patents

Aldehyde compound production method and dihydroisoxazole compound production method Download PDF

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WO2023054702A1
WO2023054702A1 PCT/JP2022/036818 JP2022036818W WO2023054702A1 WO 2023054702 A1 WO2023054702 A1 WO 2023054702A1 JP 2022036818 W JP2022036818 W JP 2022036818W WO 2023054702 A1 WO2023054702 A1 WO 2023054702A1
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mol
formula
compound
reaction
mmol
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PCT/JP2022/036818
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French (fr)
Japanese (ja)
Inventor
開 瀧澤
崚 丸山
亮太 藤本
俊浩 永田
大介 志鎌
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クミアイ化学工業株式会社
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Priority to JP2023551919A priority Critical patent/JPWO2023054702A1/ja
Priority to CN202280038539.9A priority patent/CN117396464A/en
Priority to IL311693A priority patent/IL311693A/en
Publication of WO2023054702A1 publication Critical patent/WO2023054702A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/02—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen
    • C07C47/198—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen containing ether groups, groups, groups, or groups
    • 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
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

Definitions

  • the present invention is based on formula (7):
  • R 1 and R 2 are as described below.
  • compound ie, a method for producing dihydroisoxazole.
  • dihydroisoxazole is also referred to as isoxazoline.
  • the present invention provides formula (3) or formula (4):
  • the compound of formula (3) or formula (4) is useful as a production intermediate for pharmaceuticals, agricultural chemicals, and the like.
  • WO2002/062770A1 discloses useful herbicides and compounds of formula (3) or (4) can be used as intermediates for said herbicides.
  • Pyroxasulfone is well known as a herbicide having excellent herbicidal activity.
  • Patent Document 2 discloses a process for producing dihydroisoxazole, which can also be used as an intermediate for herbicides such as pyroxasulfone.
  • Patent Document 2 (WO2020/251006A1):
  • Patent Document 5 (WO2019/117255A1) also discloses a method for producing intermediates for herbicides such as pyroxasulfone.
  • Patent Document 5 (WO2019/117255A1):
  • Patent Document 6 (WO2019/208643A1) also discloses a method for producing intermediates for herbicides such as pyroxasulfone. The manufacturing method is shown in the figure below.
  • Patent Document 6 (WO2019/208643A1):
  • Patent Document 2 WO2020/251006A1
  • Patent Document 5 WO2019/117255A1
  • Patent Document 6 WO2019/208643A1
  • Patent Document 3 discloses an oxidation method using oxygen as a method for producing an aldehyde compound.
  • Patent Document 4 discloses an oxidation method using oxygen as a method for producing an aldehyde compound.
  • the alcohol compound of formula (1) was used as a starting material to react, but the aldehyde compound of formula (3) was The yield was low (Comparative Examples 10-12).
  • An object of the present invention is to provide an efficient and industrially preferable method for producing the compound of formula (7).
  • a further object of the present invention is to provide an industrially preferable method for producing the compound of formula (3) or (4).
  • a specific object is a method for producing a compound (aldehyde compound) of formula (3) or (4) from a compound (alcohol compound) of formula (1) or formula (2) by a simple operation, It is an object of the present invention to provide a production method in which the ratio of carboxylic acid derivatives and ester derivatives produced as organisms is sufficiently low, the yield is excellent, and it is advantageous for industrial production.
  • the present invention is as follows.
  • a method for producing a compound of formula (7) comprising the following steps; Step (i) reacting the compound of formula (1) or the compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give the corresponding compound of formula (3) or formula ( 4) to obtain the compound:
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl;
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • Step (ii) reacting a compound of formula (3) or a compound of formula (4) with an oximating agent to give the corresponding compound of formula (5) or compound of formula (6) respectively:
  • Step (iii) reacting a compound of formula (5) or a compound of formula (6) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
  • a method for producing a compound of formula (7) comprising the following steps; Step (ia) reacting a compound of formula (1) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (3):
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl;
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • Step (ii-a) reacting a compound of formula (3) with an oximating agent to give a compound of formula (5):
  • Step (iii-a) reacting a compound of formula (5) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
  • a method for producing a compound of formula (7) comprising the following steps; Step (ib) reacting a compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (4):
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl;
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • Step (ii-b) reacting a compound of formula (4) with an oximating agent to give a compound of formula (6):
  • Step (iii-b) reacting a compound of formula (6) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
  • a method for producing a compound of formula (3) or a compound of formula (4) comprising the following steps; Step (i) reacting the compound of formula (1) or the compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give the corresponding compound of formula (3) or formula ( 4) to obtain the compound:
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl;
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • a method for producing a compound of formula (3) comprising the following steps; Step (ia) reacting a compound of formula (1) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (3):
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl;
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • a method for producing a compound of formula (4) comprising the following steps; Step (ib) reacting a compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (4):
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl;
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • [I-8] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes of preparation wherein the catalyst is iron(III) nitrate or a catalyst comprising iron(III) chloride, iron(III) bromide or iron(III) iodide and nitric acid, except where not applicable.
  • step (i), step (ia) or step (ib) Processes where the catalyst is a catalyst comprising iron(III) chloride or iron(III) bromide and nitric acid, except where not applicable.
  • [I-12] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes of preparation wherein the catalyst is copper(II) nitrate, or a catalyst comprising copper(II) chloride, copper(II) bromide or copper(II) iodide and nitric acid, except where not applicable.
  • [I-13] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is a catalyst comprising copper(II) chloride or copper(II) bromide and nitric acid, except where not applicable.
  • step (i), step (ia) or step (ib) is used in an amount of 0.01 mol to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
  • step (i), step (ia) or step (ib) is used in an amount of 0.02 mol to 0.05 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
  • step (i), step (ia) or step (ib) is a carboxylic acid, except those not applicable.
  • step (i), step (ia) or step (ib) is acetic acid, propionic acid or benzoic acid, except those not applicable.
  • step (i), step (ia) or step (ib) is acetic acid, except those not applicable.
  • step (i), step (ia) or step (ib) is an aromatic heterocycle having a nitrogen atom, except those not applicable.
  • step (i), step (ia) or step (ib) is N-methylimidazole, 2,2'-bipyridyl, N-methylpyrazole, pyridine or N,N-dimethylaminopyridine, except those not applicable.
  • step (i), step (ia) or step (ib) is N-methylimidazole or 2,2'-bipyridyl, except those not applicable.
  • step (i), step (ia) or step (ib) The production method according to any one of [I-1] to [I-33], wherein the base in step (i), step (ia) or step (ib) is used in an amount of 0.01 to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
  • [I-36] The production method according to any one of [I-1] to [I-35], wherein the metal in step (i), step (ia) or step (ib) A production method in which the amount of catalyst used is 0.001 to 0.3 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
  • [I-37] The production method according to any one of [I-1] to [I-35], wherein the metal in step (i), step (ia) or step (ib) A production method in which the amount of catalyst used is 0.01 to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
  • step (i), step (ia) or step (ib) A production method in which the xyl radical compound is 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl, except for those not applicable.
  • step (i), step (ia) or step (ib) A production method in which the amount of the xyl radical compound used is 0.001 to 0.3 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
  • step (i), step (ia) or step (ib) A production method in which the amount of the xyl radical compound used is 0.01 to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
  • step (i), step (ia) or step (ib) is carried out in the presence of a solvent, wherein the solvent is aromatic hydrocarbons, ethers, ketones, nitriles and esters, preferably (C2-C4)alkanenitriles and (C1-C6)alkyl(C2-C4) ) Carboxylates), excluding those not applicable.
  • a solvent is aromatic hydrocarbons, ethers, ketones, nitriles and esters, preferably (C2-C4)alkanenitriles and (C1-C6)alkyl(C2-C4) ) Carboxylates
  • step (i), step (ia) or step (ib) is carried out in the presence of a solvent, wherein the solvent is one or more selected from nitriles and esters (preferably (C2-C4) alkanenitrile and (C1-C6) alkyl (C2-C4) carboxylate) ( (preferably 1 or 2, more preferably 1), except for those that are not applicable.
  • a solvent is one or more selected from nitriles and esters (preferably (C2-C4) alkanenitrile and (C1-C6) alkyl (C2-C4) carboxylate) (preferably 1 or 2, more preferably 1), except for those that are not applicable.
  • step (i), step (ia) or step (ib) is in the presence of a solvent, wherein the solvent is toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, tetrahydrofuran, dibutyl ether, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate , butyl acetate, and pentyl acetate (preferably 1 or 2, more preferably 1).
  • the solvent is toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, tetrahydrofuran, dibutyl ether, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, propyl acetate, isoprop
  • step (i), step (ia) or step (ib) is carried out in the presence of a solvent, wherein the solvent is one or more (preferably one or two, more preferably one or two) selected from acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and pentyl acetate 1), except for methods that are not applicable.
  • a solvent wherein the solvent is one or more (preferably one or two, more preferably one or two) selected from acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and pentyl acetate 1), except for methods that are not applicable.
  • step (i), step (ia) or step (ib) is Processes of preparation carried out in the presence of a solvent, wherein said solvent is acetonitrile or butyl acetate, except for processes not applicable.
  • step (i), step (ia) or step (ib) is Processes of preparation carried out in the presence of a solvent, wherein said solvent is a (C1-C6)alkyl(C2-C4)carboxylate (preferably butyl acetate), except those processes not applicable.
  • a solvent wherein said solvent is a (C1-C6)alkyl(C2-C4)carboxylate (preferably butyl acetate), except those processes not applicable.
  • step (i), step (ia) or step (ib) is a continuous production method using a tubular flow reactor, excluding methods that are not applicable.
  • step (i), step (ia) or step (ib) is a production method that is carried out in a flow-through manner, except for methods that do not apply.
  • step (ii), step (ii-a) or step (ii-b) Processes where the agent is hydroxylamine, hydroxylamine salts or oxime compounds, except those not applicable.
  • step (ii), step (ii-a) or step (ii-b) Processes where the agent is an aqueous solution of hydroxylamine, hydroxylamine hydrochloride or hydroxylamine sulfate, except where not applicable.
  • step (ii), step (ii-a) or step (ii-b) Processes where the agent is 45% to 50% aqueous hydroxylamine solution, hydroxylamine hydrochloride or hydroxylamine sulfate, except those not applicable.
  • step (ii), step (ii-a) or step (ii-b) Processes in which the agent is hydroxylamine hydrochloride or hydroxylamine sulfate, except those not applicable.
  • step (ii), step (ii-a) or step (ii-b) Processes of manufacture in which the agent is hydroxylamine sulfate, except those not applicable.
  • R 4 and R 5 are each independently a hydrogen atom; optionally substituted (C1-C6) alkyl; optionally substituted (C3-C6) cycloalkyl; substituted optionally substituted (C2-C6) alkynyl; (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl .), except for methods that are not applicable.
  • step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 0.9 to 1.5 mol in terms of hydroxylamine (NH 2 OH) per 1 mol of the compound of formula (3) or the compound of formula (4), provided that , except for methods not applicable.
  • step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 1.0 to 1.3 mol in terms of hydroxylamine (NH 2 OH) per 1 mol of the compound of formula (3) or the compound of formula (4), provided that , except for methods not applicable.
  • step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out in the presence of a neutralizing agent, except those not applicable.
  • step (ii), step (ii-a) or step (ii-b) Processes in which the agent is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, except those not applicable.
  • step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 0.5 to 1.5 mol (preferably 0.9 to 1.5 mol) per 1 mol of the compound of formula (3) or the compound of formula (4), However, excluding methods that do not apply.
  • step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 1.0 to 1.3 mol per 1 mol of the compound of formula (3) or the compound of formula (4), except for methods not applicable.
  • step (ii), step (ii-a) or step (ii-b) is , aromatic hydrocarbons (preferably (C2-C4) alkanenitriles, (C1-C6) alkyl (C2-C4) carboxylates and (C1-C3) dichloroalkanes), ethers, ketones, nitriles, esters and halogenated aliphatic hydrocarbons, except those not applicable.
  • aromatic hydrocarbons preferably (C2-C4) alkanenitriles, (C1-C6) alkyl (C2-C4) carboxylates and (C1-C3) dichloroalkanes
  • ethers preferably (C2-C4) alkanenitriles, (C1-C6) alkyl (C2-C4) carboxylates and (C1-C3) dichloroalkanes
  • ketones ketones
  • nitriles esters
  • halogenated aliphatic hydrocarbons except those not applicable.
  • step (ii), step (ii-a) or step (ii-b) is , nitriles, esters and halogenated aliphatic hydrocarbons (preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkane)
  • nitriles preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkane
  • Processes of manufacture carried out in the presence of one or more (preferably 1 or 2, more preferably 1) solvent, except for those processes which are not applicable.
  • step (ii), step (ii-a) or step (ii-b) The reaction is carried out in the presence of a solvent, and the solvent is an ester or halogenated aliphatic hydrocarbon (preferably (C1-C6) alkyl (C2-C4) carboxylate or (C1-C3) dichloroalkane) Manufacturing methods, except those not applicable.
  • a solvent is an ester or halogenated aliphatic hydrocarbon (preferably (C1-C6) alkyl (C2-C4) carboxylate or (C1-C3) dichloroalkane) Manufacturing methods, except those not applicable.
  • step (ii), step (ii-a) or step (ii-b) is Processes carried out in the presence of a solvent, wherein the solvent is an ester (preferably (C1-C6)alkyl(C2-C4)carboxylate), except for processes not applicable.
  • a solvent wherein the solvent is an ester (preferably (C1-C6)alkyl(C2-C4)carboxylate), except for processes not applicable.
  • step (ii), step (ii-a) or step (ii-b) is , toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, tetrahydrofuran, dibutyl ether, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, pentyl acetate and dichloromethane.
  • a manufacturing method performed in the presence of one or more (preferably one or two, more preferably one).
  • step (ii), step (ii-a) or step (ii-b) is , acetonitrile, butyl acetate and dichloromethane (preferably 1 or 2, more preferably 1).
  • step (ii), step (ii-a) or step (ii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate or dichloromethane, except for processes not applicable.
  • step (ii), step (ii-a) or step (ii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate, except for processes not applicable.
  • step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out at 0°C to 80°C, except for those not applicable.
  • step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out at 10°C to 50°C, except where not applicable.
  • step (iii), step (iii-a) or step (iii-b) is one or more (preferably 1 to 3, more preferably 1 or 2, still more preferably 1) acid catalyst selected from the group consisting of mineral acids, carboxylic acids, and sulfonic acids, provided that , except for methods not applicable.
  • step (iii), step (iii-a) or step (iii-b) is nitric acid, trifluoroacetic acid, maleic acid or p-toluenesulfonic acid, except those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is nitric acid, excluding those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is trifluoroacetic acid, except for those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is maleic acid, except those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.01 to 0.60 mol per 1 mol of the compound of formula (5) or the compound of formula (6), except for methods not applicable.
  • step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.05 to 0.40 mol per 1 mol of the compound of formula (5) or the compound of formula (6), except for methods not applicable.
  • step (iii), step (iii-a) or step (iii-b) is , a process carried out in the absence of a base catalyst.
  • step (iii), step (iii-a) or step (iii-b) is , a production process carried out in the presence of a basic catalyst.
  • step (iii), step (iii-a) or step (iii-b) is , a process carried out in the presence of an equivalent of a base catalyst that is less than the equivalent of the acid catalyst.
  • step (iii), step (iii-a) or step (iii-b) is , a production method carried out in the presence of a base catalyst of more than 0 (zero) equivalent and not more than 1 equivalent with respect to 1 equivalent of the acid catalyst.
  • step (iii), step (iii-a) or step (iii-b) is , a production method carried out in the presence of 0.1 to 0.5 equivalents of a base catalyst with respect to 1 equivalent of an acid catalyst.
  • step (iii), step (iii-a) or step (iii-b) is , a production method carried out in the presence of 0.2 to 0.4 equivalents of a base catalyst with respect to 1 equivalent of an acid catalyst.
  • step (iii), step (iii-a) or step (iii-b) is a secondary amine.
  • step (iii), step (iii-a) or step (iii-b) is N-methylaniline.
  • step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.01 to 0.60 mol per 1 mol of the compound of formula (5) or the compound of formula (6).
  • step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.05 to 0.40 mol per 1 mol of the compound of formula (5) or the compound of formula (6).
  • step (iii), step (iii-a) or step (iii-b) is , aromatic hydrocarbons, ethers, ketones, nitriles, esters and halogenated aliphatic hydrocarbons (preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkanes), except those not applicable.
  • aromatic hydrocarbons preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkanes
  • step (iii), step (iii-a) or step (iii-b) is , nitriles, esters and halogenated aliphatic hydrocarbons (preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkane)
  • nitriles preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkane
  • Processes of manufacture carried out in the presence of one or more (preferably 1 or 2, more preferably 1) solvent, except for those processes which are not applicable.
  • step (iii), step (iii-a) or step (iii-b) The reaction is carried out in the presence of a solvent, and the solvent is an ester or halogenated aliphatic hydrocarbon (preferably (C1-C6) alkyl (C2-C4) carboxylate or (C1-C3) dichloroalkane) Manufacturing methods, except those not applicable.
  • a solvent is an ester or halogenated aliphatic hydrocarbon (preferably (C1-C6) alkyl (C2-C4) carboxylate or (C1-C3) dichloroalkane) Manufacturing methods, except those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is Processes of preparation carried out in the presence of a solvent, wherein the solvent is an ester (preferably (C1-C6)alkyl(C2-C4)carboxylate), except for processes not applicable.
  • a solvent wherein the solvent is an ester (preferably (C1-C6)alkyl(C2-C4)carboxylate), except for processes not applicable.
  • step (iii), step (iii-a) or step (iii-b) is , toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, tetrahydrofuran, dibutyl ether, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, pentyl acetate and dichloromethane.
  • a manufacturing method performed in the presence of one or more (preferably one or two, more preferably one).
  • step (iii), step (iii-a) or step (iii-b) is , acetonitrile, butyl acetate and dichloromethane (preferably 1 or 2, more preferably 1).
  • step (iii), step (iii-a) or step (iii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate or dichloromethane, except for processes not applicable.
  • step (iii), step (iii-a) or step (iii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate, except for processes not applicable.
  • step (iii), step (iii-a) or step (iii-b) is , manufacturing processes carried out in the presence of an aqueous solvent, except for those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is , solvent-free manufacturing methods, except those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is , -30°C to 160°C, except for those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is , -10°C to 120°C, except for those not applicable.
  • step (iii), step (iii-a) or step (iii-b) is , manufacturing processes carried out at 0° C. to 100° C., except for those not applicable.
  • step (i) The method according to any one of [I-1] to [I-118], wherein the compound of formula (3) or the compound of formula (4) produced in step (i) is Processes of preparation in which the reaction of step (ii) is carried out without isolation, except where not applicable.
  • step (ii) The method according to any one of [I-1] to [I-118], wherein the compound of formula (5) or the compound of formula (6) produced in step (ii) is Processes of preparation in which the reaction of step (iii) is carried out without isolation, except for those processes that are not applicable.
  • step (i), step (ia) or step (ib) is Manufacturing processes carried out in the presence of an aqueous solvent, except those not applicable.
  • step (i), step (ia) or step (ib) is Manufacturing processes carried out in the presence of a solvent, where the solvent is water, except for those processes that are not applicable.
  • step (i), step (ia) or step (ib) is Manufacturing processes carried out in the presence of a solvent, the solvent containing water, except for those processes not applicable.
  • step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out in the presence of a solvent, where the solvent is water, except for those processes that are not applicable.
  • step (i) The method according to any one of [I-1] to [I-136], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out in the presence of a solvent, the solvent containing water, except for those processes not applicable.
  • step (iii), step (iii-a) or step (iii-b) is Manufacturing processes carried out in the presence of a solvent, where the solvent is water, except for those processes that are not applicable.
  • step (iii), step (iii-a) or step (iii-b) is Manufacturing processes carried out in the presence of a solvent, the solvent containing water, except for those processes not applicable.
  • step (i), step (ia) or step (ib) is , production methods derived from oxygen generating agents (preferably nitric acid), excluding non-applicable methods.
  • a method for producing a compound of formula (7) comprising the following steps; Step (i) reacting the compound of formula (1) or the compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give the corresponding compound of formula (3) or formula ( 4) to obtain the compound:
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl;
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • Step (ii) reacting a compound of formula (3) or a compound of formula (4) with an oximating agent to give the corresponding compound of formula (5) or compound of formula (6) respectively:
  • Step (iii) reacting a compound of formula (5) or a compound of formula (6) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
  • a method for producing a compound of formula (3) or a compound of formula (4) comprising: producing a compound of formula (1) or formula ( A process comprising reacting the compound of 2) to obtain the corresponding compound of formula (3) or compound of formula (4), respectively:
  • R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl.
  • [II-7] The production method according to [II-6], wherein the metal catalyst is an iron catalyst or a copper catalyst.
  • [II-8] The production method according to [II-6], wherein the metal catalyst is iron (III) chloride.
  • the present invention provides a novel method for preparing compounds of formula (7). According to the present invention, an efficient and industrially preferable method for producing the compound of formula (7) is provided. Moreover, according to the present invention, the compound of formula (7) can be produced in a high yield by a simple operation. In addition, the present invention provides novel methods for preparing compounds of formula (3) or compounds of formula (4). According to the present invention, a more industrially preferable method for producing the compound of formula (3) or the compound of formula (4) is provided. Moreover, according to the present invention, by-products can be suppressed by a simple operation, and the compound of formula (3) or the compound of formula (4) can be produced in high yield.
  • the present invention can reduce the production of by-products and/or waste and improve atomic efficiency.
  • the present invention provides a method for producing a production intermediate for a herbicide such as pyroxasulfone easily and inexpensively on an industrial scale. Therefore, the method of the present invention is industrially preferable, economical, environmentally friendly, and has high industrial utility value.
  • FIG. 1 schematically shows the outline of the reactor of the present invention used in Example 11 in which the flow reaction was carried out.
  • BRIEF DESCRIPTION OF THE DRAWINGS It is a schematic diagram of an example of the reaction apparatus for enforcing the manufacturing method of this invention.
  • FIG. 2 schematically shows the outline of the reactor of the present invention used in Example 55 in which the flow reaction was carried out.
  • BRIEF DESCRIPTION OF THE DRAWINGS It is a schematic diagram of an example of the reaction apparatus for enforcing the manufacturing method of this invention.
  • FIG. 3 schematically shows the outline of the reactor of the present invention used in Example 56 in which the flow reaction was carried out.
  • BRIEF DESCRIPTION OF THE DRAWINGS It is a schematic diagram of an example of the reaction apparatus for enforcing the manufacturing method of this invention.
  • halogen atoms include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms.
  • (Ca-Cb) means that the number of carbon atoms is a to b.
  • “(C1-C4)" in “(C1-C4)alkyl” means that the alkyl has 1 to 4 carbon atoms.
  • alkyl are understood to include both straight and branched chains such as butyl and tert-butyl.
  • butyl when a specific term such as “butyl” is used, it is specific to "normal butyl” or “n-butyl”. In other words, the specific term “butyl” means straight chain “normal butyl”. and branched-chain isomers such as “tert-butyl” are specifically mentioned where intended.
  • n-, "s-” and “sec-”, “i-”, “t-” and “tert-”, [neo-], "c-” and “cyc-”, “o-” ”, “m-”, and “p-” have their usual meanings: normal, secondary (“s-” and “sec-”), iso, tertiary (“t-” and “ tert-”), neo, cyclo ("c-” and “cyc-”), ortho, meta, and para.
  • Me means methyl.
  • Et means ethyl.
  • Pr means propyl (ie normal propyl).
  • i-Pr and “Pr-i” mean isopropyl.
  • Bu means butyl (ie normal butyl).
  • s-Bu and “Bu-s” mean sec-butyl.
  • i-Bu and “Bu-i” mean isobutyl.
  • Pen pentyl (ie, normal pentyl).
  • Hex means hexyl (ie normal hexyl).
  • Dec means decyl (ie, normal decyl).
  • c-Pr and “Pr-c” mean cyclopropyl.
  • c-Bu and “Bu-c” mean cyclobutyl.
  • c-Pen and “Pen-c” mean cyclopentyl.
  • c-Hex and Hex-c mean cyclohexyl.
  • Ph means phenyl.
  • Bn means benzyl.
  • Ac means acetyl ( CH3CO- ).
  • (C1-C6) alkyl means a linear or branched alkyl having 1 to 6 carbon atoms.
  • Examples of (C1-C6)alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • (C1-C4) alkyl means a linear or branched alkyl having 1 to 4 carbon atoms.
  • Examples of (C1-C4)alkyl are suitable examples of the above examples of (C1-C6)alkyl.
  • (C2-C4) alkanenitrile means (C1-C3) alkyl-CN.
  • Examples of (C2-C4)alkanenitriles are acetonitrile, propionitrile, butyronitrile, isobutyronitrile.
  • a C2 alkanenitrile is acetonitrile.
  • propionitrile is a C3 alkanenitrile.
  • Examples of (C1-C6)alkyl(C2-C4)carboxylates are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers, Including, but not limited to, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate and isomers thereof.
  • butyl acetate is a (C4) alkyl (C2) carboxylate (ie, a C4 alkyl C2 carboxylate).
  • dichloroalkanes examples include, but are not limited to, dichloromethane, 1,2-dichloroethane, and the like.
  • dichloromethane is a C1 dichloroalkane.
  • aromatic hydrocarbon derivatives are those having 1 to 3 substituents (preferably 1 or 2) selected from the group consisting of (C1-C3)alkyl and chlorine atoms. It is benzene which may be substituted with a substituent, more preferred examples are toluene, xylene, chlorobenzene or dichlorobenzene, and further preferred examples are toluene or xylene. The foregoing may apply to all cases of the invention.
  • (C3-C6) cycloalkyl means cycloalkyl having 3 to 6 carbon atoms.
  • Examples of (C3-C6)cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • Examples of (C6-C10)aryl are phenyl, 1-naphthyl and 2-naphthyl.
  • (C6-C10)aryl(C1-C4)alkyl means (C1-C4alkyl) substituted by (C6-10)aryl, wherein the C6-10aryl moiety and the C1-C4alkyl moiety are have the same meaning as defined above.).
  • Examples of (C6-C10)aryl(C1-C4)alkyl are benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, etc. including but not limited to.
  • a cyclic hydrocarbon group means an aromatic or non-aromatic, monocyclic or polycyclic cyclic group in which all the atoms constituting the ring are carbon atoms.
  • examples of cyclic hydrocarbon groups are aromatic or non-aromatic, monocyclic, bicyclic or tricyclic 3- to 14-membered (preferably 5- to 14-membered, more preferably 5- to 10-membered) cyclic hydrocarbon groups.
  • examples of cyclic hydrocarbon groups are aromatic or non-aromatic, monocyclic or bicyclic (preferably monocyclic) 4-8 membered (preferably 5-6 membered) including, but not limited to, cyclic hydrocarbon groups of
  • cyclic hydrocarbon groups include, but are not limited to, cycloalkyl, aryl, and the like.
  • Aryl is an aromatic cyclic group among the cyclic hydrocarbon groups as defined above.
  • Cyclic hydrocarbon groups as defined or exemplified above may include non-fused cyclic (e.g. monocyclic or spirocyclic) and fused cyclic cyclic groups where possible. .
  • a cyclic hydrocarbon group as defined or exemplified above may be unsaturated, partially saturated or saturated, if possible.
  • a cyclic hydrocarbon group as defined or exemplified above is also referred to as a carbocyclic group.
  • a carbocyclic ring is a ring corresponding to a cyclic hydrocarbon group as defined or exemplified above.
  • substituted examples include one or more substituents (preferably 1 to 4 substituents), including but not limited to:
  • substituents independently selected from substituent group (a) are each independently selected from substituent group (b) may have one or more substituents (preferably 1 to 4 substituents).
  • substituent group (b) is the same as the substituent group (a).
  • a compound having isomers includes all isomers and any mixture thereof in any proportion.
  • xylene includes o-xylene, m-xylene, p-xylene and any mixture thereof in any proportion.
  • dichlorobenzene includes o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene and any mixture thereof in any proportion.
  • wavy lines in chemical formulas mean the following.
  • cis-trans isomers that is, E/Z isomers
  • E)-isomers anti-isomers
  • Z)-isomers mixtures thereof in any proportion are included in formulas with wavy underlines.
  • the method according to the present invention includes the following scheme (wherein R 1 , R 2 and R 3 are as described in [I-1] above).
  • Step (i) Step (i) will be explained. All descriptions of step (i) below apply to steps (ia) and (ib). Unless otherwise applicable.
  • step (i) is an oxidation reaction.
  • the reaction of step (i) is also called an oxidation step.
  • Step (i) is a manufacturing method comprising reacting the compound of formula (1) or formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound.
  • the compound of formula (1) or the compound of formula (2) is used as a raw material.
  • the compound of formula (1) and the compound of formula (2) are known compounds, or can be produced from known compounds according to known methods.
  • Specific examples of compounds of formula (1) include, but are not limited to; 3-methyl-1,3-butanediol (3-methylbutane-1,3-diol or 3-hydroxy-3- methylbutanol), 3-methoxy-3-methylbutanol, 3-ethoxy-3-methylbutanol, 3-methyl-3-propoxybutanol, 3-isopropoxy-3-methylbutanol, 3-butoxy-3-methyl butanol, 3-isobutoxy-3-methylbutanol, 3-(sec-butoxy)-3-methylbutanol, 3-(benzyloxy)-3-methylbutanol and the like.
  • a preferred specific example of the compound of formula (1) is 3-methoxy-3-methylbutanol from the viewpoint of usefulness of the product.
  • a preferred specific example of the compound of formula (2) is 3-methyl-2-butenol (also referred to as prenol), but is not limited thereto.
  • oxygen in step (i) The oxidation reaction of the present invention is carried out in the presence of oxygen.
  • Oxygen may be used as an oxygen-containing gas (including, for example, pure oxygen and mixed gases such as air) and as an oxygen generating agent (e.g., nitric acid), and combinations thereof. may be used. Therefore, the method of the present invention includes at least one (preferably 1 to 3, more preferably one or two) and allowed to react.
  • oxygen-containing gas oxygen or air diluted with an inert gas (eg, nitrogen, carbon dioxide, argon, preferably nitrogen, carbon dioxide, more preferably nitrogen) can be used.
  • the oxygen concentration introduced may be any concentration as long as the reaction proceeds. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is preferably 1% by volume to 100% by volume, more preferably 5% by volume to 100% by volume.
  • the concentration of oxygen generated from an oxygen generating agent such as nitric acid may also be the same as described above.
  • nitroxyl radical compound in step (i) Conventionally known compounds can be used as nitroxyl radical compounds.
  • nitroxyl radical compounds include TEMPO-based catalysts (e.g., 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-hydroxy TEMPO or 4-OH-TEMPO), 4-methoxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-MeOTEMPO), 4-acetoxy-2,2,6,6-tetra methylpiperidine 1-oxyl (4-AcOTEMPO), 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-benzyloxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-BzOTEMPO), etc.), AZADO catalysts (2-azaadamantane-N-oxyl
  • the compound of formula (1) or the compound of formula (2) (alcohol compound) is usually 0.0001 mol to 0.001 mol per 1 mol. 3 mol, preferably 0.001 mol to 0.1 mol.
  • metal catalyst in step (i) In one aspect, from the viewpoint of reactivity, yield, economic efficiency, etc., preferred examples of the metal catalyst for the oxidation reaction of the present invention include copper catalysts and iron catalysts. Specific examples of metal catalysts for the oxidation reaction of the present invention include copper catalysts (e.g., copper(II) nitrate, catalysts containing copper(II) chloride and nitric acid, catalysts containing copper(II) bromide and nitric acid, iodine copper(II) chloride and nitric acid), iron catalysts (e.g.
  • metal catalysts include copper catalysts and iron catalysts.
  • metal catalysts for the oxidation reaction of the present invention include copper catalysts (e.g., copper (II) nitrate, copper (II) chloride, copper (II) bromide, copper (II) iodide), iron catalysts ( For example, iron(III) nitrate, iron(III) chloride, iron(III) bromide), more preferably copper(II) nitrate, iron(III) chloride, iron(III) bromide, iron(III) nitrate More preferably iron(III) nitrate, iron(III) chloride, particularly preferably iron(III) chloride.
  • iron (III) chloride is cheaper than iron (III) nitrate, it is industrially and economically superior.
  • iron (III) chloride is less deliquescent than iron (III) nitrate and is easy to handle, it is easy to use industrially.
  • the metal catalyst may be in any form, and salts or hydrates thereof can also be used.
  • metal catalyst any amount of metal catalyst may be used as long as the reaction proceeds. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is preferably 0.0001 mol to 0.5 per 1 mol of the compound of formula (1) or the compound of formula (2) (alcohol compound). mol, more preferably 0.001 mol to 0.3 mol, still more preferably 0.01 mol to 0.1 mol.
  • nitric acid in step (i) The oxidation reaction of the present invention is carried out in the presence of nitric acid.
  • nitric acid is preferably used with copper(II) chloride, copper(II) bromide, copper(II) iodide, iron(III) chloride and iron(III) bromide.
  • nitric acid is used with a metal catalyst.
  • nitric acid it is preferable to use an aqueous nitric acid solution.
  • concentration of nitric acid in the nitric acid aqueous solution is not particularly limited, it is preferably 0.1 to 100%, more preferably 1 to 100%, still more preferably 10 to 90%, still more preferably 30 to 80%.
  • the nitric acid may be part of the catalyst (e.g., co-catalyst, promoter), an oxidant, an oxygen generator, a plurality of may be Any amount of nitric acid may be used as long as the reaction proceeds.
  • the catalyst e.g., co-catalyst, promoter
  • an oxidant e.g., oxygen generator
  • a plurality of may be Any amount of nitric acid may be used as long as the reaction proceeds.
  • it is generally 0.01 mol to 0.1 mol, preferably 0.02 mol to 0.09 mol, more preferably 0.02 mol to 0.05 mol. In still another embodiment, from the same viewpoint as above, it is usually 0.5 mol to 1 mol, preferably 0.5 mol to 0.9 mol, more preferably 0.5 mol to 0.8 mol.
  • an acid in the oxidation reaction of the present invention examples include carboxylic acids. Specific examples include preferably acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid and benzoic acid, more preferably acetic acid and propionic acid. , benzoic acid, more preferably acetic acid and propionic acid, still more preferably acetic acid, but not limited thereto.
  • the oxidation reaction of the present invention may or may not use an acid. When an acid is used, examples of acid are given above.
  • any amount of acid may be used as long as the reaction proceeds.
  • an acid is usually 0.1 per 1 mol of the compound of formula (1) or the compound of formula (2) (alcohol compound).
  • mol to 10 mol preferably 0.2 mol to 5 mol, more preferably 0.5 mol to 3 mol, still more preferably 1 mol to 2 mol.
  • bases include aromatic heterocyclic compounds having a nitrogen atom. Specific examples preferably include N-methylimidazole (NMI), N-methylpyrazole, pyridine, N,N-dimethylaminopyridine (DMAP), 2,2′-bipyridyl (BiPy), more preferably N -methylimidazole, 2,2'-bipyridyl, including but not limited to.
  • the oxidation reaction of the present invention may or may not use a base. When a base is used, examples of bases are as described above.
  • the form of the base may be any form as long as the reaction proceeds.
  • the base form can be appropriately selected by those skilled in the art.
  • any amount of base may be used as long as the reaction proceeds.
  • a base is usually 0.001 per 1 mol of the compound of formula (1) or the compound of formula (2) (alcohol compound). mol to 1 mol, preferably 0.001 mol to 0.3 mol, more preferably 0.01 mol to 0.1 mol.
  • the oxidation reaction of the present invention is preferably carried out in the presence of a solvent. Any solvent may be used for the oxidation reaction of the present invention as long as the reaction proceeds.
  • solvents examples include ethers (eg, tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether), carboxylic acid esters (eg, (C1-C6)alkyl(C2- C4) carboxylates (e.g., methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers)), ketones (e.g., acetone, 2- butanone, methyl isobutyl ketone), aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene), nitriles (e.g., (C2-C4) alkanenitrile, (specifically, T
  • preferred examples of the solvent for the oxidation reaction of the present invention are carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates), nitriles (preferably (C1-C6)alkyl(C2-C4)carboxylates) and any combination thereof in any proportion.
  • Preferred specific examples of solvents for the oxidation reaction of the present invention are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, acetonitrile, propionitrile and any combination thereof in any proportion. include.
  • More preferred specific examples are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, acetonitrile and any combination thereof in any proportion, more preferably butyl acetate and its isomers or acetonitrile, more preferably butyl acetate or acetonitrile.
  • preferred examples of solvents for the oxidation reaction of the present invention are carboxylic acid esters (preferably (C1-C6)alkyl(C2-C4)carboxylates).
  • More preferred specific examples are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isomers thereof and any combination thereof in any proportion, more preferably butyl acetate and isomers thereof. and more preferably butyl acetate.
  • reaction of step (i) may be carried out in the presence of a water solvent.
  • a water solvent for example, water from an aqueous nitric acid solution (eg, 69% nitric acid) used as an oxygen generator can be understood as a water solvent.
  • any amount of the solvent may be used as long as the reaction system can be sufficiently stirred. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0 (zero) to 10 L (liter), preferably 0.1 to 1 mol of the compound of formula (1) or the compound of formula (2) Including but not limited to 5L, more preferably 0.3-2L.
  • the ratio of the two or more solvents may be any ratio as long as the reaction proceeds.
  • the solvent may be a single layer or separated into two layers as long as the reaction proceeds.
  • step (i) is the compound of formula (3) or the compound of formula (4) corresponding to the compound of formula (1) or the compound of formula (2) used as starting material.
  • Specific examples, preferred specific examples, and more preferred specific examples thereof are as described below for the raw material of step (ii).
  • the compound of formula (3) or the compound of formula (4), which is the product of step (i), can be used as a starting material for step (ii).
  • the compound of formula (3) or the compound of formula (4) obtained in step (i) may be isolated and used in the next step, may be further purified and used in the next step, or may be isolated. It may be used in the next step without However, it is efficient to use it in the next step without isolation.
  • Step (ii) Step (ii) will be explained. All descriptions of step (ii) below apply to steps (ii-a) and (ii-b). Unless otherwise applicable.
  • step (ii) is oximation.
  • the reaction of step (ii) is also referred to as the oximation step.
  • Step (ii) is a step of reacting the compound of formula (3) or the compound of formula (4) with an oximating agent to produce the compound of formula (5) or the compound of formula (6).
  • step (ii); compound of formula (3) or compound of formula (4) A compound of formula (3) or a compound of formula (4) is used as a starting material for step (ii).
  • the compound of formula (3) or the compound of formula (4) is a known compound, or can be produced from a known compound according to a known method.
  • compounds of formula (3) or compounds of formula (4) include, but are not limited to; 3-methyl-2-butenal (also known as prenal), 3-hydroxy-3-methyl butanal (also known as 3-hydroxy-3-methyl-butan-1-al), 3-methoxy-3-methylbutanal, 3-ethoxy-3-methylbutanal, 3-methyl-3-propoxybutanal, 3-isopropoxy-3-methylbutanal, 3-butoxy-3-methylbutanal, 3-isobutoxy-3-methylbutanal, 3-(sec-butoxy)-3-methylbutanal, 3-methyl-3 -phenoxybutanal, 3-(benzyloxy)-3-methylbutanal, 3-hydroxy-3-methylpentanal, 3-ethyl-3-hydroxypentanal, 3-hydroxy-3,4-dimethylpentanal, 3-hydroxy-3,4,4-trimethylpentanal, 4-chloro-3-hydroxy-3-methylbutanal, 4,4,4-trifluoro-3-hydroxy-3-methylbutanal, 2-( 1-hydroxycyclopropyl
  • Preferred specific examples of the compound of formula (3) or the compound of formula (4) from the viewpoint of usefulness of the product are 3-hydroxy-3-methylbutanal and 3-methoxy-3-methylbutanal. is.
  • Preferred specific examples of the compound of formula (3) are as follows from the viewpoint of usefulness of the product, etc.; are), 3-methoxy-3-methylbutanal, 3-ethoxy-3-methylbutanal, 3-methyl-3-propoxybutanal, 3-isopropoxy-3-methylbutanal, 3-butoxy- 3-methylbutanal, 3-isobutoxy-3-methylbutanal, 3-(sec-butoxy)-3-methylbutanal, 3-(benzyloxy)-3-methylbutanal and the like.
  • a more preferred specific example of the compound of formula (3) from the same viewpoint as above is 3-methoxy-3-methylbutanal.
  • a preferred specific example of the compound of formula (4) is 3-methyl-2-butenal (also referred to as prenal).
  • the oximating agent used in step (ii) can be any oximating agent as long as the reaction proceeds.
  • oximating agents that can be used in step (ii) include hydroxylamine, hydroxylamine salts and oxime compounds.
  • the oximating agent is not particularly limited as long as the reaction proceeds and safety is ensured.
  • hydroxylamine (free) include, but are not limited to, 50% hydroxylamine aqueous solution, 60% hydroxylamine aqueous solution, 70% hydroxylamine aqueous solution, 80% hydroxylamine aqueous solution, 90% hydroxylamine aqueous solution, and the like.
  • hydroxylamine salts include, but are not limited to, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate (e.g., 50% aqueous solution), hydroxylamine carbonate, hydroxylamine phosphate, hydroxylamine acetate, hydroxylamine oxalate, and the like. Not limited.
  • an oxime compound as an oximating agent is represented by the following formula.
  • the compound of formula (8) is a known compound, or can be produced from a known compound according to a known method.
  • Specific examples of compounds of formula (3) or compounds of formula (4) in which R 4 and R 5 do not form a ring include, but are not limited to; formoxime, acetone oxime (also known as acetoxime), 2-butanone oxime (methyl ethyl ketone oxime), methyl isopropyl ketone oxime, methyl tertiary butyl ketone oxime, 2-pentanone oxime, 3-pentanone oxime, 1-cyclohexyl-1- propanone oxime, 2-hexanone oxime, 3-hexanone oxime, 3-heptanone oxime, 4-octanone oxime, 5-nonanone oxime, acetoaldoxime, benzoaldoxime, acetophenone oxime, 4′-hydroxyacetophenone oxime, benzophen
  • compounds of formula (3) or compounds of formula (4) in which R 4 and R 5 form a non-conjugated ring include, but are not limited to; Cyclopropanone oxime, cyclobutanone oxime, cyclopentanone oxime, cyclohexanone oxime, cycloheptanone oxime, cyclooctanone oxime, cyclononanone oxime, cyclodecanone oxime and the like.
  • the oximating agent used in step (ii) may be used alone or in combination of two or more at any ratio.
  • the form of the oximating agent used in step (i) may be any form as long as the reaction proceeds and safety is ensured. As long as the reaction proceeds and safety is ensured, examples of its form include solids and liquids, aqueous solutions of any concentration, solutions of solvents other than water (eg, organic solvents), and the like.
  • the form of hydroxylamine may be in any form as long as the reaction proceeds and safety is ensured.
  • preferred examples of the hydroxylamine (free) form include aqueous solutions with a concentration of 10% or more and less than 70%, preferably 45% or more and 55% or less.
  • any amount of the oximating agent may be used in step (ii) as long as the reaction proceeds.
  • 1 mol of the compound of formula (3) or the compound of formula (4) is converted to hydroxylamine (NH 2 OH) , 0.9 to 1.5 equivalents, preferably 0.9 to 1.3 equivalents.
  • the amount used can be appropriately adjusted by those skilled in the art.
  • the meaning of the term "in terms of hydroxylamine ( NH2OH )" is as follows.
  • step (ii) is preferably carried out using a neutralizing agent.
  • Neutralizing agents are bases for neutralizing hydroxylamine salts to liberate free hydroxylamine.
  • neutralizing agents include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, water barium oxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, barium carbonate, etc.), alkali metal hydrogen carbonates (e.g., , lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal carboxylates (e.g., lithium acetate, sodium acetate, potassium acetate, etc.), amines (e.g., triethylamine, tributylamine, diisopropylethylamine, 1,8 -diazabicyclo[5.4.0]-7-undec-7-ene (DBU), pyridine,
  • neutralizing agents include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., ammonia, more preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, ammonia, More preferably it contains sodium hydroxide.
  • sodium hydroxide are sodium hydroxide beads, 48% aqueous sodium hydroxide solution, 25% aqueous sodium hydroxide solution, 10% aqueous sodium hydroxide solution, preferably 48% aqueous sodium hydroxide solution, 25% aqueous sodium hydroxide solution, and more It preferably contains, but is not limited to, 48% sodium hydroxide aqueous solution.
  • Neutralizing agents may be used alone or in combination of two or more in any proportion.
  • the form of the neutralizing agent may be any form as long as the reaction proceeds. Examples of its form include solids, liquids and gases of the neutralizing agent alone, as well as aqueous solutions of any concentration and solutions in solvents other than water (eg, organic solvents), and the like.
  • the form of the neutralizing agent can be appropriately selected by those skilled in the art.
  • the amount of the neutralizing agent used in step (ii) may be any amount as long as the reaction proceeds. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0.5 to 3.0 mol, preferably 0.5 to 1 mol, per 1 mol of the compound of formula (3) or the compound of formula (4) 0.5 mol, more preferably 0.8 to 1.5 mol, still more preferably 1.0 to 1.3 mol.
  • step (ii)) From the viewpoints of smooth progress of the reaction, safety, etc., the reaction of step (ii) is preferably carried out in the presence of a solvent. Any solvent may be used as long as the reaction in step (ii) proceeds and safety is ensured.
  • solvents examples include water, alcohols (e.g., methanol, ethanol, 2-propanol, butanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), etc.), ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), nitriles (e.g., (C2-C4 ) alkanenitrile, (specifically, for example, acetonitrile, etc.)), carboxylic acid esters (for example, (C1-C6) alkyl (C2-C4) carboxylate, (specifically, for example, methyl acetate, acetic acid ethyl, prop
  • Preferred examples of the solvent in step (ii) from the viewpoint of reactivity, yield, safety, economic efficiency, etc. are water, alcohols, ethers, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, Halogenated aliphatic hydrocarbons and any combination thereof in any proportion, more preferably water, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons and any proportion Any combination thereof, more preferably water, nitriles (preferably (C2-C4) alkanenitriles), carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates), halogenated fats group hydrocarbons (preferably (C1-C3) dichloroalkanes) and any combination thereof in any proportion.
  • nitriles preferably (C2-C4) alkanenitriles
  • carboxylic acid esters preferably (C1-C6) alkyl (C2-C4) carboxylates
  • water is preferred in either case.
  • combinations of water and nitriles preferably (C2-C4)alkanenitrile
  • combinations of water and carboxylic acid esters preferably (C1-C6) alkyl (C2-C4) carboxylates
  • a combination of any proportion of water and halogenated aliphatic hydrocarbons preferably (C1-C3) dichloroalkane is preferred.
  • solvents in step (ii) are water, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, tetrahydrofuran (THF), toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isomers thereof , toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, propy
  • the presence of water is preferred in either case.
  • combinations of water and acetonitrile in any proportion are preferred.
  • a combination of water and butyl acetate and its isomers in any proportion is preferred, and a combination of water and butyl acetate in any proportion is more preferred.
  • any combination of water and dichloromethane in any proportion is preferred.
  • the solvent may separate into a single layer or two layers as long as the reaction proceeds.
  • the water derived from the aqueous hydroxylamine solution can be understood as a solvent.
  • a neutralizing agent e.g., hydroxylamine hydrochloride, hydroxylamine sulfate, etc.
  • water from an aqueous solution of the neutralizing agent e.g., 48% aqueous sodium hydroxide solution
  • solvent e.g., 48% aqueous sodium hydroxide solution
  • Water produced by neutralization can also be understood as solvent.
  • the amount of solvent used in step (ii) may be any amount as long as the reaction system can be sufficiently stirred. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0 (zero) to 10 L (liter), preferably 0.02 to 1 mol of the compound of formula (3) or the compound of formula (4) 5 L, more preferably 0.02 to 1 L, still more preferably 0.1 to 1 L. However, the amount used can be appropriately adjusted by those skilled in the art.
  • the ratio of the two or more solvents may be any ratio as long as the reaction proceeds. The ratio can be adjusted appropriately by those skilled in the art.
  • the solvent may separate into a single layer or two layers as long as the reaction proceeds.
  • reaction temperature in step (ii) is not particularly limited. -30°C (minus 30°C) to 160°C, preferably -10°C to 80°C, more preferably 0°C to 80°C, still more preferably 10°C, from the viewpoint of yield, suppression of by-products, economic efficiency, etc. Up to 50°C, more preferably room temperature (10°C to 35°C) can be exemplified. However, the reaction temperature can be adjusted appropriately by those skilled in the art.
  • reaction time of step (ii) The reaction time of step (ii) is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the time is 0.5 hours to 48 hours, preferably 0.5 hours to 24 hours, more preferably 0.5 hours to 12 hours. However, the reaction time can be adjusted appropriately by those skilled in the art.
  • the product of step (ii) is the compound of formula (5) or the compound of formula (6) corresponding to the compound of formula (3) or the compound of formula (4) used as starting material.
  • Specific examples include, but are not limited to; 3-methyl-2-butenal oxime, 3-hydroxy-3-methylbutanal oxime (3-hydroxy-3-methyl-butane-1- oxime), 3-methoxy-3-methylbutanal oxime, 3-ethoxy-3-methylbutanal oxime, 3-methyl-3-propoxybutanal oxime, 3-isopropoxy-3-methylbutanal oxime , 3-butoxy-3-methylbutanal oxime, 3-isobutoxy-3-methylbutanal oxime, 3-(sec-butoxy)-3-methylbutanal oxime, 3-methyl-3-phenoxybutanal oxime, 3 -(benzyloxy)-3-methylbutanal oxime, 3-hydroxy-3-methyl-pentanal
  • Preferred specific examples of the compound of formula (5) are 3-hydroxy-3-methylbutanal oxime and 3-methoxy-3-methylbutanal oxime, more preferably 3 -Methoxy-3-methylbutanal oxime.
  • a preferred specific example of formula (6) is 3-methyl-2-butenaloxime.
  • step (ii) The compound of formula (5) or the compound of formula (6), which is the product of step (ii), can be used as a starting material for step (iii).
  • the compound of formula (5) or the compound of formula (6) obtained in step (ii) may be isolated and used in the next step, may be further purified and used in the next step, or may be isolated It may be used in the next step without However, it is efficient to use it in the next step without isolation.
  • Step (iii) Step (iii) will be explained. All descriptions of step (iii) below apply to steps (iii-a) and (iii-b). Unless otherwise applicable.
  • step (iii) is a cyclization reaction.
  • Step (iii) is also referred to as a cyclization step.
  • Step (iii) is a step of reacting the compound of formula (5) or the compound of formula (6) in the presence of a catalyst to produce the compound of formula (7).
  • step (iii); compound of formula (5) or compound of formula (6) The compound of formula (5) or the compound of formula (6) is used as the starting material for step (iii).
  • the compound of formula (5) or the compound of formula (6) is a known compound, or can be produced from a known compound according to a known method.
  • compounds of formula (5) or compounds of formula (6) can be prepared by the method of step (ii) above. Specific examples and preferred specific examples of the compound of formula (5) or the compound of formula (6) are as described above.
  • the catalyst in step (iii) can be any catalyst as long as the reaction proceeds.
  • an acid catalyst can be used, or an acid catalyst and a base catalyst can be used.
  • (Acid catalyst in step (iii)) In one aspect of the invention, compounds of formula (7) are prepared in the presence of an acid catalyst.
  • the acid catalyst may be any acid catalyst as long as the reaction proceeds. Additionally, as long as the reaction proceeds, any of the following forms may be used and are within the scope of the present invention. Free acids can be used as acid catalysts.
  • Acid catalysts may be used in the form of salts. When the acid catalyst is a salt, the acid catalyst may be a single salt or a double salt.
  • the acid catalyst may be used in the anhydride form.
  • Acid catalysts may be used in the form of hydrates.
  • the acid catalyst may be used in the form of dimers and the like.
  • acid catalysts in step (iii) include, but are not limited to:
  • Mineral acids can be used as acid catalysts in step (iii).
  • mineral acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.
  • Carboxylic acids, their salts and anhydrides can be used as acid catalysts in step (iii). Accordingly, the carboxylic acid may be used as the free acid or as its salt. Additionally, the carboxylic acid may be used as its anhydride. Specific examples of carboxylic acids include acetic acid, trifluoroacetic acid (TFA), trichloroacetic acid, dichloroacetic acid, maleic acid, citric acid, benzoic acid, phthalic acid. Specific examples of preferred carboxylic acids include trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid.
  • TFA trifluoroacetic acid
  • trichloroacetic acid dichloroacetic acid
  • maleic acid citric acid
  • benzoic acid phthalic acid
  • preferred carboxylic acids include trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid.
  • carboxylates are ammonium trifluoroacetate (CF 3 COO - NH 4 + )), N-methylanilium trifluoroacetate (CF 3 COO - C 6 H 5 N + (CH 3 )H 2 )including.
  • carboxylic anhydrides include trifluoroacetic anhydride, maleic anhydride, phthalic anhydride.
  • a specific example of a preferred carboxylic anhydride includes maleic anhydride.
  • Sulfonic acids can be used as acid catalysts in step (iii). Accordingly, the sulfonic acid may be used as the free acid or as its salt. Additionally, the sulfonic acid may be used as its anhydride.
  • sulfonic acids include methanesulfonic acid, trifluoromethanesulfonic acid (TfOH), benzenesulfonic acid, p-toluenesulfonic acid (including p-toluenesulfonic acid monohydrate (TsOH.H 2 O)), 10- Contains camphorsulfonic acid.
  • sulfonates include pyridinium p-toluenesulfonate (PPTS).
  • PPTS pyridinium p-toluenesulfonate
  • sulfonic anhydrides include methanesulfonic anhydride, trifluoromethanesulfonic anhydride.
  • preferred examples of the acid catalyst are as follows, but are not limited thereto.
  • One or more (preferably 1 to 3, more preferably 1 or 2, still more preferably 1) acids selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids and phosphoric acids are preferred.
  • Amines are preferable as the basic catalyst.
  • R 6 , R 7 and R 8 are each independently a hydrogen atom, optionally substituted (C1-C6) alkyl; optionally substituted (C3-C6) cycloalkyl; substituted optionally substituted (C2-C6)alkenyl; optionally substituted (C2-C6)alkynyl; or optionally substituted aryl; or any two of R 6 , R 7 and R 8 are taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclic ring wherein the ring formed is optionally substituted wherein R 6 , R 7 and R 8 is not a hydrogen atom) primary amines, secondary amines, tertiary amines, or heterocyclic amines.
  • primary amines include, but are not limited to, methylamine, ethylamine, propylamine, butylamine, aniline, and the like.
  • secondary amines include diethylamine, dipropylamine, diisopropylamine, N-methylaniline (PhNHMe; herein sometimes abbreviated as N-MeAniline), N-ethylaniline, piperidine, Including, but not limited to, morpholine and the like.
  • tertiary amines are triethylamine, tripropylamine, tributylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-dimethylaniline, N,N - including but not limited to diethylaniline and the like;
  • heterocyclic amines are pyridine, 4-(dimethylamino)-pyridine, 4-pyrrolidinopyridine, 2,6-lutidine, quinoline, isoquinoline, 1,8-diazabicyclo[5.4.0] -7-undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and the like.
  • Examples of amines also include imidazolinones.
  • Specific examples of imidazolinones include optical isomers such as (2S,5S)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone and diastereomers thereof, and analogs thereof including.
  • imidazolinones are expensive, it is industrially preferable not to use imidazolinones.
  • preferred examples of the base of the acid-base catalyst include secondary amines or heterocyclic amines.
  • Preferred specific examples of acid-base catalyst bases include N-methylaniline or pyridine.
  • the amount of the acid catalyst used is 0.01 to 1.0 mol per 1 mol of the compound of formula (5) or the compound of formula (6), from the viewpoint of yield, suppression of by-products, economic efficiency, etc. , preferably 0.01 to 0.60 mol, more preferably 0.02 to 0.50 mol, and 0.05 to 0.40 mol.
  • the amount of the basic catalyst used is 0 (zero) to 1.0 per 1 mol of the compound of formula (5) or the compound of formula (6) from the viewpoint of yield, suppression of by-products, economic efficiency, etc. Molar ranges can be exemplified.
  • the amount of the basic catalyst used is 0.01 to 1.0 mol, preferably 0.01 to 0.60 mol, more preferably 0.02 to 0.50 mol, and 0.05 to 0.05 mol. A range of 0.40 mol can be exemplified.
  • the ratio of the base catalyst to the acid-base catalyst may be 1:1, or may not be 1:1.
  • step (iii)) The reaction of step (iii) can be carried out in the presence or absence of a solvent (no solvent).
  • a solvent used in the reaction of step (iii)
  • any solvent may be used as long as the reaction of step (iii) proceeds.
  • solvents when using solvents include water, alcohols (e.g., methanol, ethanol, 2-propanol, butanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), etc.), ethers ( For example, tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), nitriles (e.g., (C2-C4) alkanenitrile, (specifically, for example, acetonitrile, etc.)), carboxylic acid esters (e.g., (C1-C6) alkyl (C2-C4) carboxylate, specifically, (e.g., methyl acetate, ethyl acetate
  • Preferred examples of the solvent in step (ii) from the viewpoint of reactivity, yield, safety, economic efficiency, etc. are water, alcohols, ethers, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, Halogenated aliphatic hydrocarbons and any combination thereof in any proportion, more preferably water, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons and any proportion Any combination thereof, more preferably water, nitriles (preferably (C2-C4) alkanenitriles), carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates), halogenated fats group hydrocarbons (preferably (C1-C3) dichloroalkanes) and any combination thereof in any proportion.
  • nitriles preferably (C2-C4) alkanenitriles
  • carboxylic acid esters preferably (C1-C6) alkyl (C2-C4) carboxylates
  • Water may or may not be present.
  • combinations of water and nitriles preferably (C2-C4)alkanenitrile
  • combinations of water and carboxylic acid esters preferably (C1-C6) alkyl (C2-C4) carboxylates
  • a combination of any proportion of water and halogenated aliphatic hydrocarbons preferably (C1-C3) dichloroalkane is preferred.
  • solvents in step (iii) are water, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, tetrahydrofuran (THF), toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isomers thereof , toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, prop
  • Water may or may not be present. .
  • a combination of water and acetonitrile in any proportion, or acetonitrile is preferred.
  • a combination of water and butyl acetate and its isomers in any proportion, or butyl acetate and its isomers is preferred, and a combination of water and butyl acetate in any proportion or butyl acetate is more preferred.
  • a combination of water and dichloromethane in any proportion, or dichloromethane is preferred. In either case, the solvent may separate into a single layer or two layers as long as the reaction proceeds.
  • any amount may be used as long as the reaction system can be sufficiently stirred. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0 (zero) to 10 L (liter), preferably 0.1 to 1 mol of the compound of formula (5) or the compound of formula (6) 5L.
  • the ratio of the two or more solvents may be any ratio as long as the reaction proceeds.
  • the solvent may be a single layer or separated into two layers as long as the reaction proceeds.
  • step (ii) and step (iii) are performed without isolating the compound of formula (5) or the compound of formula (6)
  • the amount of solvent and the like in step (iii) is Alternatively, it can be set by the ratio with the compound of formula (4).
  • the amount of solvent used in step (iii) is 0 (zero) to 10 L (liter), preferably 0.1 to 5 L, per 1 mol of the compound of formula (3) or the compound of formula (4). is.
  • reaction temperature of step (iii) The reaction temperature of step (iii) is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the temperature is -30°C (minus 30°C) to 160°C, preferably -10°C to 120°C, more preferably 0 to 100°C.
  • reaction time of step (iii) is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the time is 0.5 hours to 72 hours, preferably 1 hour to 60 hours, more preferably 1 hour to 48 hours.
  • the product of step (iii) is the compound of formula (7) corresponding to the compound of formula (5) or the compound of formula (6) used as starting material.
  • Specific examples include, but are not limited to; 5,5-dimethyl-4,5-dihydroisoxazole, 5-ethyl-5-methyl-4,5-dihydroisoxazole, 5, 5-diethyl-4,5-dihydroisoxazole, 5-isopropyl-5-methyl-4,5-dihydroisoxazole, 5-(tert-butyl)-5-methyl-4,5-dihydroisoxazole , 5-(chloromethyl)-5-methyl-4,5-dihydroisoxazole, 5-methyl-5-(trifluoromethyl)-4,5-dihydroisoxazole, 5-cyclopropyl-5-methyl -4,5-dihydroisoxazole, 5-cyclobutyl-5-methyl-4,5-dihydroxazole,
  • reaction embodiment The following descriptions of "reaction embodiments" apply to steps (i), steps (ia), and steps (ib). Unless otherwise applicable.
  • This reaction can be carried out in a batch system (batch system) using a reactor, or can be carried out in a flow reaction using a continuous reactor.
  • a continuous reactor is a reactor for supplying raw materials and allowing reactions to proceed continuously at the same time.
  • As a continuous reactor there is a flow reactor.
  • a flow reactor is a reactor in which raw materials can be continuously fed and reacted continuously.
  • Flow reactors are broadly classified into tubular flow reactors (including tubular flow reactors) and tank flow reactors, both of which can carry out reactions in a continuous manner.
  • the flow reactor of the present invention may be provided with temperature control means for controlling the temperature of the flow reactor, for example, may be provided with a temperature control unit for heating and cooling.
  • the temperature control section may be of any suitable type, examples of temperature control sections include baths and jackets.
  • the style of the bath and jacket may be of any suitable style.
  • the material of the flow reactor is not particularly limited as long as it is not attacked by the raw material and solvent. Examples include glass, porcelain (eg, ceramics), and the like.
  • the continuous reaction of the present invention does not exclude implementation in a tank-type flow reactor.
  • preferred flow reactors include, for example, tubular flow reactors.
  • the tubular flow reactor of the present invention may be any one capable of continuously circulating a liquid or gas-liquid mixture. , or a combination of these shapes.
  • the material of the tube is not particularly limited as long as it is resistant to raw materials and solvents. (for example, ceramics), etc., but metals with excellent pressure resistance are preferable.
  • the tubular flow reactor of the present invention may also be provided with temperature control means for controlling the temperature, for example, a temperature control section for heating and cooling may be provided.
  • the temperature control section may be of any suitable type, and examples of temperature control sections include baths, jackets, and the like.
  • the style of the bath and jacket may be of any suitable style.
  • a spiral reactor, shell-and-tube reactor, plate heat exchange reactor, or the like can be used.
  • tubes in the tubular flow reactor of the present invention may be straight, curved, or coiled.
  • a preferred arrangement method includes, for example, a tubular reactor in which tubes are arranged in a coil.
  • the number of tubes may be one, but two or more tubes may be bundled regularly or irregularly at appropriate intervals.
  • the present specification will be described based on a tubular flow reactor having a single tube. can also be used in a tubular flow reactor in which the are bundled regularly or irregularly at appropriate intervals.
  • the tubular flow reactor of the present invention may have a mixer, if necessary.
  • the mixer is not particularly limited as long as it has a function of continuously mixing two or more fluids such as gas and liquid or liquid and liquid.
  • Examples include Y-shaped mixer, T-shaped mixer, pipe Line type mixers (line mixers including static mixers, etc.) and the like can be mentioned.
  • Line mixers, including static mixers and the like, may be tubular flow reactors.
  • metal catalyst, nitroxyl radical, nitric acid, alcohol compound (1) or alcohol compound (2) and a predetermined amount of solvent are added to the reactor (add more if necessary). good), and the reaction mixture is stirred at a given temperature for a given time in the presence of oxygen.
  • the reaction temperature is not particularly limited.
  • Reaction time is not particularly limited.
  • the time is 0.1 hour to 48 hours, preferably 0.1 hour to 24 hours, more preferably 1 hour to 12 hours.
  • flow-through reaction The following description of "flow-through reaction” applies to step (i), step (ia) and step (ib). In addition, it may apply to all steps except where not applicable.
  • a metal catalyst, nitroxyl radical, alcohol compound (1) or alcohol compound (2), and a predetermined amount of a mixture of a solvent (additional amounts may be added if necessary) are placed in a tubular reactor. is circulated, and oxygen is circulated and reacted from another tube.
  • a tubular reactor equipped with a heating device it is preferable to use a tubular reactor equipped with a heating device, and to pass the mixture through the reaction tube heated to a predetermined temperature.
  • the reaction temperature is not particularly limited. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is 0°C (zero) to 120°C, preferably 40°C to 100°C.
  • the equivalent diameter of the tube in the tubular reactor of the present invention is not particularly limited as long as it is a size that allows the liquid or gas-liquid mixture to flow continuously. It is preferable that the thickness is 0.5 mm or more from the point of view of production efficiency and reaction may occur. Examples of preferable equivalent diameters include 0.5 mm to 50 mm, preferably 0.5 mm to 30 mm.
  • the length of the tube of the tubular flow reactor of the present invention is not particularly limited as long as the temperature of the raw material compound can be raised and sufficient reaction can occur.
  • it is 1 m or more, preferably 1 m to 100 m, more preferably 5 m to 80 m.
  • it is necessary to react at a predetermined temperature and/or for a sufficient reaction time. Not limited.
  • the flow velocity in the flow reactor of the present invention depends on the equivalent diameter of the tube, but for example, the lower limit is usually 0.1 m/min or more, preferably 1.0 m/min or more. is. In addition, for example, the upper limit is usually 4.0 m/min or less, preferably 3.0 m/min or less.
  • the pressure in the tubular flow reactor is, for example, 0.1 MPa to 10 MPa, preferably 0.1 MPa to 5 MPa, more preferably 0.1 MPa to 1 MPa, but is not limited thereto.
  • the same organic solvents are preferably carboxylic acid esters, more preferably (C1-C6) alkyl (C2-C4) carboxylates.
  • Said same organic solvent is more preferably selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers.
  • the same organic solvent mentioned above is more preferably butyl acetate and its isomers, particularly preferably butyl acetate.
  • room temperature is from 10°C to 35°C.
  • Acetonitrile (7.9 g, 1.0 L/mol), iron (III) bromide (89 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.0 mol%) were placed in a 50 mL eggplant-shaped flask.
  • Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), propionic acid (741 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2 , 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C.
  • reaction tube part inner diameter 1 mm, length 40 m
  • the reaction tube was heated to 80 ° C., and then at 0.6 MPa, the raw material solution was supplied at a flow rate of 1 mL / min, and oxygen gas was supplied. It was supplied to the reaction tube at 30 mL/min.
  • a reaction mixture was sampled from the outlet of a pressure regulating valve attached to the outlet of the reaction tube, and GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows; 3-Methoxy-3-methylbutanal (target product (3-a)): 93%, 3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
  • the apparatus used is shown in FIG.
  • Butyl acetate (112.9 mL, 0.75 L/mol), iron (III) chloride (490 mg, 3.0 mmol, 2.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) Then, while stirring at 60° C., 69% nitric acid (6.85 g, 75 mmol, 50 mol %) was added dropwise over 5 hours, and 5 vol % oxygen-containing nitrogen was added at 20 mL/min.
  • Example 17 The reaction and analysis were carried out in the same manner as in Example 17, except that the solvent and reaction time were changed as shown in Table 1. Table 1 shows the results. In addition, the results of Example 17 are also summarized in Table 1.
  • Butyl acetate (112.9 mL, 0.75 L/mol), iron (III) chloride (490 mg, 3.0 mmol, 2.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) In addition, 69% nitric acid (8.22 g, 90 mmol, 60 mol %) was added dropwise over 6 hours while stirring at 60°C, and the mixture was reacted at the same temperature for 2 hours. GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows; 3-methyl-2-butenal (target product (4-a)): 94%, 3-methyl-2-butenoic acid (side product (10-a)): N.D. .
  • Example 24 The reaction and analysis were carried out in the same manner as in Example 24, except that the amount of iron chloride used, the amount of 4-hydroxy TEMPO used (equiv.), the amount of solvent, and the reaction temperature were changed as shown in Table 2. rice field. Table 2 shows the results. In addition, the results of Example 24 are also summarized in Table 2.
  • an aqueous sodium hydroxide solution 25 wt %, 16 g, 100 mmol, 100 mol %) was added dropwise with stirring over 30 minutes, followed by a 2 M aqueous hydroxylamine sulfate solution (34.85 g, hydroxylamine ( 104 mmol as hydroxylamine (NH 2 OH) and 104 mol % as hydroxylamine (NH 2 OH)) were added dropwise over 30 minutes.
  • the resulting mixture was filtered and partitioned into an organic layer and an aqueous layer, and the organic layer and aqueous layer were separated at 20-25°C.
  • the reaction formula is the same as in Example 31.
  • Butyl acetate (75.0 mL, 0.50 L/mol), iron (III) chloride (243 mg, 1.5 mmol, 1.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) In addition, 69% nitric acid (8.90 g, 97.5 mmol, 65 mol %) was added dropwise over 6.5 hours while stirring at 60°C, and the mixture was reacted at the same temperature for 0.5 hours. GC analysis (area percentage) of the reaction mixture was performed.
  • 3-Methyl-2-butenal (15.0 g, 178 mmol, 100 mol %) was dissolved in dichloromethane (90 ml, 0.5 L/mol).
  • a 50% hydroxylamine aqueous solution (11.8 g, 178 mmol, 100 mol %) was added dropwise thereto so that the internal temperature was 30 to 40° C. (exothermic reaction). After the dropwise addition was completed, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, saline (10 ml) was added and stirred. The resulting mixture was partitioned into organic and aqueous layers. The organic layer and aqueous layer were separated to obtain an organic layer.
  • Trifluoroacetic acid (TFA, 2.03 g, specific gravity: 1.49, 1.36 ml, 17.8 mmol, 10 mol%) was added thereto and stirred at room temperature for 48 hours.
  • the main components excluding the solvent etc. in the reaction mixture were as follows; 5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 94%, 3-methyl-2-butenal oxime (intermediate (6-a)): 1%.
  • Diethyl ether (40 ml) was added to the reaction mixture and the resulting mixture was partitioned between organic and aqueous layers. The organic layer and aqueous layer were separated to obtain an organic layer.
  • the reaction formula is the same as in Example 33.
  • 3-Methyl-2-butenal (10.0 g, 119 mmol, 100 mol %) was dissolved in dichloromethane (60 ml, 0.5 L/mol).
  • a 50% hydroxylamine aqueous solution (7.9 g, 119 mmol, 100 mol %) was added dropwise thereto so that the internal temperature was 30 to 40° C. (exothermic reaction).
  • the mixture was stirred at room temperature for 4 hours.
  • saline (10 ml) was added and stirred.
  • the resulting mixture was partitioned into organic and aqueous layers. The organic layer and aqueous layer were separated to obtain an organic layer.
  • the reaction formula is the same as in Example 33.
  • the aqueous layer was extracted with a small amount of dichloromethane. At this time, the pH of the aqueous layer was 6.6.
  • the organic layers obtained above were combined in a 50 ml round-bottomed flask (the amount of dichloromethane used was 23 ml in total, 0.2 L/mol in total).
  • Maleic acid (1.35 g, 11.7 mmol, 10 mol %) was added thereto and stirred at 30° C. for 48 hours.
  • the components other than the solvent etc. in the reaction mixture were as follows; 5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a )): 96%.
  • the reaction formula is the same as in Example 33.
  • Hydroxylamine sulfate (10.5 g, 128 mmol as hydroxylamine (NH 2 OH), 110 mol% as hydroxylamine (NH 2 OH)) was added to water (5 ml) and dichloromethane (12 ml, 0.1 L/mol) in a 25 ml eggplant flask. was added, and then a 25% sodium hydroxide aqueous solution (about 20 g, 128 mmol, 110 mol %) was added while stirring under ice-cooling until the pH reached 6.9.
  • the reaction formula is the same as in Example 33.
  • Hydroxylamine sulfate (9.56 g, 117 mmol as hydroxylamine (NH 2 OH), 100 mol% as hydroxylamine (NH 2 OH)) was added to water (12 ml) and dichloromethane (12 ml, 0.1 L/mol) in a 25 ml eggplant flask. was added, and aqueous ammonia (7.09 g, purity 28%, 117 mmol, 100 mol %) was added while stirring under ice-cooling. 3-Methyl-2-butenal (10.2 g, purity 98% (GC area %), 119 mmol, 102 mol %) was added thereto so as not to exceed 30°C, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane.
  • the reaction formula is the same as in Example 38.
  • Example 38 The reaction and analysis were carried out in the same manner as in Example 38, except that the organic solvent, amount of hydroxylamine used, catalyst and stirring conditions (aging conditions) were changed as shown in Table 3. Table 3 shows the results. In addition, the results of Example 38 are also summarized in Table 3.
  • Trifluoroacetic acid (0.29 g, 2.53 mmol, 35 mol%) and N-methylaniline (0.09 g, 0.87 mmol, 12 mol%) were added and stirred at 50°C for 24 hours.
  • the target components excluding the solvent etc. in the reaction mixture were as follows; 5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 80%.
  • the reaction formula is the same as in Example 45.
  • Example 45 The reaction and analysis were carried out in the same manner as in Example 45, except that the addition of the oximating agent and neutralizing agent was changed.
  • the results of Examples 45-48 are shown in Table 4.
  • the reaction formula is the same as in Example 33.
  • Example 49 The reaction and analysis were carried out in the same manner as in Example 49, except that the acid catalyst, base catalyst, solvent, temperature and reaction time were changed.
  • the results of Examples 49-54 are shown in Table 5.
  • 3-methyl-2-butenol (11.45 g, 133 mmol, 100 mol%) and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (916 mg, 5.32 mmol, 4 mol%) was dissolved in 50 mL of butyl acetate to prepare a solution.
  • a solution was prepared by dissolving iron (III) chloride (215 mg, 1.33 mmol, 1 mol%) and 69% nitric acid aqueous solution (607 mg, 6.64 mmol, 5.0 mol%) in 50 mL of butyl acetate under a nitrogen atmosphere. bottom.
  • reaction tube part inner diameter 1 mm, length 20 m
  • reaction tube part inner diameter 1 mm, length 20 m
  • the two raw material solutions prepared above were flowed at a flow rate of After being fed to a Y-tube mixer at 0.05 mL/min and mixed, it was fed to a reaction tube heated to 80° C., and oxygen gas was supplied at 3.15 mL/min at the same time.
  • a reaction mixture was sampled from the outlet of a pressure regulating valve attached to the outlet of the reaction tube, and GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows; 3-methyl-2-butenal (target product (4-a)): 96%. 3-methyl-2-butenoic acid (side product (10-a)): N.D. .
  • the apparatus used is shown in FIG.
  • Butyl acetate (38.0 mL, 0.38 L/mol) and 69% nitric acid (9.13 g, 100 mmol, 100 mol%) were added to a 200 mL four-necked flask, and iron chloride was added while stirring at 60°C.
  • (III) (162 mg, 1.0 mmol, 1.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (345 mg, 2.0 mmol, 2.0 mol %) and 3-methyl-2-butenol (8.61 g, 100 mmol, 100 mol %) were added in order. After that, the gas generated at the same temperature was collected.
  • 3-Methoxy-3-methylbutanol (20.00 g, 169.23 mmol, 100 mol%) was dissolved in dichloromethane (169.23 ml, 1.0 L/mol) in a 500 mL four-necked flask, followed by tetrabutylammonium bromide. (0.55 g, 1.69 mmol, 1 mol%), 2,2,6,6-tetramethylpiperidine 1-oxyl (0.026 g, 0.17 mmol, 0.1 mol%), phosphoric acid (1.95 g, 16 .92 mmol, 10 mol %) was added.
  • Iron (III) nitrate nonahydrate 101 mg, 0.25 mmol, 0.5 mol%) and 2,2'-bipyridyl (39 mg, 0.25 mmol, 0.5 mol%) were added to a 50 mL eggplant-shaped flask.
  • 2,2,6,6-tetramethylpiperidine 1-oxyl 55 mg, 0.35 mmol, 0.7 mol%)
  • N-bromosuccinimide 53 mg, 0.30 mmol, 0.6 mol%
  • the reaction formula is the same as in Example 15. (The reaction and analysis were performed in the same manner as in Example 24, except that the reaction temperature in Example 24 was changed to 20°C.)
  • Butyl acetate (112.9 mL, 0.75 L/mol), iron (III) chloride (490 mg, 3.0 mmol, 2.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) Then, while stirring at 20° C., 69% nitric acid (6.85 g, 75 mmol, 50 mol %) was added dropwise over 5 hours, and 5 vol % oxygen-containing nitrogen was added at 20 mL/min.
  • the present invention provides novel methods for producing compounds of formula (3), compounds of formula (4), and compounds of formula (7), which are useful as intermediates for the production of pharmaceuticals, agricultural chemicals, and the like.
  • the production method of the present invention is economical and environmentally friendly, and has high industrial utility value. Therefore, the present invention has high industrial applicability.

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Abstract

The present invention addresses the problem of providing an industrially preferable method for producing an aldehyde represented by formula (3) or (4): (3) (4).　The present invention produces a compound of formula (3) or compound of formula (4) by causing a corresponding compound of formula (1) or compound of formula (2) to undergo, in the presence of a metal catalyst, nitric acid, oxygen, and a nitroxyl radical compound, reaction represented by the following reaction formulae.　The present invention further addresses the problem of providing an industrially preferable method for producing a dihydroisoxazole represented by formula (7): (7). The obtained compound of formula (3) or compound of formula (4) is subjected to an oximation step and a cyclization step to produce the compound of formula (7).

Description

アルデヒド化合物及びジヒドロイソキサゾール化合物の製造方法Method for producing aldehyde compound and dihydroisoxazole compound
　本発明は、式（７）：  The present invention is based on formula (7):
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
（式中、Ｒ１及びＲ２は、後述の通りである。）の化合物、すなわちジヒドロイソオキサゾールの製造方法に関する。本明細書中、ジヒドロイソオキサゾールはイソオキサゾリンとも言う。
　更に、本発明は、式（３）又は式（４）：  (In the formula, R 1 and R 2 are as described below.) compound, ie, a method for producing dihydroisoxazole. In the present specification, dihydroisoxazole is also referred to as isoxazoline.
Further, the present invention provides formula (3) or formula (4):
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式中、Ｒ１、Ｒ２及びＲ３は、後述の通りである。）の化合物、すなわちアルデヒドの製造方法に関する。 (Wherein, R 1 , R 2 and R 3 are as described below).
　式（３）又は式（４）の化合物は、医薬及び農薬等の製造中間体として有用である。特許文献１（WO2002/062770A1）は有用な除草剤を開示し、式（３）又は式（４）の化合物は当該除草剤の中間体として用いることができる。当該除草剤の中でも、ピロキサスルホン（Pyroxasulfone）は優れた除草活性を有する除草剤としてよく知られている。特許文献２（WO2020/251006A1）は、ジヒドロイソオキサゾールの製造方法を開示し、ジヒドロイソオキサゾールもまたピロキサスルホン等の除草剤の中間体として用いることができる。 The compound of formula (3) or formula (4) is useful as a production intermediate for pharmaceuticals, agricultural chemicals, and the like. WO2002/062770A1 discloses useful herbicides and compounds of formula (3) or (4) can be used as intermediates for said herbicides. Among these herbicides, Pyroxasulfone is well known as a herbicide having excellent herbicidal activity. Patent Document 2 (WO2020/251006A1) discloses a process for producing dihydroisoxazole, which can also be used as an intermediate for herbicides such as pyroxasulfone.
　特許文献２（WO2020/251006A1）のスキーム：  The scheme of Patent Document 2 (WO2020/251006A1):
Figure JPOXMLDOC01-appb-C000007
  
Figure JPOXMLDOC01-appb-C000007
  
　上図ににおいて、特許文献２（WO2020/251006A1）に記載の方法では、アルコールを次亜塩素酸ナトリウムと反応させて、続けてオキシム化、環化を行う。 In the above figure, in the method described in Patent Document 2 (WO2020/251006A1), alcohol is reacted with sodium hypochlorite, followed by oximation and cyclization.
　特許文献５（WO2019/117255A1）もまた、ピロキサスルホン等の除草剤の中間体の製造方法を開示する。 Patent Document 5 (WO2019/117255A1) also discloses a method for producing intermediates for herbicides such as pyroxasulfone.
　特許文献５（WO2019/117255A1）のスキーム：  The scheme of Patent Document 5 (WO2019/117255A1):
Figure JPOXMLDOC01-appb-C000008
  
Figure JPOXMLDOC01-appb-C000008
  
　上図に示すように、特許文献５（WO2019/117255A1）に記載の方法では、オキシム化を行った後、環化反応を行う。 As shown in the figure above, in the method described in Patent Document 5 (WO2019/117255A1), oximation is performed and then cyclization reaction is performed.
　特許文献６（WO2019/208643A1）もまた、ピロキサスルホン等の除草剤の中間体の製造方法を開示する。その製造方法を下図に示す。 Patent Document 6 (WO2019/208643A1) also discloses a method for producing intermediates for herbicides such as pyroxasulfone. The manufacturing method is shown in the figure below.
　特許文献６（WO2019/208643A1）のスキーム：  The scheme of Patent Document 6 (WO2019/208643A1):
Figure JPOXMLDOC01-appb-C000009
  
Figure JPOXMLDOC01-appb-C000009
  
　しかしながら、更に効率がよい式（７）の化合物の製造方法が要望されていた。例えば、特許文献２（WO2020/251006A1）の製造方法は、中間体のアルデヒド化合物の製造方法に改善が要望されていた。特許文献５（WO2019/117255A1）及び特許文献６（WO2019/208643A1）の製造方法もまた、原料のアルデヒド化合物の製造方法に改善が要望されていた。 However, there has been a demand for a more efficient method for producing the compound of formula (7). For example, in the production method of Patent Document 2 (WO2020/251006A1), there has been a demand for improvement in the production method of the intermediate aldehyde compound. In the production methods of Patent Document 5 (WO2019/117255A1) and Patent Document 6 (WO2019/208643A1), there has also been a demand for improvement in the method of producing the starting aldehyde compound.
　例えば、特許文献３（WO2005/082825A1）及び特許文献４（CN101709026A）では、アルデヒド化合物の製造方法として、酸素を用いた酸化法が開示されている。特許文献３（WO2005/082825A1）及び特許文献４（CN101709026A）の実施例の反応条件を用いて、式（１）のアルコール化合物を原料に用いて反応させたが、式（３）のアルデヒド化合物は低い収率であった（比較例１０～１２）。 For example, Patent Document 3 (WO2005/082825A1) and Patent Document 4 (CN101709026A) disclose an oxidation method using oxygen as a method for producing an aldehyde compound. Using the reaction conditions of Examples of Patent Document 3 (WO2005/082825A1) and Patent Document 4 (CN101709026A), the alcohol compound of formula (1) was used as a starting material to react, but the aldehyde compound of formula (3) was The yield was low (Comparative Examples 10-12).
　上記式（３）の化合物の工業的な重要性から、従来技術よりもさらに工業的に好ましい式（３）の化合物の製造方法が望まれていた。 Due to the industrial importance of the compound of formula (3), a method for producing the compound of formula (3) that is more industrially preferable than conventional techniques has been desired.
国際公開第２００２／０６２７７０号WO2002/062770 国際公開第２０２０／２５１００６号WO2020/251006 国際公開第２００５／０８２８２５号WO2005/082825 中国特許出願公開第１０１７０９０２６号明細書Chinese Patent Application Publication No. 101709026 国際公開第２０１９／１１７２５５号WO2019/117255 国際公開第２０１９／２０８６４３号WO2019/208643
　本発明の目的は、上記式（７）の化合物の効率がよく工業的に好ましい製造方法を提供することにある。
　本発明のさらなる目的は、上記式（３）又は式（４）の化合物の工業的に好ましい製造方法を提供することにある。　具体的な目的は、式（１）又は式（２）の化合物（アルコール化合物）から式（３）又は式（４）の化合物（アルデヒド化合物）を簡単な操作により製造する方法であって、副生物として生成するカルボン酸誘導体及びエステル誘導体類の割合が十分に低く、収率に優れ、工業的な製造に有利な製造方法を提供することにある。 An object of the present invention is to provide an efficient and industrially preferable method for producing the compound of formula (7).
A further object of the present invention is to provide an industrially preferable method for producing the compound of formula (3) or (4). A specific object is a method for producing a compound (aldehyde compound) of formula (3) or (4) from a compound (alcohol compound) of formula (1) or formula (2) by a simple operation, It is an object of the present invention to provide a production method in which the ratio of carboxylic acid derivatives and ester derivatives produced as organisms is sufficiently low, the yield is excellent, and it is advantageous for industrial production.
　上記のような状況に鑑み、本発明者が式（３）又は式（４）の化合物の製造方法について鋭意研究した。その結果、意外にも、式（３）又は式（４）の化合物の以下の製造方法を提供することにより、前記課題が解決可能であることが見出された。本発明者はこの知見に基づき本発明を完成するに至った。 In view of the circumstances described above, the present inventors have made intensive research on methods for producing compounds of formula (3) or (4). As a result, it was unexpectedly found that the above problems can be solved by providing the following process for producing the compound of formula (3) or (4). The present inventor has completed the present invention based on this finding.
　すなわち、一つの態様では、本発明は以下の通りである。 That is, in one aspect, the present invention is as follows.
　〔Ｉ－１〕　式（７）の化合物の製造方法であって、以下の工程を含む製造方法；
　工程（ｉ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）の化合物又は式（２）の化合物を反応させて、それぞれ対応する式（３）の化合物又は式（４）の化合物を得る： [I-1] A method for producing a compound of formula (7), comprising the following steps;
Step (i) reacting the compound of formula (1) or the compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give the corresponding compound of formula (3) or formula ( 4) to obtain the compound:
Figure JPOXMLDOC01-appb-C000010
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）
　工程（ｉｉ）　式（３）の化合物又は式（４）の化合物をオキシム化剤と反応させて、それぞれ対応する式（５）の化合物又は式（６）の化合物を得る：
Figure JPOXMLDOC01-appb-C000010
(wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. )
Step (ii) reacting a compound of formula (3) or a compound of formula (4) with an oximating agent to give the corresponding compound of formula (5) or compound of formula (6) respectively:
Figure JPOXMLDOC01-appb-C000011
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）
　工程（ｉｉｉ）　酸触媒の存在下で、又は酸触媒と塩基触媒の存在下で、式（５）の化合物又は式（６）の化合物を反応させて、式（７）の化合物を得る：
Figure JPOXMLDOC01-appb-C000011
(wherein R 1 , R 2 and R 3 are as defined above).
Step (iii) reacting a compound of formula (5) or a compound of formula (6) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
Figure JPOXMLDOC01-appb-C000012
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）。
Figure JPOXMLDOC01-appb-C000012
(wherein R 1 , R 2 and R 3 are as defined above).
　〔Ｉ－２〕　式（７）の化合物の製造方法であって、以下の工程を含む製造方法；
　工程（ｉ－ａ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）の化合物を反応させて、式（３）の化合物を得る： [I-2] A method for producing a compound of formula (7), comprising the following steps;
Step (ia) reacting a compound of formula (1) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (3):
Figure JPOXMLDOC01-appb-C000013
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）
　工程（ｉｉ－ａ）　式（３）の化合物をオキシム化剤と反応させて、式（５）の化合物を得る：
Figure JPOXMLDOC01-appb-C000013
(wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. )
Step (ii-a) reacting a compound of formula (3) with an oximating agent to give a compound of formula (5):
Figure JPOXMLDOC01-appb-C000014
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）
　工程（ｉｉｉ－ａ）　酸触媒の存在下で、又は酸触媒と塩基触媒の存在下で、式（５）の化合物を反応させて、式（７）の化合物を得る：
Figure JPOXMLDOC01-appb-C000014
(wherein R 1 , R 2 and R 3 are as defined above).
Step (iii-a) reacting a compound of formula (5) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
Figure JPOXMLDOC01-appb-C000015
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）。
Figure JPOXMLDOC01-appb-C000015
(wherein R 1 , R 2 and R 3 are as defined above).
　〔Ｉ－３〕　式（７）の化合物の製造方法であって、以下の工程を含む製造方法；
　工程（ｉ－ｂ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（２）の化合物を反応させて、式（４）の化合物を得る： [I-3] A method for producing a compound of formula (7), comprising the following steps;
Step (ib) reacting a compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (4):
Figure JPOXMLDOC01-appb-C000016
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）
　工程（ｉｉ－ｂ）　式（４）の化合物をオキシム化剤と反応させて、式（６）の化合物を得る：
Figure JPOXMLDOC01-appb-C000016
(wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. )
Step (ii-b) reacting a compound of formula (4) with an oximating agent to give a compound of formula (6):
Figure JPOXMLDOC01-appb-C000017
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）
　工程（ｉｉｉ－ｂ）　酸触媒の存在下で、又は酸触媒と塩基触媒の存在下で、式（６）の化合物を反応させて、式（７）の化合物を得る：
Figure JPOXMLDOC01-appb-C000017
(wherein R 1 , R 2 and R 3 are as defined above).
Step (iii-b) reacting a compound of formula (6) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
Figure JPOXMLDOC01-appb-C000018
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）。
Figure JPOXMLDOC01-appb-C000018
(wherein R 1 , R 2 and R 3 are as defined above).
　〔Ｉ－４〕　式（３）の化合物又は式（４）の化合物の製造方法であって、以下の工程を含む製造方法；
　工程（ｉ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）の化合物又は式（２）の化合物を反応させて、それぞれ対応する式（３）の化合物又は式（４）の化合物を得る： [I-4] A method for producing a compound of formula (3) or a compound of formula (4), comprising the following steps;
Step (i) reacting the compound of formula (1) or the compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give the corresponding compound of formula (3) or formula ( 4) to obtain the compound:
Figure JPOXMLDOC01-appb-C000019
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）。
Figure JPOXMLDOC01-appb-C000019
(wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. ).
　〔Ｉ－５〕　式（３）の化合物の製造方法であって、以下の工程を含む製造方法；
　工程（ｉ－ａ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）の化合物を反応させて、式（３）の化合物を得る： [I-5] A method for producing a compound of formula (3), comprising the following steps;
Step (ia) reacting a compound of formula (1) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (3):
Figure JPOXMLDOC01-appb-C000020
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）。
Figure JPOXMLDOC01-appb-C000020
(wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. ).
　〔Ｉ－６〕　式（４）の化合物の製造方法であって、以下の工程を含む製造方法；
　工程（ｉ－ｂ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（２）の化合物を反応させて、式（４）の化合物を得る： [I-6] A method for producing a compound of formula (4), comprising the following steps;
Step (ib) reacting a compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give a compound of formula (4):
Figure JPOXMLDOC01-appb-C000021
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）。
Figure JPOXMLDOC01-appb-C000021
(wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. ).
　〔Ｉ－７〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、鉄触媒又は銅触媒である製造方法、ただし、該当しない方法を除く。 [I-7] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is an iron or copper catalyst, except where not applicable.
　〔Ｉ－８〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、硝酸鉄（ＩＩＩ）であるか、又は塩化鉄（ＩＩＩ）、臭化鉄（ＩＩＩ）又はヨウ化鉄（ＩＩＩ）と硝酸を含む触媒である製造方法、ただし、該当しない方法を除く。 [I-8] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes of preparation wherein the catalyst is iron(III) nitrate or a catalyst comprising iron(III) chloride, iron(III) bromide or iron(III) iodide and nitric acid, except where not applicable.
　〔Ｉ－９〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、硝酸鉄（ＩＩＩ）であるか、又は塩化鉄（ＩＩＩ）又は臭化鉄（ＩＩＩ）と硝酸を含む触媒である製造方法、ただし、該当しない方法を除く。 [I-9] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes of preparation wherein the catalyst is iron(III) nitrate or a catalyst comprising iron(III) chloride or iron(III) bromide and nitric acid, except where not applicable.
　〔Ｉ－１０〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、塩化鉄（ＩＩＩ）又は臭化鉄（ＩＩＩ）と硝酸を含む触媒である製造方法、ただし、該当しない方法を除く。 [I-10] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is a catalyst comprising iron(III) chloride or iron(III) bromide and nitric acid, except where not applicable.
　〔Ｉ－１１〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、塩化鉄（ＩＩＩ）と硝酸を含む触媒である製造方法、ただし、該当しない方法を除く。 [I-11] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is a catalyst comprising iron(III) chloride and nitric acid, except for processes not applicable.
　〔Ｉ－１２〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、硝酸銅（ＩＩ）であるか、又は塩化銅（ＩＩ）、臭化銅（ＩＩ）又はヨウ化銅（ＩＩ）と硝酸を含む触媒である製造方法、ただし、該当しない方法を除く。 [I-12] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes of preparation wherein the catalyst is copper(II) nitrate, or a catalyst comprising copper(II) chloride, copper(II) bromide or copper(II) iodide and nitric acid, except where not applicable.
　〔Ｉ－１３〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、塩化銅（ＩＩ）又は臭化銅（ＩＩ）と硝酸を含む触媒である製造方法、ただし、該当しない方法を除く。 [I-13] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is a catalyst comprising copper(II) chloride or copper(II) bromide and nitric acid, except where not applicable.
　〔Ｉ－１４〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、塩化鉄（ＩＩＩ）、臭化鉄（ＩＩＩ）又はヨウ化鉄（ＩＩＩ）である製造方法、ただし、該当しない方法を除く。 [I-14] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is iron(III) chloride, iron(III) bromide or iron(III) iodide, except those where not applicable.
　〔Ｉ－１５〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、塩化鉄（ＩＩＩ）又は臭化鉄（ＩＩＩ）である製造方法、ただし、該当しない方法を除く。 [I-15] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is iron(III) chloride or iron(III) bromide, except where not applicable.
　〔Ｉ－１６〕　〔Ｉ－１〕から〔Ｉ－６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒が、塩化鉄（ＩＩＩ）である製造方法、ただし、該当しない方法を除く。 [I-16] The production method according to any one of [I-1] to [I-6], wherein the metal in step (i), step (ia) or step (ib) Processes where the catalyst is iron(III) chloride, except where not applicable.
　〔Ｉ－１７〕　〔Ｉ－１〕から〔Ｉ－１６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．０１モル～１モルである製造方法、ただし、該当しない方法を除く。 [I-17] The production method according to any one of [I-1] to [I-16], wherein nitric acid in step (i), step (ia) or step (ib) is used in an amount of 0.01 mol to 1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－１８〕　〔Ｉ－１〕から〔Ｉ－１６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．０２モル～０．９モルである製造方法、ただし、該当しない方法を除く。 [I-18] The production method according to any one of [I-1] to [I-16], wherein nitric acid in step (i), step (ia) or step (ib) is used in an amount of 0.02 mol to 0.9 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－１９〕　〔Ｉ－１〕から〔Ｉ－１６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．０１モル～０．１モルである製造方法、ただし、該当しない方法を除く。 [I-19] The production method according to any one of [I-1] to [I-16], wherein nitric acid in step (i), step (ia) or step (ib) is used in an amount of 0.01 mol to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－２０〕　〔Ｉ－１〕から〔Ｉ－１６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．０２モル～０．０５モルである製造方法、ただし、該当しない方法を除く。 [I-20] The production method according to any one of [I-1] to [I-16], wherein nitric acid in step (i), step (ia) or step (ib) is used in an amount of 0.02 mol to 0.05 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－２１〕　〔Ｉ－１〕から〔Ｉ－１６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．５モル～１モルである製造方法、ただし、該当しない方法を除く。 [I-21] The production method according to any one of [I-1] to [I-16], wherein nitric acid in step (i), step (ia) or step (ib) is used in an amount of 0.5 mol to 1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－２２〕　〔Ｉ－１〕から〔Ｉ－１６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．５モル～０．９モルである製造方法、ただし、該当しない方法を除く。 [I-22] The production method according to any one of [I-1] to [I-16], wherein nitric acid in step (i), step (ia) or step (ib) is used in an amount of 0.5 mol to 0.9 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－２３〕　〔Ｉ－１〕から〔Ｉ－１６〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．５モル～０．８モルである製造方法、ただし、該当しない方法を除く。 [I-23] The production method according to any one of [I-1] to [I-16], wherein nitric acid in step (i), step (ia) or step (ib) is used in an amount of 0.5 mol to 0.8 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－２４〕　〔Ｉ－１〕から〔Ｉ－２３〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応を酸の存在下で行う製造方法、ただし、該当しない方法を除く。 [I-24] The production method according to any one of [I-1] to [I-23], wherein the reaction of step (i), step (ia) or step (ib) in the presence of an acid, except for those not applicable.
　〔Ｉ－２５〕　〔Ｉ－１〕から〔Ｉ－２４〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸がカルボン酸である製造方法、ただし、該当しない方法を除く。 [I-25] The production method according to any one of [I-1] to [I-24], wherein the acid in step (i), step (ia) or step (ib) is a carboxylic acid, except those not applicable.
　〔Ｉ－２６〕　〔Ｉ－１〕から〔Ｉ－２４〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸が酢酸、プロピオン酸又は安息香酸である製造方法、ただし、該当しない方法を除く。 [I-26] The production method according to any one of [I-1] to [I-24], wherein the acid in step (i), step (ia) or step (ib) is acetic acid, propionic acid or benzoic acid, except those not applicable.
　〔Ｉ－２７〕　〔Ｉ－１〕から〔Ｉ－２４〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸が酢酸である製造方法、ただし、該当しない方法を除く。 [I-27] The production method according to any one of [I-1] to [I-24], wherein the acid in step (i), step (ia) or step (ib) is acetic acid, except those not applicable.
　〔Ｉ－２８〕　〔Ｉ－１〕から〔Ｉ－２７〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応を塩基の存在下で行う製造方法、ただし、該当しない方法を除く。 [I-28] The production method according to any one of [I-1] to [I-27], wherein the reaction of step (i), step (ia) or step (ib) in the presence of a base, except for methods not applicable.
　〔Ｉ－２９〕　〔Ｉ－１〕から〔Ｉ－２８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の塩基が窒素原子を有する芳香族ヘテロ環である製造方法、ただし、該当しない方法を除く。 [I-29] The production method according to any one of [I-1] to [I-28], wherein the base in step (i), step (ia) or step (ib) is an aromatic heterocycle having a nitrogen atom, except those not applicable.
　〔Ｉ－３０〕　〔Ｉ－１〕から〔Ｉ－２８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の塩基がＮ－メチルイミダゾール、２，２’－ビピリジル、Ｎ－メチルピラゾール、ピリジン又はＮ，Ｎ－ジメチルアミノピリジンである製造方法、ただし、該当しない方法を除く。 [I-30] The production method according to any one of [I-1] to [I-28], wherein the base in step (i), step (ia) or step (ib) is N-methylimidazole, 2,2'-bipyridyl, N-methylpyrazole, pyridine or N,N-dimethylaminopyridine, except those not applicable.
　〔Ｉ－３１〕　〔Ｉ－１〕から〔Ｉ－２８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の塩基がＮ－メチルイミダゾール又は２，２’－ビピリジルである製造方法、ただし、該当しない方法を除く。 [I-31] The production method according to any one of [I-1] to [I-28], wherein the base in step (i), step (ia) or step (ib) is N-methylimidazole or 2,2'-bipyridyl, except those not applicable.
　〔Ｉ－３２〕　〔Ｉ－１〕から〔Ｉ－３１〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．５～３モルである製造方法、ただし、該当しない方法を除く。 [I-32] The production method according to any one of [I-1] to [I-31], wherein the acid in step (i), step (ia) or step (ib) is used in an amount of 0.5 to 3 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－３３〕　〔Ｉ－１〕から〔Ｉ－３１〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、１～２モルである製造方法、ただし、該当しない方法を除く。 [I-33] The production method according to any one of [I-1] to [I-31], wherein the acid in step (i), step (ia) or step (ib) is used in an amount of 1 to 2 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－３４〕　〔Ｉ－１〕から〔Ｉ－３３〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の塩基の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．００１～０．３モルである製造方法、ただし、該当しない方法を除く。 [I-34] The production method according to any one of [I-1] to [I-33], wherein the base in step (i), step (ia) or step (ib) is used in an amount of 0.001 to 0.3 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－３５〕　〔Ｉ－１〕から〔Ｉ－３３〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の塩基の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．０１～０．１モルである製造方法、ただし、該当しない方法を除く。 [I-35] The production method according to any one of [I-1] to [I-33], wherein the base in step (i), step (ia) or step (ib) is used in an amount of 0.01 to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－３６〕　〔Ｉ－１〕から〔Ｉ－３５〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．００１～０．３モルである製造方法、ただし、該当しない方法を除く。 [I-36] The production method according to any one of [I-1] to [I-35], wherein the metal in step (i), step (ia) or step (ib) A production method in which the amount of catalyst used is 0.001 to 0.3 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－３７〕　〔Ｉ－１〕から〔Ｉ－３５〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の金属触媒の使用量が、式（１）の化合物又は式（２）の化合物1モルに対して、０．０１～０．１モルである製造方法、ただし、該当しない方法を除く。 [I-37] The production method according to any one of [I-1] to [I-35], wherein the metal in step (i), step (ia) or step (ib) A production method in which the amount of catalyst used is 0.01 to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－３８〕　〔Ｉ－１〕から〔Ｉ－３７〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）のニトロキシルラジカル化合物が、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシルである製造方法、ただし、該当しない方法を除く。 [I-38] The production method according to any one of [I-1] to [I-37], wherein the nitro in step (i), step (ia) or step (ib) A production method in which the xyl radical compound is 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl, except for those not applicable.
　〔Ｉ－３９〕　〔Ｉ－１〕から〔Ｉ－３８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）のニトロキシルラジカル化合物の使用量が、式（１）の化合物又は式（２）の化合物１モルに対して、０．００１～０．３モルである製造方法、ただし、該当しない方法を除く。 [I-39] The production method according to any one of [I-1] to [I-38], wherein the nitro in step (i), step (ia) or step (ib) A production method in which the amount of the xyl radical compound used is 0.001 to 0.3 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－４０〕　〔Ｉ－１〕から〔Ｉ－３８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）のニトロキシルラジカル化合物の使用量が、式（１）の化合物又は式（２）の化合物１モルに対して、０．０１～０．１モルである製造方法、ただし、該当しない方法を除く。 [I-40] The production method according to any one of [I-1] to [I-38], wherein the nitro in step (i), step (ia) or step (ib) A production method in which the amount of the xyl radical compound used is 0.01 to 0.1 mol per 1 mol of the compound of formula (1) or the compound of formula (2), except for methods not applicable.
　〔Ｉ－４１〕　〔Ｉ－１〕から〔Ｉ－４０〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸素の濃度が、１～１００体積％である製造方法、ただし、該当しない方法を除く。 [I-41] The production method according to any one of [I-1] to [I-40], wherein oxygen in step (i), step (ia) or step (ib) concentration is 1 to 100% by volume, except for methods that are not applicable.
　〔Ｉ－４２〕　〔Ｉ－１〕から〔Ｉ－４０〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸素の濃度が、５～１００体積％である製造方法、ただし、該当しない方法を除く。 [I-42] The production method according to any one of [I-1] to [I-40], wherein oxygen in step (i), step (ia) or step (ib) The concentration of is 5 to 100% by volume, except for methods that are not applicable.
　〔Ｉ－４３〕　〔Ｉ－１〕から〔Ｉ－４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、ここで当該溶媒が芳香族炭化水素類、エーテル類、ケトン類、ニトリル類及びエステル類好ましくは（Ｃ２－Ｃ４）アルカンニトリル及び（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）から選ばれる製造方法、ただし、該当しない方法を除く。 [I-43] The method according to any one of [I-1] to [I-42], wherein the reaction in step (i), step (ia) or step (ib) is carried out in the presence of a solvent, wherein the solvent is aromatic hydrocarbons, ethers, ketones, nitriles and esters, preferably (C2-C4)alkanenitriles and (C1-C6)alkyl(C2-C4) ) Carboxylates), excluding those not applicable.
　〔Ｉ－４４〕　〔Ｉ－１〕から〔Ｉ－４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、ここで当該溶媒がニトリル類及びエステル類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル及び（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）から選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）である製造方法、ただし、該当しない方法を除く。 [I-44] The method according to any one of [I-1] to [I-42], wherein the reaction in step (i), step (ia) or step (ib) is carried out in the presence of a solvent, wherein the solvent is one or more selected from nitriles and esters (preferably (C2-C4) alkanenitrile and (C1-C6) alkyl (C2-C4) carboxylate) ( (preferably 1 or 2, more preferably 1), except for those that are not applicable.
　〔Ｉ－４５〕　〔Ｉ－１〕から〔Ｉ－４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、ここで当該溶媒がトルエン、キシレン、クロロベンゼン、ジクロロベンゼン、クロロトルエン、テトラヒドロフラン、ジブチルエーテル、アセトン、メチルイソブチルケトン、アセトニトリル、プロピオニトリル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸ペンチルから選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）である製造方法。 [I-45] The method according to any one of [I-1] to [I-42], wherein the reaction in step (i), step (ia) or step (ib) is in the presence of a solvent, wherein the solvent is toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, tetrahydrofuran, dibutyl ether, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate , butyl acetate, and pentyl acetate (preferably 1 or 2, more preferably 1).
　〔Ｉ－４６〕　〔Ｉ－１〕から〔Ｉ－４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、ここで当該溶媒がアセトニトリル、プロピオニトリル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル及び酢酸ペンチルから選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）である、ただし、該当しない方法を除く。 [I-46] The method according to any one of [I-1] to [I-42], wherein the reaction in step (i), step (ia) or step (ib) is carried out in the presence of a solvent, wherein the solvent is one or more (preferably one or two, more preferably one or two) selected from acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and pentyl acetate 1), except for methods that are not applicable.
　〔Ｉ－４７〕　〔Ｉ－１〕から〔Ｉ－４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、ここで当該溶媒がアセトニトリル又は酢酸ブチルである製造方法、ただし、該当しない方法を除く。 [I-47] The method according to any one of [I-1] to [I-42], wherein the reaction in step (i), step (ia) or step (ib) is Processes of preparation carried out in the presence of a solvent, wherein said solvent is acetonitrile or butyl acetate, except for processes not applicable.
　〔Ｉ－４８〕　〔Ｉ－１〕から〔Ｉ－４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、ここで当該溶媒が（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート（好ましくは酢酸ブチル）である製造方法、ただし、該当しない方法を除く。 [I-48] The method according to any one of [I-1] to [I-42], wherein the reaction in step (i), step (ia) or step (ib) is Processes of preparation carried out in the presence of a solvent, wherein said solvent is a (C1-C6)alkyl(C2-C4)carboxylate (preferably butyl acetate), except those processes not applicable.
　〔Ｉ－４９〕　〔Ｉ－１〕から〔Ｉ－４８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が、回分式（バッチ式）で行われる製造方法、ただし、該当しない方法を除く。 [I-49] The production method according to any one of [I-1] to [I-48], wherein the reaction of step (i), step (ia) or step (ib) is a batch method (batch type), excluding methods that do not apply.
　〔Ｉ－５０〕　〔Ｉ－１〕から〔Ｉ－４８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が、管型流通反応器を用いて連続して行われる製造方法、ただし、該当しない方法を除く。 [I-50] The production method according to any one of [I-1] to [I-48], wherein the reaction of step (i), step (ia) or step (ib) is a continuous production method using a tubular flow reactor, excluding methods that are not applicable.
　〔Ｉ－５１〕　〔Ｉ－１〕から〔Ｉ－４８〕のいずれか１項に記載の製造方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が、流通式で行われる製造方法、ただし、該当しない方法を除く。 [I-51] The production method according to any one of [I-1] to [I-48], wherein the reaction of step (i), step (ia) or step (ib) is a production method that is carried out in a flow-through manner, except for methods that do not apply.
　〔Ｉ－５２〕　〔Ｉ－１〕から〔Ｉ－５１〕のいずれか１項に記載の方法であって、バッチ式の反応温度が１０℃～８０℃で行われる、製造方法、ただし、該当しない方法を除く。 [I-52] The production method according to any one of [I-1] to [I-51], wherein the batch-type reaction temperature is 10°C to 80°C, provided that applicable Except how not.
　〔Ｉ－５３〕　〔Ｉ－１〕から〔Ｉ－５１〕のいずれか１項に記載の方法であって、バッチ式の反応温度が３０℃～７０℃で行われる製造方法、ただし、該当しない方法を除く。 [I-53] The production method according to any one of [I-1] to [I-51], wherein the batch reaction temperature is 30°C to 70°C, but not applicable Except how.
　〔Ｉ－５４〕　〔Ｉ－１〕から〔Ｉ－５１〕のいずれか１項に記載の方法であって、流通式の反応温度が０℃～１２０℃で行われる製造方法、ただし、該当しない方法を除く。 [I-54] The production method according to any one of [I-1] to [I-51], in which the flow reaction temperature is 0°C to 120°C, but not applicable Except how.
　〔Ｉ－５５〕　〔Ｉ－１〕から〔Ｉ－５１〕のいずれか１項に記載の方法であって、流通式の反応温度が４０℃～１００℃で行われる製造方法、ただし、該当しない方法を除く。 [I-55] The production method according to any one of [I-1] to [I-51], in which the flow reaction temperature is 40°C to 100°C, but not applicable Except how.
　〔Ｉ－５６〕　〔Ｉ－１〕から〔Ｉ－５５〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の濃度が１０～９０％である製造方法、ただし、該当しない方法を除く。 [I-56] The method according to any one of [I-1] to [I-55], wherein nitric acid in step (i), step (ia) or step (ib) Manufacturing methods in which the concentration is 10-90%, except for those not applicable.
　〔Ｉ－５７〕　〔Ｉ－１〕から〔Ｉ－５５〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の硝酸の濃度が３０～８０％である製造方法、ただし、該当しない方法を除く。 [I-57] The method according to any one of [I-1] to [I-55], wherein nitric acid in step (i), step (ia) or step (ib) Manufacturing methods where the concentration is 30-80%, except those not applicable.
　〔Ｉ－５８〕　〔Ｉ－１〕から〔Ｉ－５７〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）のオキシム化剤が、ヒドロキシルアミン、ヒドロキシルアミン塩又はオキシム化合物である製造方法、ただし、該当しない方法を除く。 [I-58] The method according to any one of [I-1] to [I-57], wherein the oximation of step (ii), step (ii-a) or step (ii-b) Processes where the agent is hydroxylamine, hydroxylamine salts or oxime compounds, except those not applicable.
　〔Ｉ－５９〕　〔Ｉ－１〕から〔Ｉ－５７〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）のオキシム化剤が、ヒドロキシルアミン水溶液、塩酸ヒドロキシルアミン又は硫酸ヒドロキシルアミンである製造方法、ただし、該当しない方法を除く。 [I-59] The method according to any one of [I-1] to [I-57], wherein the oximation of step (ii), step (ii-a) or step (ii-b) Processes where the agent is an aqueous solution of hydroxylamine, hydroxylamine hydrochloride or hydroxylamine sulfate, except where not applicable.
　〔Ｉ－６０〕　〔Ｉ－１〕から〔Ｉ－５７〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）のオキシム化剤が、４５％～５０％ヒドロキシルアミン水溶液、塩酸ヒドロキシルアミン又は硫酸ヒドロキシルアミンである製造方法、ただし、該当しない方法を除く。 [I-60] The method according to any one of [I-1] to [I-57], wherein the oximation of step (ii), step (ii-a) or step (ii-b) Processes where the agent is 45% to 50% aqueous hydroxylamine solution, hydroxylamine hydrochloride or hydroxylamine sulfate, except those not applicable.
　〔Ｉ－６１〕　〔Ｉ－１〕から〔Ｉ－５７〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）のオキシム化剤が、塩酸ヒドロキシルアミン又は硫酸ヒドロキシルアミンである製造方法、ただし、該当しない方法を除く。 [I-61] The method according to any one of [I-1] to [I-57], wherein the oximation of step (ii), step (ii-a) or step (ii-b) Processes in which the agent is hydroxylamine hydrochloride or hydroxylamine sulfate, except those not applicable.
　〔Ｉ－６２〕　〔Ｉ－１〕から〔Ｉ－５７〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）のオキシム化剤が、硫酸ヒドロキシルアミンである製造方法、ただし、該当しない方法を除く。 [I-62] The method according to any one of [I-1] to [I-57], wherein the oximation of step (ii), step (ii-a) or step (ii-b) Processes of manufacture in which the agent is hydroxylamine sulfate, except those not applicable.
　〔Ｉ－６３〕　〔Ｉ－１〕から〔Ｉ－６２〕のいずれか１項に記載の方法であって、上記オキシム化合物が、式（８）： [I-63] The method according to any one of [I-1] to [I-62], wherein the oxime compound has the formula (8):
Figure JPOXMLDOC01-appb-C000022
　（式中、Ｒ４及びＲ５は、それぞれ独立して、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ２－Ｃ６）アルケニル；置換されていてもよい（Ｃ２－Ｃ６）アルキニル；（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）である製造方法、ただし、該当しない方法を除く。
Figure JPOXMLDOC01-appb-C000022
(wherein R 4 and R 5 are each independently a hydrogen atom; optionally substituted (C1-C6) alkyl; optionally substituted (C3-C6) cycloalkyl; substituted optionally substituted (C2-C6) alkynyl; (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl .), except for methods that are not applicable.
　〔Ｉ－６４〕　〔Ｉ－１〕から〔Ｉ－６３〕のいずれか１項に記載の方法であって、式（８）のＲ４及びＲ５が、それぞれ独立して、水素原子；（Ｃ１－Ｃ６）アルキル；（Ｃ３－Ｃ６）シクロアルキル；又は（Ｃ６－Ｃ１０）アリールである製造方法、ただし、該当しない方法を除く。 [I-64] The method according to any one of [I-1] to [I-63], wherein R 4 and R 5 in formula (8) are each independently a hydrogen atom; (C3-C6) cycloalkyl; or (C6-C10) aryl, except where not applicable.
　〔Ｉ－６５〕　〔Ｉ－１〕から〔Ｉ－６３〕のいずれか１項に記載の方法であって、式（８）が、アセトンオキシム、２－ブタノンオキシム、２－ペンタノンオキシム又は３－ペンタノンオキシムである製造方法、ただし、該当しない方法を除く。 [I-65] The method according to any one of [I-1] to [I-63], wherein formula (8) is acetone oxime, 2-butanone oxime, 2-pentanone oxime or 3 - Processes that are pentanone oximes, except those that are not applicable.
　〔Ｉ－６６〕　〔Ｉ－１〕から〔Ｉ－６３〕のいずれか１項に記載の方法であって、式（８）が、アセトンオキシム又は２－ブタノンオキシム（好ましくはアセトンオキシム）である製造方法、ただし、該当しない方法を除く。 [I-66] The method according to any one of [I-1] to [I-63], wherein formula (8) is acetone oxime or 2-butanone oxime (preferably acetone oxime) Manufacturing methods, except those not applicable.
　〔Ｉ－６７〕　〔Ｉ－１〕から〔Ｉ－６３〕のいずれか１項に記載の方法であって、式（８）のＲ４及びＲ５は互いに結合して環を形成する化合物である製造方法、ただし、該当しない方法を除く。 [I-67] The method according to any one of [I-1] to [I-63], wherein R 4 and R 5 in formula (8) are compounds that combine to form a ring. A method of manufacture, except a method that is not applicable.
　〔Ｉ－６８〕　〔Ｉ－１〕から〔Ｉ－６３〕のいずれか１項に記載の方法であって、式（８）が、シクロプロパノンオキシム、シクロブタノンオキシム、シクロペンタノンオキシム又はシクロヘキサノンオキシムである製造方法、ただし、該当しない方法を除く。 [I-68] The method according to any one of [I-1] to [I-63], wherein formula (8) is cyclopropanone oxime, cyclobutanone oxime, cyclopentanone oxime or cyclohexanone oxime except for methods that are not applicable.
　〔Ｉ－６９〕　〔Ｉ－１〕から〔Ｉ－６８〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）のオキシム化剤の使用量が、式（３）の化合物又は式（４）の化合物１モルに対して、ヒドロキシルアミン（ＮＨ２ＯＨ）に換算して０．９～１．５モルである製造方法、ただし、該当しない方法を除く。 [I-69] The method according to any one of [I-1] to [I-68], wherein the oximation of step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 0.9 to 1.5 mol in terms of hydroxylamine (NH 2 OH) per 1 mol of the compound of formula (3) or the compound of formula (4), provided that , except for methods not applicable.
　〔Ｉ－７０〕　〔Ｉ－１〕から〔Ｉ－６８〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）のオキシム化剤の使用量が、式（３）の化合物又は式（４）の化合物１モルに対して、ヒドロキシルアミン（ＮＨ２ＯＨ）に換算して１．０～１．３モルである製造方法、ただし、該当しない方法を除く。 [I-70] The method according to any one of [I-1] to [I-68], wherein the oximation of step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 1.0 to 1.3 mol in terms of hydroxylamine (NH 2 OH) per 1 mol of the compound of formula (3) or the compound of formula (4), provided that , except for methods not applicable.
　〔Ｉ－７１〕　〔Ｉ－１〕から〔Ｉ－７０〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が中和剤の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-71] The method according to any one of [I-1] to [I-70], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out in the presence of a neutralizing agent, except those not applicable.
　〔Ｉ－７２〕　〔Ｉ－１〕から〔Ｉ－７１〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の中和剤が、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム又は炭酸水素カリウムである製造方法、ただし、該当しない方法を除く。 [I-72] The method according to any one of [I-1] to [I-71], wherein the neutralization of step (ii), step (ii-a) or step (ii-b) Processes in which the agent is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, except those not applicable.
　〔Ｉ－７３〕　〔Ｉ－１〕から〔Ｉ－７１〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の中和剤が、水酸化ナトリウムである製造方法、ただし、該当しない方法を除く。 [I-73] The method according to any one of [I-1] to [I-71], wherein the neutralization of step (ii), step (ii-a) or step (ii-b) Processes in which the agent is sodium hydroxide, except those not applicable.
　〔Ｉ－７４〕　〔Ｉ－１〕から〔Ｉ－７３〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の中和剤の使用量が、式（３）の化合物又は式（４）の化合物１モルに対して、０．５～１．５モル（好ましくは０．９～１．５モル）である製造方法、ただし、該当しない方法を除く。 [I-74] The method according to any one of [I-1] to [I-73], wherein the neutralization of step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 0.5 to 1.5 mol (preferably 0.9 to 1.5 mol) per 1 mol of the compound of formula (3) or the compound of formula (4), However, excluding methods that do not apply.
　〔Ｉ－７５〕　〔Ｉ－１〕から〔Ｉ－７３〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の中和剤の使用量が、式（３）の化合物又は式（４）の化合物１モルに対して、１．０～１．３モルである製造方法、ただし、該当しない方法を除く。 [I-75] The method according to any one of [I-1] to [I-73], wherein the neutralization of step (ii), step (ii-a) or step (ii-b) A production method in which the amount of the agent used is 1.0 to 1.3 mol per 1 mol of the compound of formula (3) or the compound of formula (4), except for methods not applicable.
　〔Ｉ－７６〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が、芳香族炭化水素類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル、（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート及び（Ｃ１－Ｃ３）ジクロロアルカン）、エーテル類、ケトン類、ニトリル類、エステル類及びハロゲン化脂肪族炭化水素類から選ばれる溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-76] The method according to any one of [I-1] to [I-75], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is , aromatic hydrocarbons (preferably (C2-C4) alkanenitriles, (C1-C6) alkyl (C2-C4) carboxylates and (C1-C3) dichloroalkanes), ethers, ketones, nitriles, esters and halogenated aliphatic hydrocarbons, except those not applicable.
　〔Ｉ－７７〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が、ニトリル類、エステル類及びハロゲン化脂肪族炭化水素類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル、（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート及び（Ｃ１－Ｃ３）ジクロロアルカン）から選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）の溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-77] The method according to any one of [I-1] to [I-75], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is , nitriles, esters and halogenated aliphatic hydrocarbons (preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkane) Processes of manufacture carried out in the presence of one or more (preferably 1 or 2, more preferably 1) solvent, except for those processes which are not applicable.
　〔Ｉ－７８〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応の反応が溶媒の存在下で行われ、当該溶媒がエステル類又はハロゲン化脂肪族炭化水素類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート又は（Ｃ１－Ｃ３）ジクロロアルカン）である製造方法、ただし、該当しない方法を除く。 [I-78] The method according to any one of [I-1] to [I-75], wherein the reaction of step (ii), step (ii-a) or step (ii-b) The reaction is carried out in the presence of a solvent, and the solvent is an ester or halogenated aliphatic hydrocarbon (preferably (C1-C6) alkyl (C2-C4) carboxylate or (C1-C3) dichloroalkane) Manufacturing methods, except those not applicable.
　〔Ｉ－７９〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒がエステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）である製造方法、ただし、該当しない方法を除く。 [I-79] The method according to any one of [I-1] to [I-75], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Processes carried out in the presence of a solvent, wherein the solvent is an ester (preferably (C1-C6)alkyl(C2-C4)carboxylate), except for processes not applicable.
　〔Ｉ－８０〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、クロロトルエン、テトラヒドロフラン、ジブチルエーテル、アセトン、メチルイソブチルケトン、アセトニトリル、プロピオニトリル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸ペンチル及びジクロロメタンから選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）の存在下で行われる製造方法。 [I-80] The method according to any one of [I-1] to [I-75], wherein the reaction of step (ii), step (ii-a) or step (ii-b) is , toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, tetrahydrofuran, dibutyl ether, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, pentyl acetate and dichloromethane. A manufacturing method performed in the presence of one or more (preferably one or two, more preferably one).
　〔Ｉ－８１〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が、アセトニトリル、酢酸ブチル及びジクロロメタンから選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）の存在下で行われる製造方法。 [I-81] The method according to any one of [I-1] to [I-75], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is , acetonitrile, butyl acetate and dichloromethane (preferably 1 or 2, more preferably 1).
　〔Ｉ－８２〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が酢酸ブチル又はジクロロメタンである製造方法、ただし、該当しない方法を除く。 [I-82] The method according to any one of [I-1] to [I-75], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate or dichloromethane, except for processes not applicable.
　〔Ｉ－８３〕　〔Ｉ－１〕から〔Ｉ－７５〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が酢酸ブチルである製造方法、ただし、該当しない方法を除く。 [I-83] The method according to any one of [I-1] to [I-75], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate, except for processes not applicable.
　〔Ｉ－８４〕　〔Ｉ－１〕から〔Ｉ－８３〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が、水溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-84] The method according to any one of [I-1] to [I-83], wherein the reaction of step (ii), step (ii-a) or step (ii-b) is , manufacturing processes carried out in the presence of an aqueous solvent, except for those not applicable.
　〔Ｉ－８５〕　〔Ｉ－１〕から〔Ｉ－８４〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が０℃～８０℃で行われる製造方法、ただし、該当しない方法を除く。 [I-85] The method according to any one of [I-1] to [I-84], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out at 0°C to 80°C, except for those not applicable.
　〔Ｉ－８６〕　〔Ｉ－１〕から〔Ｉ－８４〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が１０℃～５０℃で行われる製造方法、ただし、該当しない方法を除く。 [I-86] The method according to any one of [I-1] to [I-84], wherein the reaction of step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out at 10°C to 50°C, except where not applicable.
　〔Ｉ－８７〕　〔Ｉ－１〕から〔Ｉ－８６〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の酸触媒が、鉱酸類、カルボン酸類、スルホン酸類からなる群より選ばれる１個以上（好ましくは１～３個、より好ましくは１又は２個、更に好ましくは１個）の酸触媒である製造方法、ただし、該当しない方法を除く。 [I-87] The method according to any one of [I-1] to [I-86], wherein the acid catalyst in step (iii), step (iii-a) or step (iii-b) is one or more (preferably 1 to 3, more preferably 1 or 2, still more preferably 1) acid catalyst selected from the group consisting of mineral acids, carboxylic acids, and sulfonic acids, provided that , except for methods not applicable.
　〔Ｉ－８８〕　〔Ｉ－１〕から〔Ｉ－８６〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の酸触媒が、硝酸、トリフルオロ酢酸、マレイン酸又はｐ－トルエンスルホン酸である製造方法、ただし、該当しない方法を除く。 [I-88] The method according to any one of [I-1] to [I-86], wherein the acid catalyst in step (iii), step (iii-a) or step (iii-b) is nitric acid, trifluoroacetic acid, maleic acid or p-toluenesulfonic acid, except those not applicable.
　〔Ｉ－８９〕　〔Ｉ－１〕から〔Ｉ－８６〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の酸触媒が、硝酸である製造方法、ただし、該当しない方法を除く。 [I-89] The method according to any one of [I-1] to [I-86], wherein the acid catalyst in step (iii), step (iii-a) or step (iii-b) is nitric acid, excluding those not applicable.
　〔Ｉ－９０〕　〔Ｉ－１〕から〔Ｉ－８６〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の酸触媒が、トリフルオロ酢酸である製造方法、ただし、該当しない方法を除く。 [I-90] The method according to any one of [I-1] to [I-86], wherein the acid catalyst in step (iii), step (iii-a) or step (iii-b) is trifluoroacetic acid, except for those not applicable.
　〔Ｉ－９１〕　〔Ｉ－１〕から〔Ｉ－８６〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の酸触媒が、マレイン酸である製造方法、ただし、該当しない方法を除く。 [I-91] The method according to any one of [I-1] to [I-86], wherein the acid catalyst in step (iii), step (iii-a) or step (iii-b) is maleic acid, except those not applicable.
　〔Ｉ－９２〕　〔Ｉ－１〕から〔Ｉ－９１〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の酸触媒の使用量が、式（５）の化合物又は式（６）の化合物１モルに対して、０．０１～０．６０モルである製造方法、ただし、該当しない方法を除く。 [I-92] The method according to any one of [I-1] to [I-91], wherein the acid catalyst in step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.01 to 0.60 mol per 1 mol of the compound of formula (5) or the compound of formula (6), except for methods not applicable.
　〔Ｉ－９３〕　〔Ｉ－１〕から〔Ｉ－９１〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の酸触媒の使用量が、式（５）の化合物又は式（６）の化合物１モルに対して、０．０５～０．４０モルである製造方法、ただし、該当しない方法を除く。 [I-93] The method according to any one of [I-1] to [I-91], wherein the acid catalyst in step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.05 to 0.40 mol per 1 mol of the compound of formula (5) or the compound of formula (6), except for methods not applicable.
　〔Ｉ－９４〕　〔Ｉ－１〕から〔Ｉ－９３〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、塩基触媒の非存在下で行われる製造方法。 [I-94] The method according to any one of [I-1] to [I-93], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , a process carried out in the absence of a base catalyst.
　〔Ｉ－９５〕　〔Ｉ－１〕から〔Ｉ－９３〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、塩基触媒の存在下で行われる製造方法。 [I-95] The method according to any one of [I-1] to [I-93], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , a production process carried out in the presence of a basic catalyst.
　〔Ｉ－９６〕　〔Ｉ－１〕から〔Ｉ－９５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、酸触媒の当量と同じ当量の塩基触媒の存在下で行われる製造方法。 [I-96] The method according to any one of [I-1] to [I-95], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , a process carried out in the presence of the same equivalent of a base catalyst as the equivalent of the acid catalyst.
　〔Ｉ－９７〕　〔Ｉ－１〕から〔Ｉ－９５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、酸触媒の当量よりも少ない当量の塩基触媒の存在下で行われる製造方法。 [I-97] The method according to any one of [I-1] to [I-95], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , a process carried out in the presence of an equivalent of a base catalyst that is less than the equivalent of the acid catalyst.
　〔Ｉ－９８〕　〔Ｉ－１〕から〔Ｉ－９５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、酸触媒１当量に対して、０（ゼロ）～１当量の塩基触媒の存在下で行われる製造方法。 [I-98] The method according to any one of [I-1] to [I-95], wherein the reaction of step (iii), step (iii-a) or step (iii-b) is , a production method carried out in the presence of 0 (zero) to 1 equivalent of a base catalyst with respect to 1 equivalent of an acid catalyst.
　〔Ｉ－９９〕　〔Ｉ－１〕から〔Ｉ－９５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、酸触媒１当量に対して、０（ゼロ）当量超１当量以下の塩基触媒の存在下で行われる製造方法。 [I-99] The method according to any one of [I-1] to [I-95], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , a production method carried out in the presence of a base catalyst of more than 0 (zero) equivalent and not more than 1 equivalent with respect to 1 equivalent of the acid catalyst.
　〔Ｉ－１００〕　〔Ｉ－１〕から〔Ｉ－９５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、酸触媒１当量に対して、０．１～０．５当量の塩基触媒の存在下で行われる製造方法。 [I-100] The method according to any one of [I-1] to [I-95], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , a production method carried out in the presence of 0.1 to 0.5 equivalents of a base catalyst with respect to 1 equivalent of an acid catalyst.
　〔Ｉ－１０１〕　〔Ｉ－１〕から〔Ｉ－９５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、酸触媒１当量に対して、０．２～０．４当量の塩基触媒の存在下で行われる製造方法。 [I-101] The method according to any one of [I-1] to [I-95], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , a production method carried out in the presence of 0.2 to 0.4 equivalents of a base catalyst with respect to 1 equivalent of an acid catalyst.
　〔Ｉ－１０２〕　〔Ｉ－１〕から〔Ｉ－１０１〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の塩基触媒が、第２級アミンである製造方法。 [I-102] The method according to any one of [I-1] to [I-101], wherein the base catalyst in step (iii), step (iii-a) or step (iii-b) is a secondary amine.
　〔Ｉ－１０３〕　〔Ｉ－１〕から〔Ｉ－１０１〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の塩基触媒が、Ｎ－メチルアニリンである製造方法。 [I-103] The method according to any one of [I-1] to [I-101], wherein the base catalyst in step (iii), step (iii-a) or step (iii-b) is N-methylaniline.
　〔Ｉ－１０４〕　〔Ｉ－１〕から〔Ｉ－１０３〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の塩基触媒の使用量が、式（５）の化合物又は式（６）の化合物１モルに対して、０．０１～０．６０モルである製造方法。 [I-104] The method according to any one of [I-1] to [I-103], wherein the base catalyst in step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.01 to 0.60 mol per 1 mol of the compound of formula (5) or the compound of formula (6).
　〔Ｉ－１０５〕　〔Ｉ－１〕から〔Ｉ－１０３〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の塩基触媒の使用量が、式（５）の化合物又は式（６）の化合物１モルに対して、０．０５～０．４０モルであるである製造方法。 [I-105] The method according to any one of [I-1] to [I-103], wherein the base catalyst in step (iii), step (iii-a) or step (iii-b) is used in an amount of 0.05 to 0.40 mol per 1 mol of the compound of formula (5) or the compound of formula (6).
　〔Ｉ－１０６〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、芳香族炭化水素類、エーテル類、ケトン類、ニトリル類、エステル類及びハロゲン化脂肪族炭化水素類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル、（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート及び（Ｃ１－Ｃ３）ジクロロアルカン）から選ばれる溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-106] The method according to any one of [I-1] to [I-105], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , aromatic hydrocarbons, ethers, ketones, nitriles, esters and halogenated aliphatic hydrocarbons (preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkanes), except those not applicable.
　〔Ｉ－１０７〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、ニトリル類、エステル類及びハロゲン化脂肪族炭化水素類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル、（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート及び（Ｃ１－Ｃ３）ジクロロアルカン）から選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）の溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-107] The method according to any one of [I-1] to [I-105], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , nitriles, esters and halogenated aliphatic hydrocarbons (preferably (C2-C4) alkanenitrile, (C1-C6) alkyl (C2-C4) carboxylate and (C1-C3) dichloroalkane) Processes of manufacture carried out in the presence of one or more (preferably 1 or 2, more preferably 1) solvent, except for those processes which are not applicable.
　〔Ｉ－１０８〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応の反応が溶媒の存在下で行われ、当該溶媒がエステル類又はハロゲン化脂肪族炭化水素類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート又は（Ｃ１－Ｃ３）ジクロロアルカン）である製造方法、ただし、該当しない方法を除く。 [I-108] The method according to any one of [I-1] to [I-105], wherein the reaction of step (iii), step (iii-a) or step (iii-b) The reaction is carried out in the presence of a solvent, and the solvent is an ester or halogenated aliphatic hydrocarbon (preferably (C1-C6) alkyl (C2-C4) carboxylate or (C1-C3) dichloroalkane) Manufacturing methods, except those not applicable.
　〔Ｉ－１０９〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒がエステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）である製造方法、ただし、該当しない方法を除く。 [I-109] The method according to any one of [I-1] to [I-105], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is Processes of preparation carried out in the presence of a solvent, wherein the solvent is an ester (preferably (C1-C6)alkyl(C2-C4)carboxylate), except for processes not applicable.
　〔Ｉ－１１０〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、クロロトルエン、テトラヒドロフラン、ジブチルエーテル、アセトン、メチルイソブチルケトン、アセトニトリル、プロピオニトリル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸ペンチル及びジクロロメタンから選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）の存在下で行われる製造方法。 [I-110] The method according to any one of [I-1] to [I-105], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, tetrahydrofuran, dibutyl ether, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, pentyl acetate and dichloromethane. A manufacturing method performed in the presence of one or more (preferably one or two, more preferably one).
　〔Ｉ－１１１〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、アセトニトリル、酢酸ブチル及びジクロロメタンから選ばれる１個以上（好ましくは１又は２個、更に好ましくは１個）の存在下で行われる製造方法。 [I-111] The method according to any one of [I-1] to [I-105], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , acetonitrile, butyl acetate and dichloromethane (preferably 1 or 2, more preferably 1).
　〔Ｉ－１１２〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が酢酸ブチル又はジクロロメタンである製造方法、ただし、該当しない方法を除く。 [I-112] The method according to any one of [I-1] to [I-105], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate or dichloromethane, except for processes not applicable.
　〔Ｉ－１１３〕　〔Ｉ－１〕から〔Ｉ－１０５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が酢酸ブチルである製造方法、ただし、該当しない方法を除く。 [I-113] The method according to any one of [I-1] to [I-105], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is Processes carried out in the presence of a solvent, where the solvent is butyl acetate, except for processes not applicable.
　〔Ｉ－１１４〕　〔Ｉ－１〕から〔Ｉ－１１３〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、水溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-114] The method according to any one of [I-1] to [I-113], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , manufacturing processes carried out in the presence of an aqueous solvent, except for those not applicable.
　〔Ｉ－１１５〕　〔Ｉ－１〕から〔Ｉ－１１４〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、無溶媒で行われる製造方法、ただし、該当しない方法を除く。 [I-115] The method according to any one of [I-1] to [I-114], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , solvent-free manufacturing methods, except those not applicable.
　〔Ｉ－１１６〕　〔Ｉ－１〕から〔Ｉ－１１５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、－３０℃～１６０℃で行われる製造方法、ただし、該当しない方法を除く。 [I-116] The method according to any one of [I-1] to [I-115], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , -30°C to 160°C, except for those not applicable.
　〔Ｉ－１１７〕　〔Ｉ－１〕から〔Ｉ－１１５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、－１０℃～１２０℃で行われる製造方法、ただし、該当しない方法を除く。 [I-117] The method according to any one of [I-1] to [I-115], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , -10°C to 120°C, except for those not applicable.
　〔Ｉ－１１８〕　〔Ｉ－１〕から〔Ｉ－１１５〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、０℃～１００℃で行われる製造方法、ただし、該当しない方法を除く。 [I-118] The method according to any one of [I-1] to [I-115], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is , manufacturing processes carried out at 0° C. to 100° C., except for those not applicable.
　〔Ｉ－１１９〕　〔Ｉ－１〕から〔Ｉ－１１８〕のいずれか１項に記載の方法であって、工程（ｉ）で製造した式（３）の化合物又は式（４）の化合物を単離することなく、工程（ｉｉ）の反応を行う製造方法、ただし、該当しない方法を除く。 [I-119] The method according to any one of [I-1] to [I-118], wherein the compound of formula (3) or the compound of formula (4) produced in step (i) is Processes of preparation in which the reaction of step (ii) is carried out without isolation, except where not applicable.
　〔Ｉ－１２０〕　〔Ｉ－１〕から〔Ｉ－１１８〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）で製造した式（３）の化合物又は式（４）の化合物を単離することなく、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応を行う製造方法、ただし、該当しない方法を除く。 [I-120] The method according to any one of [I-1] to [I-118], produced in step (i), step (ia) or step (ib) Processes for preparation in which the reaction of step (ii), step (ii-a) or step (ii-b) is carried out without isolating the compound of formula (3) or the compound of formula (4), provided that the method is not applicable except for.
　〔Ｉ－１２１〕　〔Ｉ－１〕から〔Ｉ－１１８〕のいずれか１項に記載の方法であって、工程（ｉｉ）で製造した式（５）の化合物又は式（６）の化合物を単離することなく、工程（ｉｉｉ）の反応を行う製造方法、ただし、該当しない方法を除く。 [I-121] The method according to any one of [I-1] to [I-118], wherein the compound of formula (5) or the compound of formula (6) produced in step (ii) is Processes of preparation in which the reaction of step (iii) is carried out without isolation, except for those processes that are not applicable.
　〔Ｉ－１２２〕　〔Ｉ－１〕から〔Ｉ－１１８〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）で製造した式（５）の化合物又は式（６）の化合物を単離することなく、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応を行う製造方法、ただし、該当しない方法を除く。 [I-122] The method according to any one of [I-1] to [I-118], produced in step (ii), step (ii-a) or step (ii-b) Processes in which the reaction of step (iii), step (iii-a) or step (iii-b) is carried out without isolating the compound of formula (5) or the compound of formula (6), provided that the method is not applicable except for.
　〔Ｉ－１２３〕　〔Ｉ－１〕から〔Ｉ－１１８〕のいずれか１項に記載の方法であって、生成物を単離することなく次工程を行う製造方法、ただし、該当しない方法を除く。 [I-123] A production method according to any one of [I-1] to [I-118], wherein the next step is carried out without isolating the product, provided that the method not applicable except.
　〔Ｉ－１２４〕　〔Ｉ－１〕から〔Ｉ－１２３〕のいずれか１項に記載の方法であって、工程（ｉ）及び工程（ｉｉ）の反応をワンポットで行う製造方法、ただし、該当しない方法を除く。 [I-124] The production method according to any one of [I-1] to [I-123], wherein the reactions of step (i) and step (ii) are performed in one pot, provided that applicable Except how not.
　〔Ｉ－１２５〕　〔Ｉ－１〕から〔Ｉ－１２３〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応とそれぞれ次工程の反応をワンポットで行う製造方法、ただし、該当しない方法を除く。 [I-125] The method according to any one of [I-1] to [I-123], wherein the reaction of step (i), step (ia) or step (ib) and Manufacturing methods in which each reaction in the next step is performed in one pot, except for methods that do not apply.
　〔Ｉ－１２６〕　〔Ｉ－１〕から〔Ｉ－１２３〕のいずれか１項に記載の方法であって、工程（ｉｉ）及び工程（ｉｉｉ）の反応をワンポットで行う製造方法、ただし、該当しない方法を除く。 [I-126] The production method according to any one of [I-1] to [I-123], wherein the reactions of steps (ii) and (iii) are performed in one pot, provided that applicable Except how not.
　〔Ｉ－１２７〕　〔Ｉ－１〕から〔Ｉ－１２３〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応とそれぞれ次工程の反応をワンポットで行う製造方法、ただし、該当しない方法を除く。 [I-127] The method according to any one of [I-1] to [I-123], wherein the reaction of step (ii), step (ii-a) or step (ii-b) and Manufacturing methods in which each reaction in the next step is performed in one pot, except for methods that do not apply.
　〔Ｉ－１２８〕　〔Ｉ－１〕から〔Ｉ－１２７〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応と、対応する工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が、同一の溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-128] The method according to any one of [I-1] to [I-127], wherein the reaction of step (i), step (ia) or step (ib) and , the reaction of the corresponding step (ii), step (ii-a) or step (ii-b) are carried out in the presence of the same solvent, except for those methods not applicable.
　〔Ｉ－１２９〕　〔Ｉ－１〕から〔Ｉ－１２７〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応と、対応する工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が、同一の溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-129] The method according to any one of [I-1] to [I-127], wherein the reaction of step (ii), step (ii-a) or step (ii-b) and , the reaction of the corresponding step (iii), step (iii-a) or step (iii-b) are carried out in the presence of the same solvent, except for those methods not applicable.
　〔Ｉ－１３０〕　〔Ｉ－１〕から〔Ｉ－１２７〕のいずれか１項に記載の方法であって、全ての工程の反応が、同一の溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-130] The production method according to any one of [I-1] to [I-127], wherein the reactions in all steps are carried out in the presence of the same solvent, provided that Except for methods that do not apply.
　〔Ｉ－１３１〕　〔Ｉ－１〕から〔Ｉ－１３０〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応と、対応する工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応において、使用される有機溶媒が同じである製造方法、ただし、該当しない方法を除く。 [I-131] The method according to any one of [I-1] to [I-130], wherein the reaction of step (i), step (ia) or step (ib) and , the corresponding reaction of step (ii), step (ii-a) or step (ii-b), the same organic solvent is used, except for those methods that are not applicable.
　〔Ｉ－１３２〕　〔Ｉ－１〕から〔Ｉ－１３０〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応と、対応する工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応において、使用される有機溶媒が同じである製造方法、ただし、該当しない方法を除く。 [I-132] The method according to any one of [I-1] to [I-130], wherein the reaction of step (ii), step (ii-a) or step (ii-b) and , the corresponding reaction of step (iii), step (iii-a) or step (iii-b), the same organic solvent is used, except for those not applicable.
　〔Ｉ－１３３〕　〔Ｉ－１〕から〔Ｉ－１３０〕のいずれか１項に記載の方法であって、全ての工程の反応において、使用される有機溶媒が同じである製造方法、ただし、該当しない方法を除く。 [I-133] The production method according to any one of [I-1] to [I-130], wherein the same organic solvent is used in the reactions in all the steps, provided that Except for methods that do not apply.
　〔Ｉ－１３４〕　〔Ｉ－１〕から〔Ｉ－１３３〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が水溶媒の存在下で行われる製造方法、ただし、該当しない方法を除く。 [I-134] The method according to any one of [I-1] to [I-133], wherein the reaction in step (i), step (ia) or step (ib) is Manufacturing processes carried out in the presence of an aqueous solvent, except those not applicable.
　〔Ｉ－１３５〕　〔Ｉ－１〕から〔Ｉ－１３３〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が水である製造方法、ただし、該当しない方法を除く。 [I-135] The method according to any one of [I-1] to [I-133], wherein the reaction in step (i), step (ia) or step (ib) is Manufacturing processes carried out in the presence of a solvent, where the solvent is water, except for those processes that are not applicable.
　〔Ｉ－１３６〕　〔Ｉ－１〕から〔Ｉ－１３３〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が水を含む製造方法、ただし、該当しない方法を除く。 [I-136] The method according to any one of [I-1] to [I-133], wherein the reaction in step (i), step (ia) or step (ib) is Manufacturing processes carried out in the presence of a solvent, the solvent containing water, except for those processes not applicable.
　〔Ｉ－１３７〕　〔Ｉ－１〕から〔Ｉ－１３６〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が水である製造方法、ただし、該当しない方法を除く。 [I-137] The method according to any one of [I-1] to [I-136], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out in the presence of a solvent, where the solvent is water, except for those processes that are not applicable.
　〔Ｉ－１３８〕　〔Ｉ－１〕から〔Ｉ－１３６〕のいずれか１項に記載の方法であって、工程（ｉｉ）、工程（ｉｉ－ａ）又は工程（ｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が水を含む製造方法、ただし、該当しない方法を除く。 [I-138] The method according to any one of [I-1] to [I-136], wherein the reaction in step (ii), step (ii-a) or step (ii-b) is Manufacturing processes carried out in the presence of a solvent, the solvent containing water, except for those processes not applicable.
　〔Ｉ－１３９〕　〔Ｉ－１〕から〔Ｉ－１３８〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が水である製造方法、ただし、該当しない方法を除く。 [I-139] The method according to any one of [I-1] to [I-138], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is Manufacturing processes carried out in the presence of a solvent, where the solvent is water, except for those processes that are not applicable.
　〔Ｉ－１４０〕　〔Ｉ－１〕から〔Ｉ－１３８〕のいずれか１項に記載の方法であって、工程（ｉｉｉ）、工程（ｉｉｉ－ａ）又は工程（ｉｉｉ－ｂ）の反応が溶媒の存在下で行われ、当該溶媒が水を含む製造方法、ただし、該当しない方法を除く。 [I-140] The method according to any one of [I-1] to [I-138], wherein the reaction in step (iii), step (iii-a) or step (iii-b) is Manufacturing processes carried out in the presence of a solvent, the solvent containing water, except for those processes not applicable.
　〔Ｉ－１４１〕　〔Ｉ－１〕から〔Ｉ－１４０〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸素が、酸素発生剤（このましくは硝酸）に由来する製造方法、ただし、該当しない方法を除く。 [I-141] The method according to any one of [I-1] to [I-140], wherein oxygen in step (i), step (ia) or step (ib) is , production methods derived from oxygen generating agents (preferably nitric acid), excluding non-applicable methods.
　〔Ｉ－１４２〕〔Ｉ－１〕から〔Ｉ－１４０〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の酸素が、酸素発生剤（このましくは硝酸）から発生する製造方法、ただし、該当しない方法を除く。 [I-142] The method according to any one of [I-1] to [I-140], wherein oxygen in step (i), step (ia) or step (ib) is , production methods generated from an oxygen generating agent (preferably nitric acid), except those not applicable.
　〔Ｉ－１４３〕　〔Ｉ－１〕から〔Ｉ－１４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が、酸素含有ガスを導入することにより行われる製造方法、ただし、該当しない方法を除く。 [I-143] The method according to any one of [I-1] to [I-142], wherein the reaction in step (i), step (ia) or step (ib) is , production processes carried out by introducing an oxygen-containing gas, except for those not applicable.
　〔Ｉ－１４４〕　〔Ｉ－１〕から〔Ｉ－１４２〕のいずれか１項に記載の方法であって、工程（ｉ）、工程（ｉ－ａ）又は工程（ｉ－ｂ）の反応が、酸素を導入することにより行われる製造方法、ただし、該当しない方法を除く。 [I-144] The method according to any one of [I-1] to [I-142], wherein the reaction in step (i), step (ia) or step (ib) is , production processes carried out by introducing oxygen, except for those not applicable.
　〔Ｉ－１４５〕　〔Ｉ－１〕から〔Ｉ－１４４〕のいずれか１項に記載の方法であって、Ｒ１、Ｒ２及びＲ３がメチルである製造方法、ただし、該当しない方法を除く。 [I-145] The production method according to any one of [I-1] to [I-144], wherein R 1 , R 2 and R 3 are methyl, provided that the method not applicable except.
　〔Ｉ－１４６〕　〔Ｉ－１〕から〔Ｉ－１４４〕のいずれか１項に記載の方法であって、Ｒ１及びＲ２がメチルである製造方法。 [I-146] The production method according to any one of [I-1] to [I-144], wherein R 1 and R 2 are methyl.
　〔ＩＩ－１〕　　式（７）の化合物の製造方法であって、以下の工程を含む製造方法；
　工程（ｉ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）の化合物又は式（２）の化合物を反応させて、それぞれ対応する式（３）の化合物又は式（４）の化合物を得る： [II-1] A method for producing a compound of formula (7), comprising the following steps;
Step (i) reacting the compound of formula (1) or the compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give the corresponding compound of formula (3) or formula ( 4) to obtain the compound:
Figure JPOXMLDOC01-appb-C000023
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）。
　工程（ｉｉ）　式（３）の化合物又は式（４）の化合物をオキシム化剤と反応させて、それぞれ対応する式（５）の化合物又は式（６）の化合物を得る：
Figure JPOXMLDOC01-appb-C000023
(wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. ).
Step (ii) reacting a compound of formula (3) or a compound of formula (4) with an oximating agent to give the corresponding compound of formula (5) or compound of formula (6) respectively:
Figure JPOXMLDOC01-appb-C000024
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）。
　工程（ｉｉｉ）　酸触媒の存在下で、又は酸触媒と塩基触媒の存在下で、式（５）の化合物又は式（６）の化合物を反応させて、式（７）の化合物を得る：
Figure JPOXMLDOC01-appb-C000024
(wherein R 1 , R 2 and R 3 are as defined above).
Step (iii) reacting a compound of formula (5) or a compound of formula (6) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
Figure JPOXMLDOC01-appb-C000025
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）。
　〔ＩＩ－２〕　　〔ＩＩ－１〕に記載の製造方法であって、金属触媒が鉄触媒又は銅触媒である製造方法。
　〔ＩＩ－３〕　　〔ＩＩ－１〕に記載の製造方法であって、金属触媒が塩化鉄（ＩＩＩ）である製造方法。
　〔ＩＩ－４〕　　〔ＩＩ－１〕に記載の製造方法であって、ニトロキシルラジカル化合物が４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシルである製造方法。
　〔ＩＩ－５〕　　〔ＩＩ－１〕に記載の製造方法であって、Ｒ１、Ｒ２及びＲ３がメチルである製造方法。
　〔ＩＩ－６〕　　式（３）の化合物又は式（４）の化合物の製造方法であって、金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）の化合物又は式（２）の化合物を反応させて、それぞれ対応する式（３）の化合物又は式（４）の化合物を得ることを含む製造方法：
Figure JPOXMLDOC01-appb-C000025
(wherein R 1 , R 2 and R 3 are as defined above).
[II-2] The production method according to [II-1], wherein the metal catalyst is an iron catalyst or a copper catalyst.
[II-3] The production method according to [II-1], wherein the metal catalyst is iron (III) chloride.
[II-4] The production method according to [II-1], wherein the nitroxyl radical compound is 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl.
[II-5] The production method according to [II-1], wherein R 1 , R 2 and R 3 are methyl.
[II-6] A method for producing a compound of formula (3) or a compound of formula (4), comprising: producing a compound of formula (1) or formula ( A process comprising reacting the compound of 2) to obtain the corresponding compound of formula (3) or compound of formula (4), respectively:
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）。
〔ＩＩ－７〕　　〔ＩＩ－６〕に記載の製造方法であって、金属触媒が鉄触媒又は銅触媒である製造方法。
〔ＩＩ－８〕　　〔ＩＩ－６〕に記載の製造方法であって、金属触媒が塩化鉄（ＩＩＩ）である製造方法。 (wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. ).
[II-7] The production method according to [II-6], wherein the metal catalyst is an iron catalyst or a copper catalyst.
[II-8] The production method according to [II-6], wherein the metal catalyst is iron (III) chloride.
　本発明により式（７）の化合物の新規な製造方法が提供される。本発明によれば、効率がよく工業的に好ましい式（７）の化合物の製造方法が提供される。また、本発明によれば、簡単な操作により、高い収率で式（７）の化合物を製造できる。
　加えて、本発明により式（３）の化合物又は式（４）の化合物の新規な製造方法が提供される。本発明によれば、より工業的に好ましい、式（３）の化合物又は式（４）の化合物の製造方法が提供される。また、本発明によれば、簡単な操作により、副生成物を抑制でき、高い収率で式（３）の化合物又は式（４）の化合物を製造できる。 The present invention provides a novel method for preparing compounds of formula (7). According to the present invention, an efficient and industrially preferable method for producing the compound of formula (7) is provided. Moreover, according to the present invention, the compound of formula (7) can be produced in a high yield by a simple operation.
In addition, the present invention provides novel methods for preparing compounds of formula (3) or compounds of formula (4). According to the present invention, a more industrially preferable method for producing the compound of formula (3) or the compound of formula (4) is provided. Moreover, according to the present invention, by-products can be suppressed by a simple operation, and the compound of formula (3) or the compound of formula (4) can be produced in high yield.
　更に、本発明により、副生成物及び／又は廃棄物の生成を抑制でき、そして原子効率を改善できる。結果として、本発明によりピロキサスルホン等の除草剤の製造中間体を簡便且つ安価に工業的規模で製造できる方法が提供される。従って、本発明の方法は、工業的に好ましく、経済的であり、そして環境にも優しく、高い工業的な利用価値を有する。 Furthermore, the present invention can reduce the production of by-products and/or waste and improve atomic efficiency. As a result, the present invention provides a method for producing a production intermediate for a herbicide such as pyroxasulfone easily and inexpensively on an industrial scale. Therefore, the method of the present invention is industrially preferable, economical, environmentally friendly, and has high industrial utility value.
図１は、フロー反応を実施した実施例１１で用いた本発明の反応装置の概要を模式的に示したものである。本発明の製造方法を実施するための反応装置の一例の模式図である。FIG. 1 schematically shows the outline of the reactor of the present invention used in Example 11 in which the flow reaction was carried out. BRIEF DESCRIPTION OF THE DRAWINGS It is a schematic diagram of an example of the reaction apparatus for enforcing the manufacturing method of this invention. 図２は、フロー反応を実施した実施例５５で用いた本発明の反応装置の概要を模式的に示したものである。本発明の製造方法を実施するための反応装置の一例の模式図である。FIG. 2 schematically shows the outline of the reactor of the present invention used in Example 55 in which the flow reaction was carried out. BRIEF DESCRIPTION OF THE DRAWINGS It is a schematic diagram of an example of the reaction apparatus for enforcing the manufacturing method of this invention. 図３は、フロー反応を実施した実施例５６で用いた本発明の反応装置の概要を模式的に示したものである。本発明の製造方法を実施するための反応装置の一例の模式図である。FIG. 3 schematically shows the outline of the reactor of the present invention used in Example 56 in which the flow reaction was carried out. BRIEF DESCRIPTION OF THE DRAWINGS It is a schematic diagram of an example of the reaction apparatus for enforcing the manufacturing method of this invention.
　以下、本発明について詳細に説明する。 The present invention will be described in detail below.
　本明細書において用いられる用語及び記号について以下に説明する。 The terms and symbols used in this specification are explained below.
　ハロゲン原子の例は、フッ素原子、塩素原子、臭素原子及びヨウ素原子を含む。 Examples of halogen atoms include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms.
　（Ｃａ－Ｃｂ）は、炭素原子数がａ～ｂ個であることを意味する。例えば、「（Ｃ１－Ｃ４）アルキル」の「（Ｃ１－Ｃ４）」は、アルキルの炭素原子数が１～４であることを意味する。 (Ca-Cb) means that the number of carbon atoms is a to b. For example, "(C1-C4)" in "(C1-C4)alkyl" means that the alkyl has 1 to 4 carbon atoms.
　本明細書中、「アルキル」のような一般的用語は、ブチル及びｔｅｒｔ－ブチルのような直鎖及び分枝鎖の両方を含むと理解される。しかしながら、「ブチル」のような具体的な用語が使用された場合は、これは「ノルマルブチル」、すなわち「ｎ－ブチル」に対して特異的である。言い換えれば、具体的な用語「ブチル」は直鎖の「ノルマルブチル」を意味する。そして「ｔｅｒｔ－ブチル」のような分枝鎖異性体は、意図した場合に具体的に言及される。 In this specification, generic terms such as "alkyl" are understood to include both straight and branched chains such as butyl and tert-butyl. However, when a specific term such as "butyl" is used, it is specific to "normal butyl" or "n-butyl". In other words, the specific term "butyl" means straight chain "normal butyl". and branched-chain isomers such as "tert-butyl" are specifically mentioned where intended.
　接頭語「ｎ－」、「ｓ－」及び「ｓｅｃ－」、「ｉ－」、「ｔ－」及び「ｔｅｒｔ－」、［ｎｅｏ－］、「ｃ－」及び「ｃｙｃ－」、「ｏ－」、「ｍ－」、並びに「ｐ－」は、それらの以下の通常の意味を有する：ノルマル、セカンダリー（「ｓ－」及び「ｓｅｃ－」）、イソ、ターシャリー（「ｔ－」及び「ｔｅｒｔ－」）、ネオ、シクロ（「ｃ－」及び「ｃｙｃ－」）、オルト、メタ、並びにパラ。 The prefixes "n-", "s-" and "sec-", "i-", "t-" and "tert-", [neo-], "c-" and "cyc-", "o-" ”, “m-”, and “p-” have their usual meanings: normal, secondary (“s-” and “sec-”), iso, tertiary (“t-” and “ tert-"), neo, cyclo ("c-" and "cyc-"), ortho, meta, and para.
本明細書中、以下の略語が使用されることがある：
「Ｍｅ」はメチルを意味する。
「Ｅｔ」はエチルを意味する。
「Ｐｒ」、「ｎ－Ｐｒ」及び「Ｐｒ－ｎ」はプロピル（すなわち、ノルマルプロピル）を意味する。
「ｉ－Ｐｒ」及び「Ｐｒ－ｉ」はイソプロピルを意味する。
「Ｂｕ」、「ｎ－Ｂｕ」及び「Ｂｕ－ｎ」はブチル（すなわち、ノルマルブチル）を意味する。
「ｓ－Ｂｕ」及び「Ｂｕ－ｓ」はｓｅｃ－ブチルを意味する。
「ｉ－Ｂｕ」及び「Ｂｕ－ｉ」はイソブチルを意味する。
「ｔ－Ｂｕ」及び「Ｂｕ－ｔ」はｔｅｒｔ－ブチルを意味する。
「Ｐｅｎ」、「ｎ－Ｐｅｎ」および「Ｐｅｎ－ｎ」はペンチル（すなわち、ノルマルペンチル）を意味する。
「Ｈｅｘ」、「ｎ－Ｈｅｘ」および「Ｈｅｘ－ｎ」はヘキシル（すなわち、ノルマルヘキシル）を意味する。
「Ｄｅｃ」、「ｎ－Ｄｅｃ」および「Ｄｅｃ－ｎ」はデシル（すなわち、ノルマルデシル）を意味する。
「ｃ－Ｐｒ」および「Ｐｒ－ｃ」はシクロプロピルを意味する。
「ｃ－Ｂｕ」および「Ｂｕ－ｃ」はシクロブチルを意味する。
「ｃ－Ｐｅｎ」および「Ｐｅｎ－ｃ」はシクロペンチルを意味する。
「ｃ－Ｈｅｘ」および「Ｈｅｘ－ｃ」はシクロヘキシルを意味する。
「Ｐｈ」はフェニルを意味する。
「Ｂｎ」はベンジルを意味する。 The following abbreviations may be used herein:
"Me" means methyl.
"Et" means ethyl.
"Pr", "n-Pr" and "Pr-n" mean propyl (ie normal propyl).
"i-Pr" and "Pr-i" mean isopropyl.
"Bu", "n-Bu" and "Bu-n" mean butyl (ie normal butyl).
"s-Bu" and "Bu-s" mean sec-butyl.
"i-Bu" and "Bu-i" mean isobutyl.
"t-Bu" and "Bu-t" mean tert-butyl.
"Pen", "n-Pen" and "Pen-n" mean pentyl (ie, normal pentyl).
"Hex", "n-Hex" and "Hex-n" mean hexyl (ie normal hexyl).
"Dec", "n-Dec" and "Dec-n" mean decyl (ie, normal decyl).
"c-Pr" and "Pr-c" mean cyclopropyl.
"c-Bu" and "Bu-c" mean cyclobutyl.
"c-Pen" and "Pen-c" mean cyclopentyl.
"c-Hex" and "Hex-c" mean cyclohexyl.
"Ph" means phenyl.
"Bn" means benzyl.
「Ａｃ」はアセチル（ＣＨ３ＣＯ－）を意味する。 "Ac" means acetyl ( CH3CO- ).
　（Ｃ１－Ｃ６）アルキルは、１～６個の炭素原子を有する直鎖又は分岐鎖のアルキルを意味する。（Ｃ１－Ｃ６）アルキルの例は、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル等を含むが、これらに限定されない。 (C1-C6) alkyl means a linear or branched alkyl having 1 to 6 carbon atoms. Examples of (C1-C6)alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
　（Ｃ１－Ｃ４）アルキルは、１～４個の炭素原子を有する直鎖又は分岐鎖のアルキルを意味する。（Ｃ１－Ｃ４）アルキルの例は、上記の（Ｃ１－Ｃ６）アルキルの例のうちの適切な例である。 (C1-C4) alkyl means a linear or branched alkyl having 1 to 4 carbon atoms. Examples of (C1-C4)alkyl are suitable examples of the above examples of (C1-C6)alkyl.
　（Ｃ１－Ｃ３）アルキル及び類似の表現は、同様に理解される、 (C1-C3) alkyl and similar expressions are similarly understood,
　（Ｃ２－Ｃ４）アルカンニトリルは、（Ｃ１－Ｃ３）アルキル－ＣＮを意味する。（Ｃ２－Ｃ４）アルカンニトリルの例は、アセトニトリル、プロピオニトリル、ブチロニトリル、イソブチロニトリルである。例えば、Ｃ２アルカンニトリルはアセトニトリルである。例えば、プロピオニトリルはＣ３アルカンニトリルである。 (C2-C4) alkanenitrile means (C1-C3) alkyl-CN. Examples of (C2-C4)alkanenitriles are acetonitrile, propionitrile, butyronitrile, isobutyronitrile. For example, a C2 alkanenitrile is acetonitrile. For example, propionitrile is a C3 alkanenitrile.
　（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレートは、（Ｃ１－Ｃ３）アルキル－ＣＯＯ－（Ｃ１－Ｃ６）アルキル、すなわち、（Ｃ１－Ｃ３）アルキル－Ｃ（＝Ｏ）－Ｏ－（Ｃ１－Ｃ６）アルキルを意味する。（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレートの例は、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル及びその異性体、酢酸ペンチル及びその異性体、酢酸ヘキシル及びその異性体、プロピオン酸エチル、プロピオン酸プロピル、プロピオン酸イソプロピル、プロピオン酸ブチル及びその異性体等を含むが、これらに限定されない。例えば、酢酸ブチルは（Ｃ４）アルキル（Ｃ２）カルボキシレート（すなわち、Ｃ４アルキルＣ２カルボキシレート）である。 (C1-C6)alkyl (C2-C4)carboxylates are (C1-C3)alkyl-COO-(C1-C6)alkyl, i.e. (C1-C3)alkyl-C(=O)-O-(C1 —C6) means alkyl. Examples of (C1-C6)alkyl(C2-C4)carboxylates are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers, Including, but not limited to, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate and isomers thereof. For example, butyl acetate is a (C4) alkyl (C2) carboxylate (ie, a C4 alkyl C2 carboxylate).
　（Ｃ１－Ｃ３）ジクロロアルカンの例は、ジクロロメタン、１，２－ジクロロエタン等を含むが、これらに限定されない。例えば、ジクロロメタンはＣ１ジクロロアルカンである。 Examples of (C1-C3) dichloroalkanes include, but are not limited to, dichloromethane, 1,2-dichloroethane, and the like. For example, dichloromethane is a C1 dichloroalkane.
　一つの態様では、芳香族炭化水素誘導体類の好ましい例は、（Ｃ１－Ｃ３）アルキル及び塩素原子からなる群から選択される１個～３個の置換基（好ましくは１個又は２個）の置換基により置換されていてもよいベンゼンであり、より好ましい例は、トルエン、キシレン、クロロベンゼン又はジクロロベンゼンであり、更に好ましい例は、トルエン又はキシレンである。前記は本発明の全ての場合に適用してもよい。 In one aspect, preferred examples of aromatic hydrocarbon derivatives are those having 1 to 3 substituents (preferably 1 or 2) selected from the group consisting of (C1-C3)alkyl and chlorine atoms. It is benzene which may be substituted with a substituent, more preferred examples are toluene, xylene, chlorobenzene or dichlorobenzene, and further preferred examples are toluene or xylene. The foregoing may apply to all cases of the invention.
　（Ｃ３－Ｃ６）シクロアルキルは、３～６個の炭素原子を有するシクロアルキルを意味する。（Ｃ３－Ｃ６）シクロアルキルの例は、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルである。 (C3-C6) cycloalkyl means cycloalkyl having 3 to 6 carbon atoms. Examples of (C3-C6)cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
　（Ｃ６－Ｃ１０）アリールの例は、フェニル、１－ナフチル、及び２－ナフチルである。
　（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルは、（Ｃ６－１０）アリールにより置換されている（Ｃ１－Ｃ４アルキル）を意味する（ここで、Ｃ６－１０アリール部分およびＣ１－Ｃ４アルキル部分は上記の定義と同じ意味を有する。）。（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルの例は、ベンジル、１－フェニルエチル、２－フェニルエチル、３－フェニルプロピル、４－フェニルブチル、ナフタレン－１－イルメチル、ナフタレン－２－イルメチル等を含むが、これらに限定されるものではない。 Examples of (C6-C10)aryl are phenyl, 1-naphthyl and 2-naphthyl.
(C6-C10)aryl(C1-C4)alkyl means (C1-C4alkyl) substituted by (C6-10)aryl, wherein the C6-10aryl moiety and the C1-C4alkyl moiety are have the same meaning as defined above.). Examples of (C6-C10)aryl(C1-C4)alkyl are benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, etc. including but not limited to.
　環式の炭化水素基は、環を構成する原子が全て炭素原子である芳香族又は非芳香族の、単環式又は多環式の環式基を意味する。 A cyclic hydrocarbon group means an aromatic or non-aromatic, monocyclic or polycyclic cyclic group in which all the atoms constituting the ring are carbon atoms.
　一つの態様では、環式の炭化水素基の例は、芳香族又は非芳香族の、単環式、二環式又は三環式の３～１４員（好ましくは５～１４員、より好ましくは５～１０員）の環式の炭化水素基を含むが、これらに限定されない。別の態様では、環式の炭化水素基の例は、芳香族又は非芳香族の、単環式又は二環式（好ましくは単環式）の４～８員（好ましくは５～６員）の環式の炭化水素基を含むが、これらに限定されない。 In one aspect, examples of cyclic hydrocarbon groups are aromatic or non-aromatic, monocyclic, bicyclic or tricyclic 3- to 14-membered (preferably 5- to 14-membered, more preferably 5- to 10-membered) cyclic hydrocarbon groups. In another aspect, examples of cyclic hydrocarbon groups are aromatic or non-aromatic, monocyclic or bicyclic (preferably monocyclic) 4-8 membered (preferably 5-6 membered) including, but not limited to, cyclic hydrocarbon groups of
　環式の炭化水素基の例は、シクロアルキル、アリール等を含むが、これらに限定されない。 Examples of cyclic hydrocarbon groups include, but are not limited to, cycloalkyl, aryl, and the like.
　アリールは、上記で定義した通りの環式の炭化水素基のうち、芳香族の環式基である。 Aryl is an aromatic cyclic group among the cyclic hydrocarbon groups as defined above.
　上記で定義又は例示した通りの環式の炭化水素基は、可能であれば、非縮合環式（例えば、単環式又はスピロ環式）および縮合環式の環式基を包含してもよい。 Cyclic hydrocarbon groups as defined or exemplified above may include non-fused cyclic (e.g. monocyclic or spirocyclic) and fused cyclic cyclic groups where possible. .
　上記で定義又は例示した通りの環式の炭化水素基は、可能であれば、不飽和、部分飽和又は飽和のいずれでもよい。 A cyclic hydrocarbon group as defined or exemplified above may be unsaturated, partially saturated or saturated, if possible.
　上記で定義又は例示した通りの環式の炭化水素基は炭素環基とも言う。 A cyclic hydrocarbon group as defined or exemplified above is also referred to as a carbocyclic group.
　炭素環は、上記で定義または例示した通りの環式の炭化水素基に相当する環である。 A carbocyclic ring is a ring corresponding to a cyclic hydrocarbon group as defined or exemplified above.
　本明細書中、用語「置換されていてもよい」における「置換基」については、それらが化学的に許容され、本発明の効果を示す限りは、特に制限はない。 In the present specification, the "substituents" in the term "optionally substituted" are not particularly limited as long as they are chemically acceptable and exhibit the effects of the present invention.
　本明細書中、「置換されていてもよい」との用語に関する「置換基」の例は、置換基群（ａ）から独立して選択される１以上の置換基（好ましくは１～４個の置換基）を含むが、これらに限定されない。 In this specification, examples of "substituent" with respect to the term "optionally substituted" include one or more substituents (preferably 1 to 4 substituents), including but not limited to:
　置換基群（ａ）は、ハロゲン原子；ニトロ基；シアノ基；ヒドロキシ基；アミノ基；（Ｃ１－Ｃ６）アルキル；（Ｃ３－Ｃ６）シクロアルキル；フェニル；フェノキシ等を含む群である。 cyano group; hydroxy group; amino group; (C1-C6) alkyl; (C3-C6) cycloalkyl; phenyl; phenoxy and the like.
　加えて、置換基群（ａ）から独立して選択される１以上の置換基（好ましくは１～４個の置換基）は、それぞれ独立して、置換基群（ｂ）から独立して選択される１以上の置換基（好ましくは１～４個の置換基）を有していてもよい。 In addition, one or more substituents (preferably 1 to 4 substituents) independently selected from substituent group (a) are each independently selected from substituent group (b) may have one or more substituents (preferably 1 to 4 substituents).
　ここで、置換基群（ｂ）は置換基群（ａ）と同じである。 Here, the substituent group (b) is the same as the substituent group (a).
　本明細書中、異性体を有する化合物は、全ての異性体と任意の割合のそれらの任意の混合物を含む。例えば、キシレンは、ｏ－キシレン、ｍ－キシレン、ｐ－キシレン及び任意の割合のそれらの任意の混合物を含む。例えば、ジクロロベンゼンは、ｏ－ジクロロベンゼン、ｍ－ジクロロベンゼン、ｐ－ジクロロベンゼン及び任意の割合のそれらの任意の混合物を含む。 In the present specification, a compound having isomers includes all isomers and any mixture thereof in any proportion. For example, xylene includes o-xylene, m-xylene, p-xylene and any mixture thereof in any proportion. For example, dichlorobenzene includes o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene and any mixture thereof in any proportion.
　例えば、ある化合物に幾何異性体（ｃｉｓ－ｔｒａｎｓ異性体、すなわちＥ／Ｚ異性体）が存在する場合は、（Ｅ）－異性体（ａｎｔｉ－異性体）、（Ｚ）－異性体（ｓｙｎ－異性体）及び任意の割合のそれらの混合物が本発明の範囲に含まれる。具体的には、例えば、式（５）：  For example, if a compound has geometric isomers (cis-trans isomers, that is, E/Z isomers), the (E)-isomers (anti-isomers), (Z)-isomers (syn- isomers) and mixtures thereof in any proportion are included within the scope of this invention. Specifically, for example, formula (5):
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
の化合物は、式（５－Ｅ）：  The compound of formula (5-E):
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
の化合物だけであってもよく、又は式（５－Ｚ）：  may be only the compound of the formula (5-Z):
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　の化合物だけであってもよく、又は上記式（５－Ｅ）及び上記式（５－Ｚ）の任意の割合のそれらの任意の混合物であってもよい。 It may be only the compound of the above formula (5-E) and the above formula (5-Z) and any mixture thereof in any ratio.
さらに、具体的には、例えば、式（６）： More specifically, for example, formula (6):
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
の化合物は、式（６－Ｅ）：  The compound of formula (6-E):
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
の化合物だけであってもよく、又は式（６－Ｚ）：  It may be only a compound of the formula (6-Z):
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　の化合物だけであってもよく、又は上記式（６－Ｅ）及び上記式（６－Ｚ）の任意の割合のそれらの任意の混合物であってもよい。 It may be only the compound of the above formula (6-E) and the above formula (6-Z) and any mixture thereof in any ratio.
　本明細書中、化学式中の波線は、以下を意味する。
　例えば、ある化合物に幾何異性体（ｃｉｓ－ｔｒａｎｓ異性体、すなわちＥ／Ｚ異性体）が存在する場合に、（Ｅ）－異性体（ａｎｔｉ－異性体）、（Ｚ）－異性体（ｓｙｎ－異性体）及び任意の割合のそれらの混合物が波線を有する化学式に含まれる。 In the present specification, wavy lines in chemical formulas mean the following.
For example, when a compound has geometric isomers (cis-trans isomers, that is, E/Z isomers), (E)-isomers (anti-isomers), (Z)-isomers (syn- isomers) and mixtures thereof in any proportion are included in formulas with wavy underlines.
　本発明による方法は、一つの態様では、以下のスキーム（式中、Ｒ１、Ｒ２及びＲ３は、上記の〔Ｉ－１〕に記載の通りである。）を含む。 In one aspect, the method according to the present invention includes the following scheme (wherein R 1 , R 2 and R 3 are as described in [I-1] above).
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　（工程（ｉ））
　工程（ｉ）について説明する。
　以下の工程（ｉ）の全ての説明は、工程（ｉ－ａ）及び工程（ｉ－ｂ）に適用される。ただし、該当しない場合を除く。 (Step (i))
Step (i) will be explained.
All descriptions of step (i) below apply to steps (ia) and (ib). Unless otherwise applicable.
　工程（ｉ）の反応は、酸化反応である。工程（ｉ）の反応は酸化工程ともいう。工程（ｉ）は、金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）又は式（２）の化合物を反応させることを含む製造方法である。 The reaction in step (i) is an oxidation reaction. The reaction of step (i) is also called an oxidation step. Step (i) is a manufacturing method comprising reacting the compound of formula (1) or formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound.
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。） (wherein R 1 , R 2 and R 3 are as defined above).
　（工程（ｉ）の原料）
　原料として、式（１）の化合物又は式（２）の化合物を用いる。式（１）の化合物及び式（２）の化合物は公知の化合物であるか、又は公知の化合物から公知の方法に準じて製造することができる。
　式（１）の化合物の具体的な例は、以下を含むが、これらに限定されない；３－メチル－１，３－ブタンジオール（３－メチルブタン－１，３－ジオール又は３－ヒドロキシ－３－メチルブタノールとも言う）、３－メトキシ－３－メチルブタノール、３－エトキシ－３－メチルブタノール、３－メチル－３－プロポキシブタノール、３－イソプロポキシ－３－メチルブタノール、３－ブトキシ－３－メチルブタノール、３－イソブトキシ－３－メチルブタノール、３－（sec-ブトキシ）－３－メチルブタノール、３－（ベンジルオキシ）－３－メチルブタノール等。生成物の有用性等の観点から、式（１）の化合物の好ましい具体的な例は、３－メトキシ－３－メチルブタノールである。
　上記と同様の観点から、式（２）の化合物の好ましい具体的な例は、３－メチル－２－ブテノール（プレノールとも言う）であるが、これに限定されない。 (Raw material for step (i))
As a raw material, the compound of formula (1) or the compound of formula (2) is used. The compound of formula (1) and the compound of formula (2) are known compounds, or can be produced from known compounds according to known methods.
Specific examples of compounds of formula (1) include, but are not limited to; 3-methyl-1,3-butanediol (3-methylbutane-1,3-diol or 3-hydroxy-3- methylbutanol), 3-methoxy-3-methylbutanol, 3-ethoxy-3-methylbutanol, 3-methyl-3-propoxybutanol, 3-isopropoxy-3-methylbutanol, 3-butoxy-3-methyl butanol, 3-isobutoxy-3-methylbutanol, 3-(sec-butoxy)-3-methylbutanol, 3-(benzyloxy)-3-methylbutanol and the like. A preferred specific example of the compound of formula (1) is 3-methoxy-3-methylbutanol from the viewpoint of usefulness of the product.
From the same viewpoint as above, a preferred specific example of the compound of formula (2) is 3-methyl-2-butenol (also referred to as prenol), but is not limited thereto.
（工程（ｉ）の酸素）
　本発明の酸化反応は酸素の存在下で行われる。酸素は、酸素含有ガス（例えば、純酸素および空気のような混合された気体を含む）として用いられても良く、及び酸素発生剤（例えば、硝酸）として用いられてもよく、それらの組み合わせとして用いられてもよい。従って、本発明の方法は、酸素含有ガス（例えば、純酸素、空気）及び酸素発生剤（例えば、硝酸）からなる群より選択される少なくとも１種（好ましくは１種～３種、より好ましくは１種又は２種）を導入し、反応させることを含んでよい。酸素含有ガスとしては、酸素又は空気を不活性ガス（例えば、窒素、炭酸ガス、アルゴン、好ましくは窒素、炭酸ガス、より好ましくは窒素）で希釈して用いることもできる。 (oxygen in step (i))
The oxidation reaction of the present invention is carried out in the presence of oxygen. Oxygen may be used as an oxygen-containing gas (including, for example, pure oxygen and mixed gases such as air) and as an oxygen generating agent (e.g., nitric acid), and combinations thereof. may be used. Therefore, the method of the present invention includes at least one (preferably 1 to 3, more preferably one or two) and allowed to react. As the oxygen-containing gas, oxygen or air diluted with an inert gas (eg, nitrogen, carbon dioxide, argon, preferably nitrogen, carbon dioxide, more preferably nitrogen) can be used.
（工程（ｉ）の酸素濃度）
　導入される酸素濃度は、反応が進行する限りは、いずれの濃度でもよい。しかしながら、収率、副生成物抑制、経済効率等の観点から、好ましくは１体積％～１００体積％、より好ましくは５体積％～１００体積％である。硝酸などの酸素発生剤から発生する酸素の濃度も前記と同じであってもよい。 (Oxygen concentration in step (i))
The oxygen concentration introduced may be any concentration as long as the reaction proceeds. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is preferably 1% by volume to 100% by volume, more preferably 5% by volume to 100% by volume. The concentration of oxygen generated from an oxygen generating agent such as nitric acid may also be the same as described above.
　（工程（ｉ）のニトロキシルラジカル化合物）
　ニトロキシルラジカル化合物としては、従来より知られている化合物を使用することができる。ニトロキシルラジカル化合物の例は、ＴＥＭＰＯ系触媒（例えば、２，２，６，６－テトラメチルピペリジン１－オキシル（ＴＥＭＰＯ）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（４－ヒドロキシＴＥＭＰＯ又は４－ＯＨ－ＴＥＭＰＯ）、４－メトキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（４－ＭｅＯＴＥＭＰＯ）、４－アセトキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（４－ＡｃＯＴＥＭＰＯ）、４－アセトアミド－２，２，６，６－テトラメチルピペリジン１－オキシル、４－ベンジルオキシ－２，２，６，６－テトラメチルピペリジン１－オキシル、４－ベンゾイルオキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（４－ＢｚＯＴＥＭＰＯ）等）、ＡＺＡＤＯ系触媒（２－アザアダマンタン－Ｎ－オキシル（ＡＺＡＤＯ）、１－メチル－２－アザアダマンタン－Ｎ－オキシル等）、アザビシクロ［３，３，１］ノナン－Ｎ－オキシル等を含み、これらはその１種のみを単独で使用できるほか、２種以上の混合物として使用することもできる。好ましくは、２，２，６，６－テトラメチルピペリジン１－オキシル、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシルである。 (Nitroxyl radical compound in step (i))
Conventionally known compounds can be used as nitroxyl radical compounds. Examples of nitroxyl radical compounds include TEMPO-based catalysts (e.g., 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-hydroxy TEMPO or 4-OH-TEMPO), 4-methoxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-MeOTEMPO), 4-acetoxy-2,2,6,6-tetra methylpiperidine 1-oxyl (4-AcOTEMPO), 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-benzyloxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine 1-oxyl (4-BzOTEMPO), etc.), AZADO catalysts (2-azaadamantane-N-oxyl (AZADO), 1-methyl-2-aza adamantane-N-oxyl, etc.), azabicyclo[3,3,1]nonane-N-oxyl, etc., and these can be used singly or as a mixture of two or more thereof. Preferred are 2,2,6,6-tetramethylpiperidine 1-oxyl and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl.
　ニトロキシルラジカル化合物の使用量は、反応が進行する限りは、いずれの量でもよい。しかしながら、収率、副生成物抑制、経済効率等の観点から、例えば、式（１）の化合物又は式（２）の化合物（アルコール化合物）１モルに対して、通常０．０００１モル～０．３モル、好ましくは０．００１モル～０．１モルである。 Any amount of the nitroxyl radical compound may be used as long as the reaction proceeds. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., for example, the compound of formula (1) or the compound of formula (2) (alcohol compound) is usually 0.0001 mol to 0.001 mol per 1 mol. 3 mol, preferably 0.001 mol to 0.1 mol.
（工程（ｉ）の金属触媒）
　一つの態様では、反応性、収率及び経済効率等の観点から、本発明の酸化反応の金属触媒の好ましい例は、銅触媒、鉄触媒を含む。本発明の酸化反応の金属触媒の具体的な例は、銅触媒（例えば、硝酸銅（ＩＩ）、塩化銅（ＩＩ）と硝酸を含む触媒、臭化銅（ＩＩ）と硝酸を含む触媒、ヨウ化銅（ＩＩ）と硝酸を含む触媒）、鉄触媒（例えば、硝酸鉄（ＩＩＩ）、塩化鉄（ＩＩＩ）と硝酸を含む触媒、臭化鉄（ＩＩＩ）と硝酸を含む触媒）、より好ましくは、硝酸銅（ＩＩ）と硝酸を含む触媒、塩化鉄（ＩＩＩ）と硝酸を含む触媒、臭化鉄（ＩＩＩ）と硝酸を含む触媒、硝酸鉄（ＩＩＩ）、更に好ましくは硝酸鉄（ＩＩＩ）、塩化鉄（ＩＩＩ）と硝酸を含む触媒、更に好ましくは塩化鉄（ＩＩＩ）と硝酸を含む触媒である。
　別の態様では、上記と同様の観点から、本発明の酸化反応の金属触媒の好ましい例は、銅触媒、鉄触媒を含む。本発明の酸化反応の金属触媒の具体的な例は、銅触媒（例えば、硝酸銅（ＩＩ）、塩化銅（ＩＩ）、臭化銅（ＩＩ）、ヨウ化銅（ＩＩ））、鉄触媒（例えば、硝酸鉄（ＩＩＩ）、塩化鉄（ＩＩＩ）、臭化鉄（ＩＩＩ））、より好ましくは、硝酸銅（ＩＩ）、塩化鉄（ＩＩＩ）、臭化鉄（ＩＩＩ）、硝酸鉄（ＩＩＩ）、更に好ましくは硝酸鉄（ＩＩＩ）、塩化鉄（ＩＩＩ）、特に好ましくは塩化鉄（ＩＩＩ）である。塩化鉄（ＩＩＩ）は硝酸鉄（ＩＩＩ）より安価なため、工業的及び経済的にも優れている。また、塩化鉄（ＩＩＩ）は硝酸鉄（ＩＩＩ）よりも潮解性が弱く、扱いが容易なため、工業的に使用し易い。 (Metal catalyst in step (i))
In one aspect, from the viewpoint of reactivity, yield, economic efficiency, etc., preferred examples of the metal catalyst for the oxidation reaction of the present invention include copper catalysts and iron catalysts. Specific examples of metal catalysts for the oxidation reaction of the present invention include copper catalysts (e.g., copper(II) nitrate, catalysts containing copper(II) chloride and nitric acid, catalysts containing copper(II) bromide and nitric acid, iodine copper(II) chloride and nitric acid), iron catalysts (e.g. iron(III) nitrate, iron(III) chloride and nitric acid, iron(III) bromide and nitric acid), more preferably , a catalyst comprising copper(II) nitrate and nitric acid, a catalyst comprising iron(III) chloride and nitric acid, a catalyst comprising iron(III) bromide and nitric acid, iron(III) nitrate, more preferably iron(III) nitrate, Catalysts containing iron(III) chloride and nitric acid, more preferably catalysts containing iron(III) chloride and nitric acid.
In another aspect, from the same viewpoint as above, preferred examples of the metal catalyst for the oxidation reaction of the present invention include copper catalysts and iron catalysts. Specific examples of metal catalysts for the oxidation reaction of the present invention include copper catalysts (e.g., copper (II) nitrate, copper (II) chloride, copper (II) bromide, copper (II) iodide), iron catalysts ( For example, iron(III) nitrate, iron(III) chloride, iron(III) bromide), more preferably copper(II) nitrate, iron(III) chloride, iron(III) bromide, iron(III) nitrate More preferably iron(III) nitrate, iron(III) chloride, particularly preferably iron(III) chloride. Since iron (III) chloride is cheaper than iron (III) nitrate, it is industrially and economically superior. In addition, since iron (III) chloride is less deliquescent than iron (III) nitrate and is easy to handle, it is easy to use industrially.
　金属触媒は、いずれの形態であってもよく、塩又はそれらの水和物も同様に使用することができる。 The metal catalyst may be in any form, and salts or hydrates thereof can also be used.
　金属触媒の使用量は、反応が進行する限りは、いずれの量でもよい。しかしながら、収率、副生成物抑制、経済効率等の観点から、式（１）の化合物又は式（２）の化合物（アルコール化合物）１モルに対して、好ましくは０．０００１モル～０．５モル、より好ましくは０．００１モル～０．３モル、更に好ましくは０．０１モル～０．１モルである。 Any amount of metal catalyst may be used as long as the reaction proceeds. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is preferably 0.0001 mol to 0.5 per 1 mol of the compound of formula (1) or the compound of formula (2) (alcohol compound). mol, more preferably 0.001 mol to 0.3 mol, still more preferably 0.01 mol to 0.1 mol.
（工程（ｉ）の硝酸）
　本発明の酸化反応は硝酸の存在下で行われる。一つの態様では、好ましくは、硝酸は、塩化銅（ＩＩ）、臭化銅（ＩＩ）、ヨウ化銅（ＩＩ）、塩化鉄（ＩＩＩ）及び臭化鉄（ＩＩＩ）とともに用いられる。別の態様では、前述の限りではなく、硝酸は金属触媒とともに用いられる。 (Nitric acid in step (i))
The oxidation reaction of the present invention is carried out in the presence of nitric acid. In one embodiment, nitric acid is preferably used with copper(II) chloride, copper(II) bromide, copper(II) iodide, iron(III) chloride and iron(III) bromide. In another aspect, not as previously described, nitric acid is used with a metal catalyst.
　硝酸の濃度は当業者が適切に選択することができる。硝酸としては硝酸水溶液を使用することが好ましい。硝酸水溶液における硝酸の濃度は特に制限はないが、好ましくは０．１～１００％、より好ましくは１～１００％、更に好ましくは１０～９０％、更に好ましくは３０～８０％である。 A person skilled in the art can appropriately select the concentration of nitric acid. As nitric acid, it is preferable to use an aqueous nitric acid solution. Although the concentration of nitric acid in the nitric acid aqueous solution is not particularly limited, it is preferably 0.1 to 100%, more preferably 1 to 100%, still more preferably 10 to 90%, still more preferably 30 to 80%.
　硝酸は、触媒の一部（例えば、共触媒（co-catalyst）、助触媒（promotor））であってもよく、酸化剤であってもよく、酸素発生剤であってもよく、それらの複数であってもよい。
　硝酸の使用量は、反応が進行する限りは、いずれの量でもよい。しかしながら、収率、副生成物の抑制、経済効率の観点から、一つの態様では、式（１）の化合物又は式（２）の化合物（アルコール化合物）１モルに対して、通常０．０１モル～１モル、好ましくは０．０２モル～０．９モル、より好ましくは０．０２モル～０．８モルである。別の態様では、上記と同様の観点から、通常０．０１モル～０．１モル好ましくは０．０２モル～０．０９モル、より好ましくは０．０２モル～０．０５モルである。さらに別の態様では、上記と同様の観点から、通常０．５モル～１モル、好ましくは０．５モル～０．９モル、より好ましくは０．５モル～０．８モルである。 The nitric acid may be part of the catalyst (e.g., co-catalyst, promoter), an oxidant, an oxygen generator, a plurality of may be
Any amount of nitric acid may be used as long as the reaction proceeds. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, usually 0.01 mol per 1 mol of the compound of formula (1) or the compound of formula (2) (alcohol compound) ~1 mol, preferably 0.02 mol to 0.9 mol, more preferably 0.02 mol to 0.8 mol. In another aspect, from the same viewpoint as above, it is generally 0.01 mol to 0.1 mol, preferably 0.02 mol to 0.09 mol, more preferably 0.02 mol to 0.05 mol. In still another embodiment, from the same viewpoint as above, it is usually 0.5 mol to 1 mol, preferably 0.5 mol to 0.9 mol, more preferably 0.5 mol to 0.8 mol.
（工程（ｉ）の酸）
　一つの態様では、反応性、収率及び経済効率等の観点から、本発明の酸化反応では酸を用いることが好ましい。酸の例は、カルボン酸が挙げられる。具体的な例としては、好ましくは酢酸、プロピオン酸、ブタン酸、イソブタン酸、ペンタン酸、ヘキサン酸、ヘプタン酸、オクタン酸、ノナン酸、デカン酸、安息香酸を含み、より好ましくは酢酸、プロピオン酸、安息香酸であり、更に好ましくは酢酸、プロピオン酸であり、更に好ましくは酢酸であるが、これらに限定されない。
　別の態様では、本発明の酸化反応では、酸を用いてもよく、又は用いなくてもよい。酸を用いるとき、酸の例は上記の通りである。 (acid in step (i))
In one aspect, from the viewpoint of reactivity, yield, economic efficiency, etc., it is preferable to use an acid in the oxidation reaction of the present invention. Examples of acids include carboxylic acids. Specific examples include preferably acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid and benzoic acid, more preferably acetic acid and propionic acid. , benzoic acid, more preferably acetic acid and propionic acid, still more preferably acetic acid, but not limited thereto.
In another aspect, the oxidation reaction of the present invention may or may not use an acid. When an acid is used, examples of acid are given above.
　酸の使用量は、反応が進行する限りは、いずれの量でもよい。しかしながら、酸を用いるときは、収率、副生成物抑制、経済効率等の観点から、式（１）の化合物又は式（２）の化合物（アルコール化合物）１モルに対して、通常０．１モル～１０モル、好ましくは０．２モル～５モル、より好ましくは０．５モル～３モル、さらに好ましくは１モル～２モルである。 Any amount of acid may be used as long as the reaction proceeds. However, when an acid is used, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is usually 0.1 per 1 mol of the compound of formula (1) or the compound of formula (2) (alcohol compound). mol to 10 mol, preferably 0.2 mol to 5 mol, more preferably 0.5 mol to 3 mol, still more preferably 1 mol to 2 mol.
（工程（ｉ）の塩基）
　一つの態様では、反応性、収率及び経済効率等の観点から、本発明の酸化反応は塩基を用いることが好ましい。塩基の例は、窒素原子を有する芳香族ヘテロ環化合物が挙げられる。具体的な例として、好ましくはＮ－メチルイミダゾール（ＮＭＩ）、Ｎ－メチルピラゾール、ピリジン、Ｎ，Ｎ－ジメチルアミノピリジン（ＤＭＡＰ）、２，２’－ビピリジル（ＢｉＰｙ）を含み、より好ましくはＮ－メチルイミダゾール、２，２’－ビピリジルを含むが、これらに限定されない。
　別の態様では、本発明の酸化反応では、塩基を用いてもよく、又は用いなくてもよい。塩基を用いるとき、塩基の例は上記の通りである。 (Base in step (i))
In one aspect, from the viewpoint of reactivity, yield, economic efficiency, etc., it is preferable to use a base in the oxidation reaction of the present invention. Examples of bases include aromatic heterocyclic compounds having a nitrogen atom. Specific examples preferably include N-methylimidazole (NMI), N-methylpyrazole, pyridine, N,N-dimethylaminopyridine (DMAP), 2,2′-bipyridyl (BiPy), more preferably N -methylimidazole, 2,2'-bipyridyl, including but not limited to.
In another aspect, the oxidation reaction of the present invention may or may not use a base. When a base is used, examples of bases are as described above.
　塩基の形態は、反応が進行する限りは、いずれの形態でもよい。塩基の形態は、当業者が適切に選択することができる。 The form of the base may be any form as long as the reaction proceeds. The base form can be appropriately selected by those skilled in the art.
　塩基の使用量は、反応が進行する限りは、いずれの量でもよい。しかしながら、塩基を用いるときは、収率、副生成物抑制、経済効率等の観点から、式（１）の化合物又は式（２）の化合物（アルコール化合物）１モルに対して、通常０．００１モル～１モル、好ましくは０．００１モル～０．３モル、より好ましくは０．０１モル～０．１モルである。 Any amount of base may be used as long as the reaction proceeds. However, when a base is used, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is usually 0.001 per 1 mol of the compound of formula (1) or the compound of formula (2) (alcohol compound). mol to 1 mol, preferably 0.001 mol to 0.3 mol, more preferably 0.01 mol to 0.1 mol.
（工程（ｉ）の溶媒）
　反応の円滑な進行等の観点から、本発明の酸化反応は溶媒の存在下で実施することが好ましい。本発明の酸化反応の溶媒は、反応が進行する限りは、いずれの溶媒でもよい。溶媒の例は、エーテル類（例えば、テトラヒドロフラン（ＴＨＦ）、１，４－ジオキサン、ジイソプロピルエーテル、ジブチルエーテル、ジ－ｔｅｒｔ－ブチルエーテル）、カルボン酸エステル類（例えば、（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート、（具体的には、例えば、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル及びその異性体、酢酸ペンチル及びその異性体））、ケトン類（例えば、アセトン、２－ブタノン、メチルイソブチルケトン）、芳香族炭化水素誘導体類（例えば、ベンゼン、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、クロロトルエン）、ニトリル類（例えば、（Ｃ２－Ｃ４）アルカンニトリル、（具体的には、例えば、アセトニトリル、プロピオニトリル）および任意の割合のそれらの任意の組み合わせを含むが、これらに限定されない。 (solvent in step (i))
From the viewpoint of smooth progress of the reaction, etc., the oxidation reaction of the present invention is preferably carried out in the presence of a solvent. Any solvent may be used for the oxidation reaction of the present invention as long as the reaction proceeds. Examples of solvents include ethers (eg, tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether), carboxylic acid esters (eg, (C1-C6)alkyl(C2- C4) carboxylates (e.g., methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers)), ketones (e.g., acetone, 2- butanone, methyl isobutyl ketone), aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene), nitriles (e.g., (C2-C4) alkanenitrile, (specifically, acetonitrile, propionitrile) and any combination thereof in any proportion.
　収率、副生成物抑制、経済効率等の観点から、一つの態様では、本発明の酸化反応の溶媒の好ましい例は、カルボン酸エステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）、ニトリル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）および任意の割合のそれらの任意の組み合わせを含む。本発明の酸化反応の溶媒の好ましい具体的な例は、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、アセトニトリル、プロピオニトリルおよび任意の割合のそれらの任意の組み合わせを含む。より好ましい具体的な例は、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、アセトニトリルおよび任意の割合のそれらの任意の組み合わせであり、更に好ましくは酢酸ブチルおよびその異性体又はアセトニトリルであり、更に好ましくは酢酸ブチル又はアセトニトリルである。別の態様では、本発明の酸化反応の溶媒の好ましい例は、カルボン酸エステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）である。より好ましい具体的な例は、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体および任意の割合のそれらの任意の組み合わせであり、更に好ましくは酢酸ブチルおよびその異性体であり、更に好ましくは酢酸ブチルである。 From the viewpoint of yield, suppression of by-products, economic efficiency, etc., in one aspect, preferred examples of the solvent for the oxidation reaction of the present invention are carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates), nitriles (preferably (C1-C6)alkyl(C2-C4)carboxylates) and any combination thereof in any proportion. Preferred specific examples of solvents for the oxidation reaction of the present invention are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, acetonitrile, propionitrile and any combination thereof in any proportion. include. More preferred specific examples are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, acetonitrile and any combination thereof in any proportion, more preferably butyl acetate and its isomers or acetonitrile, more preferably butyl acetate or acetonitrile. In another aspect, preferred examples of solvents for the oxidation reaction of the present invention are carboxylic acid esters (preferably (C1-C6)alkyl(C2-C4)carboxylates). More preferred specific examples are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isomers thereof and any combination thereof in any proportion, more preferably butyl acetate and isomers thereof. and more preferably butyl acetate.
　加えて、工程（ｉ）の反応は水溶媒の存在下で行われてもよい。例えば、酸素発生剤として用いた硝酸水溶液（例えば、６９％硝酸）由来の水は、水溶媒として理解することができる。 In addition, the reaction of step (i) may be carried out in the presence of a water solvent. For example, water from an aqueous nitric acid solution (eg, 69% nitric acid) used as an oxygen generator can be understood as a water solvent.
　溶媒の使用量は、反応系の撹拌が十分にできる限りは、いずれの量でもよい。収率、副生成物抑制、経済効率等の観点から、式（１）の化合物又は式（２）の化合物１モルに対して、０（ゼロ）～１０Ｌ（リットル）、好ましくは０．１～５Ｌ、より好ましくは０．３～２Ｌを含むが、これらに限定されない。
２種以上の溶媒の組み合わせを用いるときは、２種以上の溶媒の割合は、反応が進行する限りは、いずれの割合でもよい。溶媒は、反応が進行する限りは、単層でもよく、２層に分離してもよい。 Any amount of the solvent may be used as long as the reaction system can be sufficiently stirred. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0 (zero) to 10 L (liter), preferably 0.1 to 1 mol of the compound of formula (1) or the compound of formula (2) Including but not limited to 5L, more preferably 0.3-2L.
When using a combination of two or more solvents, the ratio of the two or more solvents may be any ratio as long as the reaction proceeds. The solvent may be a single layer or separated into two layers as long as the reaction proceeds.
　（工程（ｉ）の生成物；式（３）の化合物又は式（４）の化合物）
　工程（ｉ）の生成物は、原料として用いた式（１）の化合物又は式（２）の化合物に相当する式（３）の化合物又は式（４）の化合物である。それらの具体的な例、好ましい具体的な例及びより好ましい具体的な例は、工程（ｉｉ）の原料として後述のとおりである。 (product of step (i); compound of formula (3) or compound of formula (4))
The product of step (i) is the compound of formula (3) or the compound of formula (4) corresponding to the compound of formula (1) or the compound of formula (2) used as starting material. Specific examples, preferred specific examples, and more preferred specific examples thereof are as described below for the raw material of step (ii).
　工程（ｉ）の生成物である式（３）の化合物又は式（４）の化合物は、工程（ｉｉ）の原料として使用することができる。工程（ｉ）で得られる式（３）の化合物又は式（４）の化合物は、単離して次工程に用いてもよく、さらに精製して次工程に用いてもよく、または単離することなく次工程に用いてもよい。しかしながら、単離することなく次工程に用いることが効率がよい。 The compound of formula (3) or the compound of formula (4), which is the product of step (i), can be used as a starting material for step (ii). The compound of formula (3) or the compound of formula (4) obtained in step (i) may be isolated and used in the next step, may be further purified and used in the next step, or may be isolated. It may be used in the next step without However, it is efficient to use it in the next step without isolation.
（工程（ｉｉ））
　工程（ｉｉ）について説明する。
　以下の工程（ｉｉ）の全ての説明は、工程（ｉｉ－ａ）及び工程（ｉｉ－ｂ）に適用される。ただし、該当しない場合を除く。 (Step (ii))
Step (ii) will be explained.
All descriptions of step (ii) below apply to steps (ii-a) and (ii-b). Unless otherwise applicable.
　工程（ｉｉ）の反応は、オキシム化である。工程（ｉｉ）の反応はオキシム化工程ともいう。工程（ｉｉ）は、式（３）の化合物又は式（４）の化合物をオキシム化剤と反応させて、式（５）の化合物又は式（６）の化合物を製造する工程である。 The reaction in step (ii) is oximation. The reaction of step (ii) is also referred to as the oximation step. Step (ii) is a step of reacting the compound of formula (3) or the compound of formula (4) with an oximating agent to produce the compound of formula (5) or the compound of formula (6).
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。） (wherein R 1 , R 2 and R 3 are as defined above).
　（工程（ｉｉ）の原料；式（３）の化合物又は式（４）の化合物）
　工程（ｉｉ）の原料として、式（３）の化合物又は式（４）はの化合物を用いる。式（３）の化合物又は式（４）の化合物は公知の化合物であるか、又は公知の化合物から公知の方法に準じて製造することができる。
　式（３）の化合物又は式（４）の化合物の具体的な例は、以下を含むが、これらに限定されない；３－メチル－２－ブテナール（プレナールとも言う）、３－ヒドロキシ－３－メチルブタナール（３－ヒドロキシ－３－メチル－ブタン－１－アールとも言う）、３－メトキシ－３－メチルブタナール、３－エトキシ－３－メチルブタナール、３－メチル－３－プロポキシブタナール、３－イソプロポキシ－３－メチルブタナール、３－ブトキシ－３－メチルブタナール、３－イソブトキシ－３－メチルブタナール、３－（sec-ブトキシ）－３－メチルブタナール、３－メチル－３－フェノキシブタナール、３－（ベンジルオキシ）－３－メチルブタナール、３－ヒドロキシ－３－メチルペンタナール、３－エチル－３－ヒドロキシペンタナール、３－ヒドロキシ－３，４－ジメチルペンタナール、３－ヒドロキシ－３，４，４－トリメチルペンタナール、４－クロロ－３－ヒドロキシ－３－メチルブタナール、４，４，４－トリフルオロ－３－ヒドロキシ－３－メチルブタナール、２－（１－ヒドロキシシクロプロピル）アセトアルデヒド、２－（１－ヒドロキシシクロブチル）アセトアルデヒド、２－（１－ヒドロキシシクロペンチル）アセトアルデヒド、２－（１－ヒドロキシシクロヘキシル）アセトアルデヒド、３－ヒドロキシ－３－メチルヘプタナール、３－ヒドロキシ－３，７－ジメチル－６－オクテナール、３－ヒドロキシ－３，７－ジメチルオクタナール、３－（９Ｈ－フルオレン－９－イリデン）－３－ヒドロキシプロパナール、３－ヒドロキシ－３，３－ジフェニル－２－プロパナール、３－ヒドロキシ－３，３－ビス（４－メチルフェニル）プロパナール、３－ヒドロキシ－３，３－ビス（４－メトキシフェニル）プロパナール、３－ヒドロキシ－３，３－ビス（４－クロロフェニル）プロパナール、３－ヒドロキシ－３－フェニルブタナール、３－ヒドロキシ－３－（４－メチルフェニル）ブタナール、３－ヒドロキシ－３－（４－メトキシフェニル）ブタナール、３－ヒドロキシ－３－（４－クロロフェニル）ブタナール等。生成物の有用性等の観点から、式（３）の化合物又は式（４）の化合物の好ましい具体的な例は、３－ヒドロキシ－３－メチルブタナール及び３－メトキシ－３－メチルブタナールである。生成物の有用性等の観点から、式（３）の化合物の好ましい具体的な例は、以下である；３－ヒドロキシ－３－メチルブタナール（３－ヒドロキシ－３－メチル－ブタン－１－アールとも言う）、３－メトキシ－３－メチルブタナール、３－エトキシ－３－メチルブタナール、３－メチル－３－プロポキシブタナール、３－イソプロポキシ－３－メチルブタナール、３－ブトキシ－３－メチルブタナール、３－イソブトキシ－３－メチルブタナール、３－（sec-ブトキシ）－３－メチルブタナール、３－（ベンジルオキシ）－３－メチルブタナール等。上記と同様の観点から式（３）の化合物のより好ましい具体的な例は、３－メトキシ－３－メチルブタナールである。
　上記と同様の観点から、式（４）の化合物の好ましい具体的な例は、３－メチル－２－ブテナール（プレナールとも言う）である。 (Raw material of step (ii); compound of formula (3) or compound of formula (4))
A compound of formula (3) or a compound of formula (4) is used as a starting material for step (ii). The compound of formula (3) or the compound of formula (4) is a known compound, or can be produced from a known compound according to a known method.
Specific examples of compounds of formula (3) or compounds of formula (4) include, but are not limited to; 3-methyl-2-butenal (also known as prenal), 3-hydroxy-3-methyl butanal (also known as 3-hydroxy-3-methyl-butan-1-al), 3-methoxy-3-methylbutanal, 3-ethoxy-3-methylbutanal, 3-methyl-3-propoxybutanal, 3-isopropoxy-3-methylbutanal, 3-butoxy-3-methylbutanal, 3-isobutoxy-3-methylbutanal, 3-(sec-butoxy)-3-methylbutanal, 3-methyl-3 -phenoxybutanal, 3-(benzyloxy)-3-methylbutanal, 3-hydroxy-3-methylpentanal, 3-ethyl-3-hydroxypentanal, 3-hydroxy-3,4-dimethylpentanal, 3-hydroxy-3,4,4-trimethylpentanal, 4-chloro-3-hydroxy-3-methylbutanal, 4,4,4-trifluoro-3-hydroxy-3-methylbutanal, 2-( 1-hydroxycyclopropyl)acetaldehyde, 2-(1-hydroxycyclobutyl)acetaldehyde, 2-(1-hydroxycyclopentyl)acetaldehyde, 2-(1-hydroxycyclohexyl)acetaldehyde, 3-hydroxy-3-methylheptanal, 3 -hydroxy-3,7-dimethyl-6-octenal, 3-hydroxy-3,7-dimethyloctanal, 3-(9H-fluoren-9-ylidene)-3-hydroxypropanal, 3-hydroxy-3,3 -diphenyl-2-propanal, 3-hydroxy-3,3-bis(4-methylphenyl)propanal, 3-hydroxy-3,3-bis(4-methoxyphenyl)propanal, 3-hydroxy-3, 3-bis(4-chlorophenyl)propanal, 3-hydroxy-3-phenylbutanal, 3-hydroxy-3-(4-methylphenyl)butanal, 3-hydroxy-3-(4-methoxyphenyl)butanal, 3 -hydroxy-3-(4-chlorophenyl)butanal and the like. Preferred specific examples of the compound of formula (3) or the compound of formula (4) from the viewpoint of usefulness of the product are 3-hydroxy-3-methylbutanal and 3-methoxy-3-methylbutanal. is. Preferred specific examples of the compound of formula (3) are as follows from the viewpoint of usefulness of the product, etc.; are), 3-methoxy-3-methylbutanal, 3-ethoxy-3-methylbutanal, 3-methyl-3-propoxybutanal, 3-isopropoxy-3-methylbutanal, 3-butoxy- 3-methylbutanal, 3-isobutoxy-3-methylbutanal, 3-(sec-butoxy)-3-methylbutanal, 3-(benzyloxy)-3-methylbutanal and the like. A more preferred specific example of the compound of formula (3) from the same viewpoint as above is 3-methoxy-3-methylbutanal.
From the same viewpoint as above, a preferred specific example of the compound of formula (4) is 3-methyl-2-butenal (also referred to as prenal).
　（工程（ｉｉ）のオキシム化剤）
　工程（ｉｉ）で使用されるオキシム化剤は、反応が進行する限りは、いずれのオキシム化剤でもよい。工程（ｉｉ）で使用できるオキシム化剤の例は、ヒドロキシルアミン、ヒドロキシルアミン塩及びオキシム化合物が挙げられる。オキシム化剤は、反応が進行し且つ安全が確保される限りは、特に限定されない。ヒドロキシルアミン（フリー）の例は、５０％ヒドロキシルアミン水溶液、６０％ヒドロキシルアミン水溶液、７０％ヒドロキシルアミン水溶液、８０％ヒドロキシルアミン水溶液、９０％ヒドロキシルアミン水溶液等を含むが、これらに限定されない。一般的に「５０％ヒドロキシルアミン水溶液（50% hydroxylamine aqueous solution）」は「ヒドロキシルアミン（５０％水溶液）（Hydroxylamine (50% solution in water)）」とも言う。ヒドロキシルアミン塩の例は、塩酸ヒドロキシルアミン、硫酸ヒドロキシルアミン、硝酸ヒドロキシルアミン（例えば、５０％水溶液）、炭酸ヒドロキシルアミン、リン酸ヒドロキシルアミン、酢酸ヒドロキシルアミン、シュウ酸ヒドロキシルアミン等を含むが、これらに限定されない。 (Oximating agent in step (ii))
The oximating agent used in step (ii) can be any oximating agent as long as the reaction proceeds. Examples of oximating agents that can be used in step (ii) include hydroxylamine, hydroxylamine salts and oxime compounds. The oximating agent is not particularly limited as long as the reaction proceeds and safety is ensured. Examples of hydroxylamine (free) include, but are not limited to, 50% hydroxylamine aqueous solution, 60% hydroxylamine aqueous solution, 70% hydroxylamine aqueous solution, 80% hydroxylamine aqueous solution, 90% hydroxylamine aqueous solution, and the like. "50% hydroxylamine aqueous solution" is also commonly referred to as "Hydroxylamine (50% solution in water)". Examples of hydroxylamine salts include, but are not limited to, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate (e.g., 50% aqueous solution), hydroxylamine carbonate, hydroxylamine phosphate, hydroxylamine acetate, hydroxylamine oxalate, and the like. Not limited.
　本明細書中、オキシム化剤としてのオキシム化合物は下記式で表される。 In this specification, an oxime compound as an oximating agent is represented by the following formula.
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　式中、Ｒ４及びＲ５は、それぞれ独立して、水素原子；（Ｃ１－Ｃ６）アルキル；（Ｃ３－Ｃ６）シクロアルキル；（Ｃ２－Ｃ６）アルケニル；（Ｃ２－Ｃ６）アルキニル；（Ｃ６－Ｃ１０）アリール；又は（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルであり、あるいはＲ４及びＲ５は、２つが互いに結合して環を形成していてもよい。 ( C1 -C6) alkyl; (C3-C6) cycloalkyl; (C2-C6) alkenyl; ( C2 -C6) alkynyl; C10) aryl; or (C6-C10) aryl(C1-C4) alkyl, or two of R 4 and R 5 may be joined together to form a ring.
　式（８）の化合物は公知の化合物であるか、又は公知の化合物から公知の方法に準じて製造することができる。
　式（３）の化合物又は式（４）の化合物のＲ４とＲ５が環を形成していない具体的な例は、以下を含むが、これらに限定されない；
　ホルムオキシム、アセトンオキシム（アセトキシムとも言う）、２－ブタノンオキシム（メチルエチルケトンオキシム）、メチルイソプロピルケトンオキシム、メチルターシャリーブチルケトンオキシム、２－ペンタノンオキシム、３－ペンタノンオキシム、１－シクロヘキシル―１―プロパノンオキシム、２－ヘキサノンオキシム、３－ヘキサノンオキシム、３－ヘプタノンオキシム、４－オクタノンオキシム、５－ノナノンオキシム、アセトアルドキシム、ベンゾアルドキシム、アセトフェノンオキシム、４′－ヒドロキシアセトフェノンオキシム、ベンゾフェノンオキシム等が挙げられる。 The compound of formula (8) is a known compound, or can be produced from a known compound according to a known method.
Specific examples of compounds of formula (3) or compounds of formula (4) in which R 4 and R 5 do not form a ring include, but are not limited to;
formoxime, acetone oxime (also known as acetoxime), 2-butanone oxime (methyl ethyl ketone oxime), methyl isopropyl ketone oxime, methyl tertiary butyl ketone oxime, 2-pentanone oxime, 3-pentanone oxime, 1-cyclohexyl-1- propanone oxime, 2-hexanone oxime, 3-hexanone oxime, 3-heptanone oxime, 4-octanone oxime, 5-nonanone oxime, acetoaldoxime, benzoaldoxime, acetophenone oxime, 4′-hydroxyacetophenone oxime, benzophenone oxime and the like.
　式（３）の化合物又は式（４）の化合物のＲ４とＲ５が非共役系の環を形成した具体的な例は、以下を含むが、これらに限定されない；
　シクロプロパノンオキシム、シクロブタノンオキシム、シクロペンタノンオキシム、シクロヘキサノンオキシム、シクロヘプタノンオキシム、シクロオクタノンオキシム、シクロノナノンオキシム、シクロデカノンオキシム等が挙げられる。 Specific examples of compounds of formula (3) or compounds of formula (4) in which R 4 and R 5 form a non-conjugated ring include, but are not limited to;
Cyclopropanone oxime, cyclobutanone oxime, cyclopentanone oxime, cyclohexanone oxime, cycloheptanone oxime, cyclooctanone oxime, cyclononanone oxime, cyclodecanone oxime and the like.
　工程（ｉｉ）で使用されるオキシム化剤は、単独で又は任意の割合の２種以上の組み合わせで使用してもよい。工程（ｉ）で使用されるオキシム化剤の形態は、反応が進行し且つ安全が確保される限りは、いずれの形態でもよい。反応が進行し且つ安全が確保される範囲で、その形態の例は、固体及び液体、並びに任意の濃度の水溶液及び水以外の溶媒（例えば、有機溶媒）の溶液等を含む。 The oximating agent used in step (ii) may be used alone or in combination of two or more at any ratio. The form of the oximating agent used in step (i) may be any form as long as the reaction proceeds and safety is ensured. As long as the reaction proceeds and safety is ensured, examples of its form include solids and liquids, aqueous solutions of any concentration, solutions of solvents other than water (eg, organic solvents), and the like.
　例えば、ヒドロキシルアミン（フリー）を用いるときは、ヒドロキシルアミンの形態は、反応が進行し且つ安全が確保される限りは、いずれの形態でもよい。安全性と経済効率を考慮して、ヒドロキシルアミン（フリー）の形態の好ましい例は、１０％以上７０％未満の濃度の水溶液、好ましくは４５％以上５５％以下の濃度の水溶液を含む。 For example, when using hydroxylamine (free), the form of hydroxylamine may be in any form as long as the reaction proceeds and safety is ensured. Considering safety and economic efficiency, preferred examples of the hydroxylamine (free) form include aqueous solutions with a concentration of 10% or more and less than 70%, preferably 45% or more and 55% or less.
　工程（ｉｉ）のオキシム化剤の使用量は、反応が進行する限りは、いずれの量でもよい。収率、副生成物抑制、経済効率等の観点から、一つの態様では、式（３）の化合物又は式（４）の化合物１モルに対して、ヒドロキシルアミン（ＮＨ２ＯＨ）に換算して、０．９～１．５当量、好ましくは０．９～１．３当量である。別の態様では、式（３）の化合物又は式（４）の化合物１モルに対して、ヒドロキシルアミン（ＮＨ２ＯＨ）に換算して、１．０～１．５当量、好ましくは１．０～１．３当量である。しかしながら、その使用量は当業者が適切に調整することができる。用語「ヒドロキシルアミン（ＮＨ２ＯＨ）に換算して」の意味は以下の通りである。例えば、１モルのＮＨ２ＯＨ・ＨＣｌは、１モルのＮＨ２ＯＨに換算される。他の例としては、１モルの（ＮＨ２ＯＨ）２・Ｈ２ＳＯ４は、２モルのＮＨ２ＯＨに換算される。更に他の例としては、１モルのアセトンオキシムは、１モルのＮＨ２ＯＨに換算される。 Any amount of the oximating agent may be used in step (ii) as long as the reaction proceeds. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., in one embodiment, 1 mol of the compound of formula (3) or the compound of formula (4) is converted to hydroxylamine (NH 2 OH) , 0.9 to 1.5 equivalents, preferably 0.9 to 1.3 equivalents. In another embodiment, 1.0 to 1.5 equivalents, preferably 1.0 equivalents, in terms of hydroxylamine (NH 2 OH), per 1 mol of the compound of formula (3) or the compound of formula (4) ~1.3 equivalents. However, the amount used can be appropriately adjusted by those skilled in the art. The meaning of the term "in terms of hydroxylamine ( NH2OH )" is as follows. For example, 1 mol of NH 2 OH.HCl is converted to 1 mol of NH 2 OH. As another example , 1 mole of ( NH2OH ) 2.H2SO4 converts to 2 moles of NH2OH . As yet another example, 1 mole of acetone oxime converts to 1 mole of NH 2 OH.
　ヒドロキシルアミン塩（例えば、塩酸ヒドロキシルアミン、硫酸ヒドロキシルアミン等）を用いるときは、工程（ｉｉ）の反応は好ましくは中和剤を用いて行われる。中和剤は、ヒドロキシルアミン塩を中和してフリーのヒドロキシルアミンを遊離するための塩基である。中和剤の例は、アルカリ金属水酸化物類（例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等）、アルカリ土類金属水酸化物類（例えば、水酸化マグネシウム、水酸化カルシウム、水酸化バリウム等）、アルカリ金属炭酸塩類（例えば、炭酸リチウム、炭酸ナトリウム、炭酸カリウム等）、アルカリ土類金属炭酸塩類（例えば、炭酸マグネシウム、炭酸カルシウム、炭酸バリウム等）、アルカリ金属炭酸水素塩類（例えば、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム等）、アルカリ金属カルボン酸塩類（例えば、酢酸リチウム、酢酸ナトリウム、酢酸カリウム等）、アミン類（例えば、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５．４．０］－７－ウンデカ－７－エン（ＤＢＵ）、ピリジン等）、アンモニア（例えば、２５～３０％アンモニア水、アンモニアガス、好ましくは２５～３０％アンモニア水）を含むが、これらに限定されない。中和剤の好ましい例は、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等、アンモニア、より好ましくは、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、アンモニア、更に好ましくは水酸化ナトリウムを含む。水酸化ナトリウムの例は、水酸化ナトリウムビーズ、４８％水酸化ナトリウム水溶液、２５％水酸化ナトリウム水溶液、１０％水酸化ナトリウム水溶液、好ましくは４８％水酸化ナトリウム水溶液、２５％水酸化ナトリウム水溶液、より好ましくは４８％水酸化ナトリウム水溶液を含むが、これらに限定されない。中和剤は、単独で又は任意の割合の２種以上の組み合わせで使用してもよい。中和剤の形態は、反応が進行する限りは、いずれの形態でもよい。その形態の例は、中和剤のみの固体、液体及びガス、並びに任意の濃度の水溶液及び水以外の溶媒（例えば、有機溶媒）の溶液等を含む。中和剤の形態は、当業者が適切に選択することができる。 When using a hydroxylamine salt (eg, hydroxylamine hydrochloride, hydroxylamine sulfate, etc.), the reaction in step (ii) is preferably carried out using a neutralizing agent. Neutralizing agents are bases for neutralizing hydroxylamine salts to liberate free hydroxylamine. Examples of neutralizing agents include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, water barium oxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, barium carbonate, etc.), alkali metal hydrogen carbonates (e.g., , lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal carboxylates (e.g., lithium acetate, sodium acetate, potassium acetate, etc.), amines (e.g., triethylamine, tributylamine, diisopropylethylamine, 1,8 -diazabicyclo[5.4.0]-7-undec-7-ene (DBU), pyridine, etc.), ammonia (eg, 25-30% ammonia water, ammonia gas, preferably 25-30% ammonia water) but not limited to these. Preferred examples of neutralizing agents include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., ammonia, more preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, ammonia, More preferably it contains sodium hydroxide. Examples of sodium hydroxide are sodium hydroxide beads, 48% aqueous sodium hydroxide solution, 25% aqueous sodium hydroxide solution, 10% aqueous sodium hydroxide solution, preferably 48% aqueous sodium hydroxide solution, 25% aqueous sodium hydroxide solution, and more It preferably contains, but is not limited to, 48% sodium hydroxide aqueous solution. Neutralizing agents may be used alone or in combination of two or more in any proportion. The form of the neutralizing agent may be any form as long as the reaction proceeds. Examples of its form include solids, liquids and gases of the neutralizing agent alone, as well as aqueous solutions of any concentration and solutions in solvents other than water (eg, organic solvents), and the like. The form of the neutralizing agent can be appropriately selected by those skilled in the art.
　工程（ｉｉ）の中和剤の使用量は、反応が進行する限りは、いずれの量でもよい。収率、副生成物抑制および経済効率等の観点から、式（３）の化合物又は式（４）の化合物１モルに対して、０．５～３．０モル、好ましくは０．５～１．５モル、より好ましくは０．８～１．５モル、更に好ましくは１．０～１．３モルである。 The amount of the neutralizing agent used in step (ii) may be any amount as long as the reaction proceeds. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0.5 to 3.0 mol, preferably 0.5 to 1 mol, per 1 mol of the compound of formula (3) or the compound of formula (4) 0.5 mol, more preferably 0.8 to 1.5 mol, still more preferably 1.0 to 1.3 mol.
（工程（ｉｉ）の溶媒）
　反応の円滑な進行、安全性等の観点から、工程（ｉｉ）の反応は溶媒の存在下で実施することが好ましい。溶媒は、工程（ｉｉ）の反応が進行し且つ安全が確保される限りは、いずれの溶媒でもよい。溶媒の例は、水、アルコール類（例えば、メタノール、エタノール、２－プロパノール、ブタノール、ｔｅｒｔ－ブタノール（ｔｅｒｔ－ブタノールはｔｅｒｔ－ブチルアルコールとも言う）等）、エーテル類（例えば、テトラヒドロフラン（ＴＨＦ）、１，４－ジオキサン、ジイソプロピルエーテル、ジブチルエーテル、ジ－ｔｅｒｔ－ブチルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）、メチル－ｔｅｒｔ－ブチルエーテル、１，２－ジメトキシエタン（ＤＭＥ）、ニトリル類（例えば、（Ｃ２－Ｃ４）アルカンニトリル、（具体的には、例えば、アセトニトリル等））、カルボン酸エステル類（例えば、（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート、（具体的には、例えば、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル及びその異性体、酢酸ペンチル及びその異性体等））、芳香族炭化水素誘導体類（例えば、ベンゼン、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ニトロベンゼン等）、ハロゲン化脂肪族炭化水素類（例えば、（Ｃ１－Ｃ３）ジクロロアルカン、（具体的には、例えば、ジクロロメタン、クロロホルム、１，２－ジクロロエタン（ＥＤＣ）等））、脂肪族炭化水素類（例えば、ヘキサン、へプタン、オクタン、シクロヘキサン、エチルシクロヘキサン等）及び任意の割合のそれらの任意の組み合わせを含むが、これらに限定されない。しかしながら、ヒドロキシルアミンを用いる安全性の観点から、工程（ｉｉ）の反応は水の存在下で行うことが好ましい。なお、いずれの場合も、反応が進行する限りは、溶媒は単層でも２層に分離してもよい。 (solvent in step (ii))
From the viewpoints of smooth progress of the reaction, safety, etc., the reaction of step (ii) is preferably carried out in the presence of a solvent. Any solvent may be used as long as the reaction in step (ii) proceeds and safety is ensured. Examples of solvents include water, alcohols (e.g., methanol, ethanol, 2-propanol, butanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), etc.), ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), nitriles (e.g., (C2-C4 ) alkanenitrile, (specifically, for example, acetonitrile, etc.)), carboxylic acid esters (for example, (C1-C6) alkyl (C2-C4) carboxylate, (specifically, for example, methyl acetate, acetic acid ethyl, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, etc.)), aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitrobenzene, etc.), halogens aliphatic hydrocarbons (e.g., (C1-C3) dichloroalkanes, (specifically, e.g., dichloromethane, chloroform, 1,2-dichloroethane (EDC), etc.)), aliphatic hydrocarbons (e.g., hexane , heptane, octane, cyclohexane, ethylcyclohexane, etc.) and any combination thereof in any proportion.However, from a safety standpoint using hydroxylamine, the reaction of step (ii) is The reaction is preferably carried out in the presence of water.In any case, the solvent may separate into a single layer or two layers as long as the reaction proceeds.
　反応性、収率、安全性、経済効率等の観点から、工程（ｉｉ）の溶媒の好ましい例は、水、アルコール類、エーテル類、ニトリル類、カルボン酸エステル類、芳香族炭化水素誘導体類、ハロゲン化脂肪族炭化水素類及び任意の割合のそれらの任意の組み合わせ、より好ましくは水、ニトリル類、カルボン酸エステル類、芳香族炭化水素誘導体類、ハロゲン化脂肪族炭化水素類及び任意の割合のそれらの任意の組み合わせ、更に好ましくは水、ニトリル類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル）、カルボン酸エステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）、ハロゲン化脂肪族炭化水素類（好ましくは（Ｃ１－Ｃ３）ジクロロアルカン）及び任意の割合のそれらの任意の組み合わせを含む。ただし、いずれの場合も水の存在が好ましい。
　従って、例えば、任意の割合の水とニトリル類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル）の組み合わせが好ましい。
　他の例としては、任意の割合の水とカルボン酸エステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）の組み合わせが好ましい。
　更に他の例としては、任意の割合の水とハロゲン化脂肪族炭化水素類（好ましくは（Ｃ１－Ｃ３）ジクロロアルカン）の組み合わせが好ましい。
　工程（ｉｉ）の溶媒の好ましい具体的な例は、水、メタノール、エタノール、２－プロパノール、ｔｅｒｔ－ブタノール、アセトニトリル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、テトラヒドロフラン（ＴＨＦ）、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ジクロロメタン及び任意の割合のそれらの任意の組み合わせ、より好ましくは水、アセトニトリル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ジクロロメタン及び任意の割合のそれらの任意の組み合わせ、更に好ましくは水、アセトニトリル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、ジクロロメタン及び任意の割合のそれらの任意の組み合わせを含む。ただし、いずれの場合も水の存在が好ましい。
　従って、例えば、任意の割合の水とアセトニトリルの組み合わせが好ましい。
　他の例としては、任意の割合の水と酢酸ブチルおよびその異性体の組み合わせが好ましく、任意の割合の水と酢酸ブチルの組み合わせがより好ましい。
　更に他の例としては、任意の割合の水とジクロロメタンの組み合わせが好ましい。
　いずれの場合も、反応が進行する限りは、溶媒は単層でも２層に分離してもよい。 Preferred examples of the solvent in step (ii) from the viewpoint of reactivity, yield, safety, economic efficiency, etc. are water, alcohols, ethers, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, Halogenated aliphatic hydrocarbons and any combination thereof in any proportion, more preferably water, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons and any proportion Any combination thereof, more preferably water, nitriles (preferably (C2-C4) alkanenitriles), carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates), halogenated fats group hydrocarbons (preferably (C1-C3) dichloroalkanes) and any combination thereof in any proportion. However, the presence of water is preferred in either case.
Thus, for example, combinations of water and nitriles (preferably (C2-C4)alkanenitrile) in any proportion are preferred.
As another example, combinations of water and carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates) in any proportion are preferred.
As yet another example, a combination of any proportion of water and halogenated aliphatic hydrocarbons (preferably (C1-C3) dichloroalkane) is preferred.
Preferred specific examples of solvents in step (ii) are water, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, tetrahydrofuran (THF), toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isomers thereof , toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, dichloromethane and including any combination thereof in any proportion. However, the presence of water is preferred in either case.
Thus, for example, combinations of water and acetonitrile in any proportion are preferred.
As another example, a combination of water and butyl acetate and its isomers in any proportion is preferred, and a combination of water and butyl acetate in any proportion is more preferred.
As yet another example, any combination of water and dichloromethane in any proportion is preferred.
In either case, the solvent may separate into a single layer or two layers as long as the reaction proceeds.
　ヒドロキシルアミン水溶液由来の水は、溶媒として理解することができる。ヒドロキシルアミン塩（例えば、塩酸ヒドロキシルアミン、硫酸ヒドロキシルアミン等）と共に中和剤を用いたときは、中和剤の水溶液（例えば、４８％水酸化ナトリウム水溶液）由来の水もまた、溶媒として理解することができる。中和により生成する水もまた、溶媒として理解することができる。 The water derived from the aqueous hydroxylamine solution can be understood as a solvent. When a neutralizing agent is used with a hydroxylamine salt (e.g., hydroxylamine hydrochloride, hydroxylamine sulfate, etc.), water from an aqueous solution of the neutralizing agent (e.g., 48% aqueous sodium hydroxide solution) is also understood as solvent. be able to. Water produced by neutralization can also be understood as solvent.
　工程（ｉｉ）の溶媒の使用量は、反応系の撹拌が十分にできる限りは、いずれの量でもよい。収率、副生成物抑制、経済効率等の観点から、式（３）の化合物又は式（４）の化合物１モルに対して、０（ゼロ）～１０Ｌ（リットル）、好ましくは０．０２～５Ｌ、より好ましくは０．０２～１Ｌ、更に好ましくは０．１～１Ｌである。しかしながら、その使用量は当業者が適切に調整することができる。２種以上の溶媒の組み合わせを用いるときは、２種以上の溶媒の割合は、反応が進行する限りは、いずれの割合でもよい。その割合は当業者が適切に調整することができる。溶媒は、反応が進行する限りは、単層でも２層に分離してもよい。 The amount of solvent used in step (ii) may be any amount as long as the reaction system can be sufficiently stirred. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0 (zero) to 10 L (liter), preferably 0.02 to 1 mol of the compound of formula (3) or the compound of formula (4) 5 L, more preferably 0.02 to 1 L, still more preferably 0.1 to 1 L. However, the amount used can be appropriately adjusted by those skilled in the art. When using a combination of two or more solvents, the ratio of the two or more solvents may be any ratio as long as the reaction proceeds. The ratio can be adjusted appropriately by those skilled in the art. The solvent may separate into a single layer or two layers as long as the reaction proceeds.
　（工程（ｉｉ）の反応温度）
　工程（ｉｉ）の反応温度は、特に制限されない。収率、副生成物抑制、経済効率等の観点から、－３０℃（マイナス３０℃）～１６０℃、好ましくは－１０℃～８０℃、より好ましくは０℃～８０℃、更に好ましくは１０℃～５０℃、更に好ましくは室温（１０℃～３５℃）を例示できる。しかしながら、反応温度は当業者が適切に調整することができる。 (Reaction temperature in step (ii))
The reaction temperature in step (ii) is not particularly limited. -30°C (minus 30°C) to 160°C, preferably -10°C to 80°C, more preferably 0°C to 80°C, still more preferably 10°C, from the viewpoint of yield, suppression of by-products, economic efficiency, etc. Up to 50°C, more preferably room temperature (10°C to 35°C) can be exemplified. However, the reaction temperature can be adjusted appropriately by those skilled in the art.
　（工程（ｉｉ）の反応時間）
　工程（ｉｉ）の反応時間は、特に制限されない。収率、副生成物抑制および経済効率等の観点から、０．５時間～４８時間、好ましくは０．５時間～２４時間、より好ましくは０．５時間～１２時間である。しかしながら、反応時間は当業者が適切に調整することができる。 (Reaction time of step (ii))
The reaction time of step (ii) is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the time is 0.5 hours to 48 hours, preferably 0.5 hours to 24 hours, more preferably 0.5 hours to 12 hours. However, the reaction time can be adjusted appropriately by those skilled in the art.
　（工程（ｉｉ）の生成物；式（５）の化合物又は式（６）の化合物）
　工程（ｉｉ）の生成物は、原料として用いた式（３）の化合物又は式（４）の化合物に相当する式（５）の化合物又は式（６）の化合物である。具体的な例は、以下を含むが、これらに限定されない；３－メチル－２－ブテナールオキシム、３－ヒドロキシ－３－メチルブタナールオキシム（３－ヒドロキシ－３－メチル－ブタン－１－アールオキシムとも言う）、３－メトキシ－３－メチルブタナールオキシム、３－エトキシ－３－メチルブタナールオキシム、３－メチル－３－プロポキシブタナールオキシム、３－イソプロポキシ－３－メチルブタナールオキシム、３－ブトキシ－３－メチルブタナールオキシム、３－イソブトキシ－３－メチルブタナールオキシム、３－（sec-ブトキシ）－３－メチルブタナールオキシム、３－メチル－３－フェノキシブタナールオキシム、３－（ベンジルオキシ）－３－メチルブタナールオキシム、３－ヒドロキシ－３－メチル－ペンタナールオキシム、３－エチル－３－ヒドロキシペンタナールオキシム、３－ヒドロキシ－３，４－ジメチルペンタナールオキシム、３－ヒドロキシ－３，４，４－トリメチルペンタナールオキシム、４－クロロ－３－ヒドロキシ－３－メチルブタナールオキシム、４，４，４－トリフルオロ－３－ヒドロキシ－３－メチルブタナールオキシム、２－（１－ヒドロキシシクロプロピル）アセトアルドキシムオキシム、２－（１－ヒドロキシシクロブチル）アセトアルドキシム、２－（１－ヒドロキシシクロペンチル）アセトアルドキシム、２－（１－ヒドロキシシクロヘキシル）アセトアルドキシム、３－ヒドロキシ－３－メチル－ヘプタナールオキシム、３－ヒドロキシ－３，７－ジメチル－６－オクテナールオキシム、３－ヒドロキシ－３，７－ジメチルオクタナールオキシム、３－（９Ｈ－フルオレン－９－イリデン）－３－ヒドロキシプロパナールオキシム、３－ヒドロキシ－３，３－ジフェニル－２－プロパナールオキシム、３－ヒドロキシ－３，３－ビス（４－メチルフェニル）プロパナールオキシム、３－ヒドロキシ－３，３－ビス（４－メトキシフェニル）プロパナールオキシム、３－ヒドロキシ－３，３－ビス（４－クロロフェニル）プロパナールオキシム、３－ヒドロキシ－３－フェニルブタナールオキシム、３－ヒドロキシ－３－（４－メチルフェニル）ブタナールオキシム、３－ヒドロキシ－３－（４－メトキシフェニル）ブタナールオキシム、３－ヒドロキシ－３－（４－クロロフェニル）ブタナールオキシム等。生成物の有用性等の観点から、式（５）の化合物の好ましい具体的な例は、３－ヒドロキシ－３－メチルブタナールオキシム及び３－メトキシ－３－メチルブタナールオキシム、より好ましくは３－メトキシ－３－メチルブタナールオキシムである。式（６）の好ましい具体的な例は、３－メチル－２－ブテナールオキシムである。 (product of step (ii); compound of formula (5) or compound of formula (6))
The product of step (ii) is the compound of formula (5) or the compound of formula (6) corresponding to the compound of formula (3) or the compound of formula (4) used as starting material. Specific examples include, but are not limited to; 3-methyl-2-butenal oxime, 3-hydroxy-3-methylbutanal oxime (3-hydroxy-3-methyl-butane-1- oxime), 3-methoxy-3-methylbutanal oxime, 3-ethoxy-3-methylbutanal oxime, 3-methyl-3-propoxybutanal oxime, 3-isopropoxy-3-methylbutanal oxime , 3-butoxy-3-methylbutanal oxime, 3-isobutoxy-3-methylbutanal oxime, 3-(sec-butoxy)-3-methylbutanal oxime, 3-methyl-3-phenoxybutanal oxime, 3 -(benzyloxy)-3-methylbutanal oxime, 3-hydroxy-3-methyl-pentanal oxime, 3-ethyl-3-hydroxypentanal oxime, 3-hydroxy-3,4-dimethylpentanal oxime, 3 -hydroxy-3,4,4-trimethylpentanal oxime, 4-chloro-3-hydroxy-3-methylbutanal oxime, 4,4,4-trifluoro-3-hydroxy-3-methylbutanal oxime, 2 -(1-hydroxycyclopropyl)acetaldoxime oxime, 2-(1-hydroxycyclobutyl)acetaldoxime, 2-(1-hydroxycyclopentyl)acetaldoxime, 2-(1-hydroxycyclohexyl)acetaldoxime, 3-hydroxy-3-methyl-heptanal oxime, 3-hydroxy-3,7-dimethyl-6-octenal oxime, 3-hydroxy-3,7-dimethyloctanal oxime, 3-(9H-fluorene-9- ylidene)-3-hydroxypropanal oxime, 3-hydroxy-3,3-diphenyl-2-propanal oxime, 3-hydroxy-3,3-bis(4-methylphenyl) propanal oxime, 3-hydroxy-3 , 3-bis(4-methoxyphenyl)propanal oxime, 3-hydroxy-3,3-bis(4-chlorophenyl)propanal oxime, 3-hydroxy-3-phenylbutanal oxime, 3-hydroxy-3-( 4-methylphenyl)butanal oxime, 3-hydroxy-3-(4-methoxyphenyl)butanal oxime, 3-hydroxy-3-(4-chlorophenyl)butanal oxime and the like. Preferred specific examples of the compound of formula (5) are 3-hydroxy-3-methylbutanal oxime and 3-methoxy-3-methylbutanal oxime, more preferably 3 -Methoxy-3-methylbutanal oxime. A preferred specific example of formula (6) is 3-methyl-2-butenaloxime.
　工程（ｉｉ）の生成物である式（５）の化合物又は式（６）の化合物は、工程（ｉｉｉ）の原料として使用することができる。工程（ｉｉ）で得られる式（５）の化合物又は式（６）の化合物は、単離して次工程に用いてもよく、さらに精製して次工程に用いてもよく、または単離することなく次工程に用いてもよい。しかしながら、単離することなく次工程に用いることが効率がよい。 The compound of formula (5) or the compound of formula (6), which is the product of step (ii), can be used as a starting material for step (iii). The compound of formula (5) or the compound of formula (6) obtained in step (ii) may be isolated and used in the next step, may be further purified and used in the next step, or may be isolated It may be used in the next step without However, it is efficient to use it in the next step without isolation.
　（工程（ｉｉｉ））
　工程（ｉｉｉ）について説明する。
　以下の工程（ｉｉｉ）の全ての説明は、工程（ｉｉｉ－ａ）及び工程（ｉｉｉ－ｂ）に適用される。ただし、該当しない場合を除く。 (Step (iii))
Step (iii) will be explained.
All descriptions of step (iii) below apply to steps (iii-a) and (iii-b). Unless otherwise applicable.
　工程（ｉｉｉ）の反応は、環化反応である。工程（ｉｉｉ）は環化工程ともいう。工程（ｉｉｉ）は、触媒の存在下で式（５）の化合物又は式（６）の化合物を反応させて、式（７）の化合物を製造する工程である。 The reaction of step (iii) is a cyclization reaction. Step (iii) is also referred to as a cyclization step. Step (iii) is a step of reacting the compound of formula (5) or the compound of formula (6) in the presence of a catalyst to produce the compound of formula (7).
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。） (wherein R 1 , R 2 and R 3 are as defined above).
　（工程（ｉｉｉ）の原料；式（５）の化合物又は式（６）の化合物）
　工程（ｉｉｉ）の原料として、式（５）の化合物又は式（６）の化合物を用いる。式（５）の化合物又は式（６）の化合物は公知の化合物であるか、又は公知の化合物から公知の方法に準じて製造することができる。加えて、式（５）の化合物又は式（６）の化合物は上記工程（ｉｉ）の方法により製造することができる。式（５）の化合物又は式（６）の化合物の具体的な例及び好ましい具体的な例は、上記の通りである。 (Raw material of step (iii); compound of formula (5) or compound of formula (6))
The compound of formula (5) or the compound of formula (6) is used as the starting material for step (iii). The compound of formula (5) or the compound of formula (6) is a known compound, or can be produced from a known compound according to a known method. In addition, compounds of formula (5) or compounds of formula (6) can be prepared by the method of step (ii) above. Specific examples and preferred specific examples of the compound of formula (5) or the compound of formula (6) are as described above.
　（工程（ｉｉｉ）の触媒）
　工程（ｉｉｉ）の触媒は、反応が進行する限りは、いずれの触媒でもよい。好ましくは、酸触媒を使用でき、又は酸触媒と塩基触媒を使用できる。
　（工程（ｉｉｉ）の酸触媒）
　本発明の一つの様態では、酸触媒の存在下で式（７）の化合物を製造する。酸触媒は、反応が進行する限りは、いずれの酸触媒でもよい。加えて、反応が進行する限りは、以下のいずれの形態が使用されてもよく、本発明の範囲に含まれる。酸触媒として、遊離の酸を使用できる。酸触媒は塩の形態で使用してもよい。
酸触媒が塩の場合は、酸触媒は単塩でもよく、複塩でもよい。酸触媒は無水物の形態で使用してもよい。酸触媒は水和物の形態で使用してもよい。酸触媒は二量体等の形態で使用してもよい。 (Catalyst of step (iii))
The catalyst in step (iii) can be any catalyst as long as the reaction proceeds. Preferably, an acid catalyst can be used, or an acid catalyst and a base catalyst can be used.
(Acid catalyst in step (iii))
In one aspect of the invention, compounds of formula (7) are prepared in the presence of an acid catalyst. The acid catalyst may be any acid catalyst as long as the reaction proceeds. Additionally, as long as the reaction proceeds, any of the following forms may be used and are within the scope of the present invention. Free acids can be used as acid catalysts. Acid catalysts may be used in the form of salts.
When the acid catalyst is a salt, the acid catalyst may be a single salt or a double salt. The acid catalyst may be used in the anhydride form. Acid catalysts may be used in the form of hydrates. The acid catalyst may be used in the form of dimers and the like.
　工程（ｉｉｉ）の酸触媒の例は、以下を含むが、これらに限定されない。 Examples of acid catalysts in step (iii) include, but are not limited to:
　ａ）鉱酸類
　工程（ｉｉｉ）の酸触媒として、鉱酸を使用することができる。鉱酸の例は、塩酸、硫酸、硝酸、リン酸を含む。 a) Mineral Acids Mineral acids can be used as acid catalysts in step (iii). Examples of mineral acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.
　ｂ）カルボン酸類
　工程（ｉｉｉ）の酸触媒として、カルボン酸、その塩及び無水物を使用することができる。従って、カルボン酸は、遊離の酸として使用してもよく、又はその塩として使用してもよい。加えて、カルボン酸はその無水物として使用してもよい。カルボン酸の具体的な例は、酢酸、トリフルオロ酢酸（ＴＦＡ）、トリクロロ酢酸、ジクロロ酢酸、マレイン酸、クエン酸、安息香酸、フタル酸を含む。好ましいカルボン酸の具体的な例は、トリフルオロ酢酸、トリクロロ酢酸、ジクロロ酢酸、マレイン酸を含む。カルボン酸塩の具体的な例は、トリフルオロ酢酸アンモニウム（ＣＦ３ＣＯＯ－ＮＨ４ ＋））、トリフルオロ酢酸Ｎ－メチルアニリウム（ＣＦ３ＣＯＯ－Ｃ６Ｈ５Ｎ＋（ＣＨ３）Ｈ２）を含む。カルボン酸無水物の具体的な例は、無水トリフルオロ酢酸、無水マレイン酸、無水フタル酸を含む。好ましいカルボン酸無水物の具体的な例は、無水マレイン酸を含む。 b) Carboxylic Acids Carboxylic acids, their salts and anhydrides can be used as acid catalysts in step (iii). Accordingly, the carboxylic acid may be used as the free acid or as its salt. Additionally, the carboxylic acid may be used as its anhydride. Specific examples of carboxylic acids include acetic acid, trifluoroacetic acid (TFA), trichloroacetic acid, dichloroacetic acid, maleic acid, citric acid, benzoic acid, phthalic acid. Specific examples of preferred carboxylic acids include trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid. Specific examples of carboxylates are ammonium trifluoroacetate (CF 3 COO - NH 4 + )), N-methylanilium trifluoroacetate (CF 3 COO - C 6 H 5 N + (CH 3 )H 2 )including. Specific examples of carboxylic anhydrides include trifluoroacetic anhydride, maleic anhydride, phthalic anhydride. A specific example of a preferred carboxylic anhydride includes maleic anhydride.
ｃ）スルホン酸類
　工程（ｉｉｉ）の酸触媒として、スルホン酸、その塩及び無水物を使用することができる。
従って、スルホン酸は、遊離の酸として使用してもよく、又はその塩として使用してもよい。加えて、スルホン酸はその無水物として使用してもよい。スルホン酸の例は、メタンスルホン酸、トリフルオロメタンスルホン酸（ＴｆＯＨ）、ベンゼンスルホン酸、ｐ－トルエンスルホン酸（ｐ－トルエンスルホン酸一水和物（ＴｓＯＨ・Ｈ２Ｏ）を含む）、１０－カンファースルホン酸を含む。スルホン酸塩の例は、ｐ－トルエンスルホン酸ピリジニウム（ＰＰＴＳ）を含む。スルホン酸無水物の例は、無水メタンスルホン酸、無水トリフルオロメタンスルホン酸を含む。 c) Sulfonic Acids Sulfonic acids, their salts and anhydrides can be used as acid catalysts in step (iii).
Accordingly, the sulfonic acid may be used as the free acid or as its salt. Additionally, the sulfonic acid may be used as its anhydride. Examples of sulfonic acids include methanesulfonic acid, trifluoromethanesulfonic acid (TfOH), benzenesulfonic acid, p-toluenesulfonic acid (including p-toluenesulfonic acid monohydrate (TsOH.H 2 O)), 10- Contains camphorsulfonic acid. Examples of sulfonates include pyridinium p-toluenesulfonate (PPTS). Examples of sulfonic anhydrides include methanesulfonic anhydride, trifluoromethanesulfonic anhydride.
　収率、経済効率等の観点から、一つの態様では、酸触媒の好ましい例は、以下の通りであるが、これらに限定されない。
　鉱酸類、カルボン酸類、スルホン酸類及びリン酸類からなる群より選ばれる１個以上（好ましくは１～３個、より好ましくは１又は２個、更に好ましくは１個）の酸が好ましい。 From the viewpoint of yield, economic efficiency, etc., in one embodiment, preferred examples of the acid catalyst are as follows, but are not limited thereto.
One or more (preferably 1 to 3, more preferably 1 or 2, still more preferably 1) acids selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids and phosphoric acids are preferred.
　塩基触媒としては、アミン類が好ましい。 Amines are preferable as the basic catalyst.
　アミン類は、下記式：  Amines have the following formula:
　Ｒ６Ｒ７Ｒ８Ｎ R6R7R8N _ _
　（式中、Ｒ６、Ｒ７及びＲ８はそれぞれ独立して、水素原子、置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ２－Ｃ６）アルケニル；置換されていてもよい（Ｃ２－Ｃ６）アルキニル；又は置換されていてもよいアリールであり；あるいはＲ６、Ｒ７及びＲ８のいずれか２つはそれらが結合している窒素原子と一緒になって、４～１２員の複素環を形成し、ここで形成された環は置換されていてもよい。ここで、Ｒ６、Ｒ７及びＲ８の少なくとも一つは水素原子ではない）の第１級アミン、第２級アミン、第３級アミン、又は複素環式アミンであってよい。 (wherein R 6 , R 7 and R 8 are each independently a hydrogen atom, optionally substituted (C1-C6) alkyl; optionally substituted (C3-C6) cycloalkyl; substituted optionally substituted (C2-C6)alkenyl; optionally substituted (C2-C6)alkynyl; or optionally substituted aryl; or any two of R 6 , R 7 and R 8 are taken together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclic ring wherein the ring formed is optionally substituted wherein R 6 , R 7 and R 8 is not a hydrogen atom) primary amines, secondary amines, tertiary amines, or heterocyclic amines.
　第１級アミンの具体的な例は、メチルアミン、エチルアミン、プロピルアミン、ブチルアミン、アニリン等を含むが、これらに限定されない。第２級アミンの具体的な例は、ジエチルアミン、ジプロピルアミン、ジイソプロピルアミン、Ｎ－メチルアニリン（ＰｈＮＨＭｅ；本明細書中、Ｎ－ＭｅＡｎｉｌｉｎｅと略記することがある）、Ｎ－エチルアニリン、ピペリジン、モルホリン等を含むが、これらに限定されない。 Specific examples of primary amines include, but are not limited to, methylamine, ethylamine, propylamine, butylamine, aniline, and the like. Specific examples of secondary amines include diethylamine, dipropylamine, diisopropylamine, N-methylaniline (PhNHMe; herein sometimes abbreviated as N-MeAniline), N-ethylaniline, piperidine, Including, but not limited to, morpholine and the like.
　第３級アミンの具体的な例は、トリエチルアミン、トリプロピルアミン、トリブチルアミン、ジイソプロピルエチルアミン、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、Ｎ，Ｎ－ジメチルアニリン、Ｎ，Ｎ－ジエチルアニリン等を含むが、これらに限定されない。 Specific examples of tertiary amines are triethylamine, tripropylamine, tributylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-dimethylaniline, N,N - including but not limited to diethylaniline and the like;
　複素環式アミンの具体的な例は、ピリジン、４－（ジメチルアミノ）－ピリジン、４－ピロリジノピリジン、２，６－ルチジン、キノリン、イソキノリン、１，８－ジアザビシクロ［５．４．０］－７－ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）等を含むが、これらに限定されない。 Specific examples of heterocyclic amines are pyridine, 4-(dimethylamino)-pyridine, 4-pyrrolidinopyridine, 2,6-lutidine, quinoline, isoquinoline, 1,8-diazabicyclo[5.4.0] -7-undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and the like.
　４－（ジメチルアミノ）－ピリジン、４－ピロリジノピリジン、１，８－ジアザビシクロ［５．４．０］－７－ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）は、３級アミンにも属する。 4-(dimethylamino)-pyridine, 4-pyrrolidinopyridine, 1,8-diazabicyclo[5.4.0]-7-undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0 ]non-5-enes (DBN) also belong to tertiary amines.
　アミン類の例は、イミダゾリノン類もまた含む。イミダゾリノン類の具体的な例は、（２Ｓ，５Ｓ）－２－ｔｅｒｔ－ブチル－３－メチル－５－ベンジル－４－イミダゾリノン及びそのジアステレオマー等の光学異性体、並びにそれらの類縁体を含む。しかしながら、イミダゾリノン類は高価であるから、イミダゾリノン類を使用しないことが工業的に好ましい。 Examples of amines also include imidazolinones. Specific examples of imidazolinones include optical isomers such as (2S,5S)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone and diastereomers thereof, and analogs thereof including. However, since imidazolinones are expensive, it is industrially preferable not to use imidazolinones.
　収率、経済効率等の観点から、酸塩基触媒の塩基の好ましい例は、第２級アミン又は複素環式アミンを含む。酸塩基触媒の塩基の好ましい具体的な例は、Ｎ－メチルアニリン又はピリジンを含む。 From the viewpoint of yield, economic efficiency, etc., preferred examples of the base of the acid-base catalyst include secondary amines or heterocyclic amines. Preferred specific examples of acid-base catalyst bases include N-methylaniline or pyridine.
　酸触媒の使用量は、収率、副生成物の抑制、経済効率等の観点から、式（５）の化合物又は式（６）の化合物１モルに対して、０．０１～１．０モル、好ましくは０．０１～０．６０モル、より好ましくは０．０２～０．５０モル、０．０５～０．４０モルの範囲を例示できる。塩基触媒の使用量は、収率、副生成物の抑制、経済効率等の観点から、式（５）の化合物又は式（６）の化合物１モルに対して、０（ゼロ）～１．０モルの範囲を例示できる。塩基触媒を用いる場合は、塩基触媒の使用量は、０．０１～１．０モル、好ましくは０．０１～０．６０モル、より好ましくは０．０２～０．５０モル、０．０５～０．４０モルの範囲を例示できる。塩基触媒を用いる場合は、塩基触媒と酸塩基触媒の比率は１：１であってもよく、１：１でなくともよい。 The amount of the acid catalyst used is 0.01 to 1.0 mol per 1 mol of the compound of formula (5) or the compound of formula (6), from the viewpoint of yield, suppression of by-products, economic efficiency, etc. , preferably 0.01 to 0.60 mol, more preferably 0.02 to 0.50 mol, and 0.05 to 0.40 mol. The amount of the basic catalyst used is 0 (zero) to 1.0 per 1 mol of the compound of formula (5) or the compound of formula (6) from the viewpoint of yield, suppression of by-products, economic efficiency, etc. Molar ranges can be exemplified. When a basic catalyst is used, the amount of the basic catalyst used is 0.01 to 1.0 mol, preferably 0.01 to 0.60 mol, more preferably 0.02 to 0.50 mol, and 0.05 to 0.05 mol. A range of 0.40 mol can be exemplified. When a base catalyst is used, the ratio of the base catalyst to the acid-base catalyst may be 1:1, or may not be 1:1.
（工程（ｉｉｉ）の溶媒）
　工程（ｉｉｉ）の反応は、溶媒の存在下又は非存在下（無溶媒）で行うことができる。工程（ｉｉｉ）の反応で溶媒を使用する場合は、工程（ｉｉｉ）の反応が進行する限りは、いずれの溶媒でもよい。溶媒を使用する場合は、溶媒の例は、水、アルコール類（例えば、メタノール、エタノール、２－プロパノール、ブタノール、ｔｅｒｔ－ブタノール（ｔｅｒｔ－ブタノールはｔｅｒｔ－ブチルアルコールとも言う）等）、エーテル類（例えば、テトラヒドロフラン（ＴＨＦ）、１，４－ジオキサン、ジイソプロピルエーテル、ジブチルエーテル、ジ－ｔｅｒｔ－ブチルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）、メチル－ｔｅｒｔ－ブチルエーテル、１，２－ジメトキシエタン（ＤＭＥ）、ニトリル類（例えば、（Ｃ２－Ｃ４）アルカンニトリル、（具体的には、例えば、アセトニトリル等））、カルボン酸エステル類（例えば、（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート、具体的には、例えば、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル及びその異性体、酢酸ペンチル及びその異性体等））、芳香族炭化水素誘導体類（例えば、ベンゼン、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ニトロベンゼン等）、ハロゲン化脂肪族炭化水素類（例えば、（Ｃ１－Ｃ３）ジクロロアルカン、具体的には、例えば、ジクロロメタン、クロロホルム、１，２－ジクロロエタン（ＥＤＣ）等）、脂肪族炭化水素類（例えば、ヘキサン、へプタン、オクタン、シクロヘキサン、エチルシクロヘキサン等）及び任意の割合のそれらの任意の組み合わせを含むが、これらに限定されない。なお、いずれの場合も、反応が進行する限りは、溶媒は単層でも２層に分離してもよい。 (Solvent in step (iii))
The reaction of step (iii) can be carried out in the presence or absence of a solvent (no solvent). When a solvent is used in the reaction of step (iii), any solvent may be used as long as the reaction of step (iii) proceeds. Examples of solvents when using solvents include water, alcohols (e.g., methanol, ethanol, 2-propanol, butanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), etc.), ethers ( For example, tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), nitriles (e.g., (C2-C4) alkanenitrile, (specifically, for example, acetonitrile, etc.)), carboxylic acid esters (e.g., (C1-C6) alkyl (C2-C4) carboxylate, specifically, (e.g., methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, etc.)), aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene , nitrobenzene, etc.), halogenated aliphatic hydrocarbons (e.g., (C1-C3) dichloroalkanes, specifically, e.g., dichloromethane, chloroform, 1,2-dichloroethane (EDC), etc.), aliphatic hydrocarbons (eg, hexane, heptane, octane, cyclohexane, ethylcyclohexane, etc.) and any combination thereof in any proportion. In any case, the solvent may be separated into a single layer or two layers as long as the reaction proceeds.
　反応性、収率、安全性、経済効率等の観点から、工程（ｉｉ）の溶媒の好ましい例は、水、アルコール類、エーテル類、ニトリル類、カルボン酸エステル類、芳香族炭化水素誘導体類、ハロゲン化脂肪族炭化水素類及び任意の割合のそれらの任意の組み合わせ、より好ましくは水、ニトリル類、カルボン酸エステル類、芳香族炭化水素誘導体類、ハロゲン化脂肪族炭化水素類及び任意の割合のそれらの任意の組み合わせ、更に好ましくは水、ニトリル類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル）、カルボン酸エステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）、ハロゲン化脂肪族炭化水素類（好ましくは（Ｃ１－Ｃ３）ジクロロアルカン）及び任意の割合のそれらの任意の組み合わせを含む。水はあってもよく、なくてもよい。
　従って、例えば、任意の割合の水とニトリル類（好ましくは（Ｃ２－Ｃ４）アルカンニトリル）の組み合わせが好ましい。
　他の例としては、任意の割合の水とカルボン酸エステル類（好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレート）の組み合わせが好ましい。
　更に他の例としては、任意の割合の水とハロゲン化脂肪族炭化水素類（好ましくは（Ｃ１－Ｃ３）ジクロロアルカン）の組み合わせが好ましい。
　工程（ｉｉｉ）の溶媒の好ましい具体的な例は、水、メタノール、エタノール、２－プロパノール、ｔｅｒｔ－ブタノール、アセトニトリル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、テトラヒドロフラン（ＴＨＦ）、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ジクロロメタン及び任意の割合のそれらの任意の組み合わせ、より好ましくは水、アセトニトリル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、トルエン、キシレン、クロロベンゼン、ジクロロベンゼン、ジクロロメタン及び任意の割合のそれらの任意の組み合わせ、更に好ましくは水、アセトニトリル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチルおよびその異性体、ジクロロメタン及び任意の割合のそれらの任意の組み合わせを含む。水はあってもよく、なくてもよい。。
　従って、例えば、任意の割合の水とアセトニトリルの組み合わせ、又はアセトニトリルが好ましい。
　他の例としては、任意の割合の水と酢酸ブチルおよびその異性体の組み合わせ、又は酢酸ブチルおよびその異性体が好ましく、任意の割合の水と酢酸ブチルの組み合わせ又は酢酸ブチルがより好ましい。
　更に他の例としては、任意の割合の水とジクロロメタンの組み合わせ、又はジクロロメタンが好ましい。
　いずれの場合も、反応が進行する限りは、溶媒は単層でも２層に分離してもよい。 Preferred examples of the solvent in step (ii) from the viewpoint of reactivity, yield, safety, economic efficiency, etc. are water, alcohols, ethers, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, Halogenated aliphatic hydrocarbons and any combination thereof in any proportion, more preferably water, nitriles, carboxylic acid esters, aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons and any proportion Any combination thereof, more preferably water, nitriles (preferably (C2-C4) alkanenitriles), carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates), halogenated fats group hydrocarbons (preferably (C1-C3) dichloroalkanes) and any combination thereof in any proportion. Water may or may not be present.
Thus, for example, combinations of water and nitriles (preferably (C2-C4)alkanenitrile) in any proportion are preferred.
As another example, combinations of water and carboxylic acid esters (preferably (C1-C6) alkyl (C2-C4) carboxylates) in any proportion are preferred.
As yet another example, a combination of any proportion of water and halogenated aliphatic hydrocarbons (preferably (C1-C3) dichloroalkane) is preferred.
Preferred specific examples of solvents in step (iii) are water, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, tetrahydrofuran (THF), toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isomers thereof , toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion, more preferably water, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, dichloromethane and including any combination thereof in any proportion. Water may or may not be present. .
Thus, for example, a combination of water and acetonitrile in any proportion, or acetonitrile is preferred.
As another example, a combination of water and butyl acetate and its isomers in any proportion, or butyl acetate and its isomers is preferred, and a combination of water and butyl acetate in any proportion or butyl acetate is more preferred.
As yet another example, a combination of water and dichloromethane in any proportion, or dichloromethane is preferred.
In either case, the solvent may separate into a single layer or two layers as long as the reaction proceeds.
　本明細書において、溶媒の非存在下を無溶媒ともいう。 In the present specification, the absence of solvent is also referred to as solvent-free.
　工程（ｉｉｉ）の反応で溶媒を使用する場合の使用量は、反応系の撹拌が十分にできる限りは、いずれの量でもよい。収率、副生成物抑制、経済効率等の観点から、式（５）の化合物又は式（６）の化合物１モルに対して、０（ゼロ）～１０Ｌ（リットル）、好ましくは０．１～５Ｌである。２種以上の溶媒の組み合わせを用いるときは、２種以上の溶媒の割合は、反応が進行する限りは、いずれの割合でもよい。溶媒は、反応が進行する限りは、単層でもよく、２層に分離してもよい。 When using a solvent in the reaction of step (iii), any amount may be used as long as the reaction system can be sufficiently stirred. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0 (zero) to 10 L (liter), preferably 0.1 to 1 mol of the compound of formula (5) or the compound of formula (6) 5L. When using a combination of two or more solvents, the ratio of the two or more solvents may be any ratio as long as the reaction proceeds. The solvent may be a single layer or separated into two layers as long as the reaction proceeds.
　工程（ｉｉ）及び工程（ｉｉｉ）を、式（５）の化合物又は式（６）の化合物を単離することなく行う様態においては、工程（ｉｉｉ）の溶媒等の量は、式（３）又は式（４）の化合物との比率により設定することができる。例えば、工程（ｉｉｉ）の溶媒の使用量は、、式（３）の化合物又は式（４）の化合物１モルに対して、０（ゼロ）～１０Ｌ（リットル）、好ましくは０．１～５Ｌである。 In embodiments in which step (ii) and step (iii) are performed without isolating the compound of formula (5) or the compound of formula (6), the amount of solvent and the like in step (iii) is Alternatively, it can be set by the ratio with the compound of formula (4). For example, the amount of solvent used in step (iii) is 0 (zero) to 10 L (liter), preferably 0.1 to 5 L, per 1 mol of the compound of formula (3) or the compound of formula (4). is.
　（工程（ｉｉｉ）の反応温度）
　工程（ｉｉｉ）の反応温度は、特に制限されない。収率、副生成物抑制、経済効率等の観点から、－３０℃（マイナス３０℃）～１６０℃、好ましくは－１０℃～１２０℃、より好ましくは０～１００℃である。 (Reaction temperature of step (iii))
The reaction temperature of step (iii) is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the temperature is -30°C (minus 30°C) to 160°C, preferably -10°C to 120°C, more preferably 0 to 100°C.
　（工程（ｉｉｉ）の反応時間）
　工程（ｉｉｉ）の反応時間は、特に制限されない。収率、副生成物抑制および経済効率等の観点から、０．５時間～７２時間、好ましくは１時間～６０時間、より好ましくは１時間～４８時間である。 (Reaction time of step (iii))
The reaction time of step (iii) is not particularly limited. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the time is 0.5 hours to 72 hours, preferably 1 hour to 60 hours, more preferably 1 hour to 48 hours.
　（工程（ｉｉｉ）の生成物；式（７）の化合物）
　工程（ｉｉｉ）の生成物は、原料として用いた式（５）の化合物又は式（６）の化合物に相当する式（７）の化合物である。具体的な例は、以下を含むが、これらに限定されない；５，５－ジメチル－４，５－ジヒドロイソキサゾール、５－エチル－５－メチル－４，５－ジヒドロイソキサゾール、５，５－ジエチル－４，５－ジヒドロイソキサゾール、５－イソプロピル－５－メチル－４，５－ジヒドロイソキサゾール、５－（ｔｅｒｔ－ブチル）－５－メチル－４，５－ジヒドロイソキサゾール、５－（クロロメチル）－５－メチル－４，５－ジヒドロイソキサゾール、５－メチル－５－（トリフルオロメチル）－４，５－ジヒドロイソキサゾール、５－シクロプロピル－５－メチル－４，５－ジヒドロイソキサゾール、５－シクロブチル－５－メチル－４，５－ジヒドロイソキサゾール、５－シクロペンチル－５－メチル－４，５－ジヒドロイソキサゾール、５－シクロヘキシル－５－メチル－４，５－ジヒドロイソキサゾール、５－ブチル－５－メチル－４，５－ジヒドロイソキサゾール、５－メチル－５－（４－メチルペンタ－３－エン－１－イル）－４，５－ジヒドロイソキサゾール、５－メチル－５－（４－メチルペンチル）－４，５－ジヒドロイソキサゾール、４’Ｈ－スピロ［フルオレン－９，５’－イソキサゾール］、５，５－ジフェニル－４，５－ジヒドロイソキサゾール、５，５－ビス（４－メチルフェニル）－４，５－ジヒドロイソキサゾール、５，５－ビス（４－メトキシフェニル）－４，５－ジヒドロイソキサゾール、５，５－ビス（４－クロロフェニル）－４，５－ジヒドロイソキサゾール、５－メチル－５－フェニル－４，５－ジヒドロイソキサゾール、５－エチル－５－フェニル－４，５－ジヒドロイソキサゾール、５－（４－メチルフェニル）－５－メチル－４，５－ジヒドロイソキサゾール、５－（４－メトキシフェニル）－５－メチル－４，５－ジヒドロイソキサゾール、５－（４－クロロフェニル）－５－メチル－４，５－ジヒドロイソキサゾール等。生成物の有用性等の観点から、式（７）の化合物の好ましい具体的な例は、５，５－ジメチル－４，５－ジヒドロイソキサゾールである。 (product of step (iii); compound of formula (7))
The product of step (iii) is the compound of formula (7) corresponding to the compound of formula (5) or the compound of formula (6) used as starting material. Specific examples include, but are not limited to; 5,5-dimethyl-4,5-dihydroisoxazole, 5-ethyl-5-methyl-4,5-dihydroisoxazole, 5, 5-diethyl-4,5-dihydroisoxazole, 5-isopropyl-5-methyl-4,5-dihydroisoxazole, 5-(tert-butyl)-5-methyl-4,5-dihydroisoxazole , 5-(chloromethyl)-5-methyl-4,5-dihydroisoxazole, 5-methyl-5-(trifluoromethyl)-4,5-dihydroisoxazole, 5-cyclopropyl-5-methyl -4,5-dihydroisoxazole, 5-cyclobutyl-5-methyl-4,5-dihydroisoxazole, 5-cyclopentyl-5-methyl-4,5-dihydroisoxazole, 5-cyclohexyl-5- methyl-4,5-dihydroisoxazole, 5-butyl-5-methyl-4,5-dihydroisoxazole, 5-methyl-5-(4-methylpent-3-en-1-yl)-4, 5-dihydroisoxazole, 5-methyl-5-(4-methylpentyl)-4,5-dihydroisoxazole, 4'H-spiro[fluorene-9,5'-isoxazole], 5,5-diphenyl -4,5-dihydroisoxazole, 5,5-bis(4-methylphenyl)-4,5-dihydroisoxazole, 5,5-bis(4-methoxyphenyl)-4,5-dihydroisoxazole sol, 5,5-bis(4-chlorophenyl)-4,5-dihydroisoxazole, 5-methyl-5-phenyl-4,5-dihydroisoxazole, 5-ethyl-5-phenyl-4,5 -dihydroisoxazole, 5-(4-methylphenyl)-5-methyl-4,5-dihydroisoxazole, 5-(4-methoxyphenyl)-5-methyl-4,5-dihydroisoxazole, 5-(4-chlorophenyl)-5-methyl-4,5-dihydroisoxazole and the like. A preferred specific example of the compound of formula (7) is 5,5-dimethyl-4,5-dihydroisoxazole from the viewpoint of usefulness of the product.
（反応の実施形態）
　以下の「反応の実施形態」についての説明は、工程（ｉ）、工程（ｉ－ａ）、工程（ｉ－ｂ）に適用される。ただし、該当しない場合を除く。
　本反応は、反応釜を用いた回分式（バッチ式）で実施することができ、また、連続式の反応器を用いたフロー反応でも実施することができる。連続式の反応器とは、原料の供給、反応を連続的に同時に進行させるための反応器である。連続式の反応器として、流通反応器（フローリアクタ）がある。流通反応器は、原料を連続して供給し、連続して反応を行うことができる反応器である。流通反応器は、管型流通反応器（チューブ型流通反応器を含む）と槽型流通反応器に大別されるが、いずれも連続式で反応を行うことができる。本発明の流通反応器は、流通反応器の温度を制御する温度制御手段が設けられていてもよく、例えば、加熱や冷却のための温度制御部が設けられていてもよい。温度制御部は適切な如何なるものであってもよく、温度制御部の例は、バス及びジャケットを包含する。バス及びジャケットの様式は、適切な如何なる様式であってもよい。また、流通反応器の材質としては、原料物質、溶媒に侵されないものであれば特に制限はなく、例えば、金属（例えば、チタン、ニッケル、ステンレス、ハステロイＣ）、樹脂（例えば、フッ素樹脂）、ガラス、磁器（例えば、セラミックス）等が挙げられる。　　 (Reaction embodiment)
The following descriptions of "reaction embodiments" apply to steps (i), steps (ia), and steps (ib). Unless otherwise applicable.
This reaction can be carried out in a batch system (batch system) using a reactor, or can be carried out in a flow reaction using a continuous reactor. A continuous reactor is a reactor for supplying raw materials and allowing reactions to proceed continuously at the same time. As a continuous reactor, there is a flow reactor. A flow reactor is a reactor in which raw materials can be continuously fed and reacted continuously. Flow reactors are broadly classified into tubular flow reactors (including tubular flow reactors) and tank flow reactors, both of which can carry out reactions in a continuous manner. The flow reactor of the present invention may be provided with temperature control means for controlling the temperature of the flow reactor, for example, may be provided with a temperature control unit for heating and cooling. The temperature control section may be of any suitable type, examples of temperature control sections include baths and jackets. The style of the bath and jacket may be of any suitable style. In addition, the material of the flow reactor is not particularly limited as long as it is not attacked by the raw material and solvent. Examples include glass, porcelain (eg, ceramics), and the like.
　本発明の連続式の反応は、槽型流通反応器での実施を排除するものではない。しかしながら、好ましい流通反応器としては、例えば、管型流通反応器が挙げられる。本発明の管型流通反応器は、液状又は気液状の混合物を連続して流通させることができるものであればよく、管の断面の形状は円管状、角管状、多角形管状、楕円管状等のいずれであってもよく、これらの形状を組み合わせたものであってもよい。また、管の材質としては、原料、溶媒に侵されないものであれば特に制限はなく、例えば、金属（例えば、チタン、ニッケル、ステンレス、ハステロイＣ）、樹脂（例えば、フッ素樹脂）、ガラス、磁器（例えば、セラミックス）等が挙げられるが、耐圧性に優れた金属製が好ましい。本発明の管型流通反応器も温度を制御する温度制御手段が設けられていてもよく、例えば、加熱や冷却のための温度制御部が設けられていてもよい。温度制御部は適切な如何なるものであってもよく、温度制御部の例は、バス及びジャケット等を包含する。バス及びジャケットの様式は、適切な如何なる様式であってもよい。このような流通反応装置として、例えば、スパイラル型、シェルアンドチューブ型、プレート熱交換型などの反応装置を使用することができる。 The continuous reaction of the present invention does not exclude implementation in a tank-type flow reactor. However, preferred flow reactors include, for example, tubular flow reactors. The tubular flow reactor of the present invention may be any one capable of continuously circulating a liquid or gas-liquid mixture. , or a combination of these shapes. The material of the tube is not particularly limited as long as it is resistant to raw materials and solvents. (for example, ceramics), etc., but metals with excellent pressure resistance are preferable. The tubular flow reactor of the present invention may also be provided with temperature control means for controlling the temperature, for example, a temperature control section for heating and cooling may be provided. The temperature control section may be of any suitable type, and examples of temperature control sections include baths, jackets, and the like. The style of the bath and jacket may be of any suitable style. As such a flow reactor, for example, a spiral reactor, shell-and-tube reactor, plate heat exchange reactor, or the like can be used.
　本発明の管型流通反応器における管の配置方法としては特に制限はなく、例えば、直線状であってもよいし、曲線状であってもよいし、コイル状であってもよい。好ましい配置法としては、例えば、管をコイル状に配置した管型反応器が挙げられる。また、管は１本であってもよいが、２本以上の複数の管を適当な間隔で規則的又は不規則的に束ねたものであってもよい。本明細書では、便宜のために１本の管を有する管型流通反応器に基づいて説明するが、生産効率を上げたい場合には、本明細書の説明に従って、２本以上の複数の管を適当な間隔で規則的又は不規則的に束ねた管型流通反応器を用いることもできる。
　また、本発明の管型流通反応器は、必要に応じて、混合器を有していてもよい。混合器は、気体と液体又は液体と液体など２種以上の流体を連続的に混合できる機能を有するものであれば特に制限はなく、例えば、Ｙ字型混合器、Ｔ字型混合器、パイプライン型混合器（スタティックミキサー等を含むラインミキサー）等が挙げられる。スタティックミキサー等を含むラインミキサーは、管型流通反応器であってもよい。 There are no particular restrictions on the arrangement of tubes in the tubular flow reactor of the present invention. For example, they may be straight, curved, or coiled. A preferred arrangement method includes, for example, a tubular reactor in which tubes are arranged in a coil. Also, the number of tubes may be one, but two or more tubes may be bundled regularly or irregularly at appropriate intervals. For the sake of convenience, the present specification will be described based on a tubular flow reactor having a single tube. can also be used in a tubular flow reactor in which the are bundled regularly or irregularly at appropriate intervals.
Moreover, the tubular flow reactor of the present invention may have a mixer, if necessary. The mixer is not particularly limited as long as it has a function of continuously mixing two or more fluids such as gas and liquid or liquid and liquid. Examples include Y-shaped mixer, T-shaped mixer, pipe Line type mixers (line mixers including static mixers, etc.) and the like can be mentioned. Line mixers, including static mixers and the like, may be tubular flow reactors.
　（バッチ式の反応）
　以下の「バッチ式の反応」についての説明は、工程（ｉ）、工程（ｉ－ａ）、工程（ｉ－ｂ）に適用される。
　バッチ式を採用する場合には、反応器に金属触媒、ニトロキシルラジカル、硝酸、アルコール化合物（１）又はアルコール化合物（２）及び溶媒の所定量を添加して（必要であればさらに添加してよい）、酸素の存在下、所定温度、所定時間で、反応混合物を撹拌する。反応温度は特に制限されない。しかしながら、収率、副生成物抑制、経済効率等の観点から、０℃（ゼロ）～１００℃、好ましくは１０℃～８０℃、より好ましくは３０℃～７０℃、更に好ましくは４０℃～６０℃である。　
　反応時間は特に制限されない。しかしながら、収率、副生成物抑制および経済効率等の観点から、０．１時間～４８時間、好ましくは０．１時間～２４時間、より好ましくは１時間～１２時間である。 (batch type reaction)
The following description of "batchwise reaction" applies to step (i), step (ia) and step (ib).
In the case of adopting a batch system, metal catalyst, nitroxyl radical, nitric acid, alcohol compound (1) or alcohol compound (2) and a predetermined amount of solvent are added to the reactor (add more if necessary). good), and the reaction mixture is stirred at a given temperature for a given time in the presence of oxygen. The reaction temperature is not particularly limited. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., the °C.
Reaction time is not particularly limited. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., the time is 0.1 hour to 48 hours, preferably 0.1 hour to 24 hours, more preferably 1 hour to 12 hours.
　（流通式の反応）
　以下の「流通式の反応」についての説明は、工程（ｉ）、工程（ｉ－ａ）、工程（ｉ－ｂ）に適用される。加えて、該当しない場合を除き、全ての工程に適用してもよい。　流通式を採用する場合には、管型反応器に金属触媒、ニトロキシルラジカル、アルコール化合物（１）又はアルコール化合物（２）及び溶媒の所定量の混合物（必要であればさらに添加してよい）を流通させ、別の管から酸素を流通させ反応させる。この場合、用いる管型反応器は加熱装置を有するものを使用し、所定温度に加熱した反応管中に混合物を流通させることが好ましい。反応温度は特に制限されない。しかしながら、収率、副生成物抑制、経済効率等の観点から、０℃（ゼロ）～１２０℃、好ましくは４０℃～１００℃である。　 (flow-through reaction)
The following description of "flow-through reaction" applies to step (i), step (ia) and step (ib). In addition, it may apply to all steps except where not applicable. When a flow system is employed, a metal catalyst, nitroxyl radical, alcohol compound (1) or alcohol compound (2), and a predetermined amount of a mixture of a solvent (additional amounts may be added if necessary) are placed in a tubular reactor. is circulated, and oxygen is circulated and reacted from another tube. In this case, it is preferable to use a tubular reactor equipped with a heating device, and to pass the mixture through the reaction tube heated to a predetermined temperature. The reaction temperature is not particularly limited. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is 0°C (zero) to 120°C, preferably 40°C to 100°C.
　本発明の管型反応器における管の等価直径としては、液状又は気液状の混合物が連続して流通することができる大きさであれば特に制限はないが、本発明の化学反応においては気体と反応することもあり、また生産効率の点からも、０．５ｍｍ以上であることが好ましい。好ましい等価直径の例としては、０．５ｍｍ～５０ｍｍ、好ましくは０．５ｍｍ～３０ｍｍ程度が挙げられる。
　本発明における「等価直径（Ｄｅ）」とは、次の式で定義される値である。
　　　　　Ｄｅ　＝　４・Ａｆ／Ｗｐ
（式中、Ａｆは流路断面積を示し、Ｗｐは濡れ縁長さを示す。）
　例えば、半径ｒの円管状の管の等価直径は、
　　　　　Ｄｅ　＝　４・πｒ２／２πｒ
　　　　　　　　＝　２ｒ The equivalent diameter of the tube in the tubular reactor of the present invention is not particularly limited as long as it is a size that allows the liquid or gas-liquid mixture to flow continuously. It is preferable that the thickness is 0.5 mm or more from the point of view of production efficiency and reaction may occur. Examples of preferable equivalent diameters include 0.5 mm to 50 mm, preferably 0.5 mm to 30 mm.
The "equivalent diameter (De)" in the present invention is a value defined by the following formula.
De=4·Af/Wp
(In the formula, Af indicates the channel cross-sectional area and Wp indicates the wetted edge length.)
For example, the equivalent diameter of a circular tube of radius r is
De = 4·πr 2 /2πr
= 2r
　本発明の管型流通反応器の管の長さは、原料化合物が昇温されて、且つ十分な反応ができる範囲であれば特に制限はない。例えば、１ｍ以上、好ましくは１ｍ～１００ｍ、より好ましくは５ｍ～８０ｍの範囲である。本発明の方法を効率的に行うためには、所定の温度で反応させる必要があるので、及び／又は十分な反応時間のために、一般的には５ｍ以上の長さが好ましいが、これに限定されない。 The length of the tube of the tubular flow reactor of the present invention is not particularly limited as long as the temperature of the raw material compound can be raised and sufficient reaction can occur. For example, it is 1 m or more, preferably 1 m to 100 m, more preferably 5 m to 80 m. In order to efficiently carry out the method of the present invention, it is necessary to react at a predetermined temperature and/or for a sufficient reaction time. Not limited.
　本発明の流通反応器、好ましくは管型流通反応器における流速は、管の等価直径にもよるが、例えば、その下限は、通常は０．１ｍ／分以上、好ましくは１．０ｍ／分以上である。加えて、例えば、その上限は、通常は４．０ｍ／分以下、好ましくは３．０ｍ／分以下である。
　管型流通反応器内の圧力としては、例えば、０．１ＭＰａ～１０ＭＰａ、好ましくは０．１ＭＰａ～５ＭＰａ、より好ましくは０．１ＭＰａ～１ＭＰａであるが、これらに限定されない。 The flow velocity in the flow reactor of the present invention, preferably a tubular flow reactor, depends on the equivalent diameter of the tube, but for example, the lower limit is usually 0.1 m/min or more, preferably 1.0 m/min or more. is. In addition, for example, the upper limit is usually 4.0 m/min or less, preferably 3.0 m/min or less.
The pressure in the tubular flow reactor is, for example, 0.1 MPa to 10 MPa, preferably 0.1 MPa to 5 MPa, more preferably 0.1 MPa to 1 MPa, but is not limited thereto.
（本発明の溶媒）
　上述に加え、更に別の態様では、全ての工程の反応が有機溶媒の存在下で行われることが好ましい。更に、全ての工程の反応が同一の有機溶媒の存在下で行われることが、効率がよく且つ好ましい。
　更に別の態様では、上記の同一の有機溶媒が好ましくはカルボン酸エステル類であり、より好ましくは（Ｃ１－Ｃ６）アルキル（Ｃ２－Ｃ４）カルボキシレートである。上記の同一の有機溶媒は、更に好ましくは、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル及びその異性体、酢酸ペンチル及びその異性体からなる群から選ばれる。上記の同一の有機溶媒は、更に好ましくは酢酸ブチル及びその異性体であり、特に好ましくは酢酸ブチルである。 (Solvent of the present invention)
In addition to the above, in still another aspect, it is preferred that all step reactions be carried out in the presence of an organic solvent. Furthermore, it is efficient and preferable that the reactions in all the steps are carried out in the presence of the same organic solvent.
In yet another aspect, the same organic solvents are preferably carboxylic acid esters, more preferably (C1-C6) alkyl (C2-C4) carboxylates. Said same organic solvent is more preferably selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers. The same organic solvent mentioned above is more preferably butyl acetate and its isomers, particularly preferably butyl acetate.
　以下、実施例により本発明を更に詳細に説明するが、本発明は、これら実施例によって何ら限定されない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited by these examples.
　本明細書中、実施例及び比較例の分析には、次の機器及び条件を用いた。 In this specification, the following equipment and conditions were used for the analysis of Examples and Comparative Examples.
　（ＧＣ分析：ガスクロマトグラフィー分析）
　次の機器及び条件、又はそれらと同等又は類似の分析方法を用いた。
機器：ＧＣ－２０１４（株式会社島津製作所製）
カラム：ＤＢ－１（３０ｍ×０．２５ｍｍφ×０．２５μｍ）
昇温条件：６０℃（５分）→１５℃／分→２８０℃（０分）
インジェクション温度：２８０℃
検出温度：２８０℃
検出方法：ＦＩＤ
カラム流量：２ｍＬ/分 (GC analysis: gas chromatography analysis)
The following equipment and conditions, or equivalent or similar analytical methods were used.
Equipment: GC-2014 (manufactured by Shimadzu Corporation)
Column: DB-1 (30 m × 0.25 mmφ × 0.25 μm)
Temperature rising conditions: 60°C (5 minutes) → 15°C/min → 280°C (0 minutes)
Injection temperature: 280°C
Detection temperature: 280°C
Detection method: FID
Column flow rate: 2 mL/min
　ガスクロマトグラフィー（ＧＣ）分析方法；ＧＣ分析方法に関しては、必要に応じて、以下の文献を参照することができる。
文献（ａ）：（社）日本化学会編、「新実験化学講座９　分析化学　ＩＩ」、第６０～８６頁（１９７７年）、発行者　飯泉新吾、丸善株式会社（例えば、カラムに使用可能な固定相液体に関しては、第６６頁を参照できる。）
文献（ｂ）：（社）日本化学会編、「実験化学講座２０－１　分析化学」第５版、第１２１～１２９頁（２００７年）、発行者　村田誠四郎、丸善株式会社（例えば、中空キャピラリー分離カラムの具体的な使用方法に関しては、第１２４～１２５頁を参照できる。） Gas Chromatography (GC) Analysis Method; Regarding the GC analysis method, the following documents can be referred to as necessary.
Document (a): The Chemical Society of Japan, “New Experimental Chemistry Course 9: Analytical Chemistry II”, pp. 60-86 (1977), published by Shingo Iizumi, Maruzen Co., Ltd. (for example, For stationary phase liquids see page 66.)
Literature (b): The Chemical Society of Japan, "Experimental Chemistry Course 20-1 Analytical Chemistry" 5th edition, pp. 121-129 (2007), published by Seishiro Murata, Maruzen Co., Ltd. (for example, hollow See pages 124-125 for specific methods of using capillary separation columns.)
（流通式の反応装置）
反応管；GL Sciences 3004-28082
SUS-316 stainless steel tubing 1/16(in)*1.0(mm)*10(m) （実施例１１で使用）又は
EYELA PTFE TUBE 1/16(in)*1.0(mm)*10(m)（実施例５５及び実施例５６で使用）
加熱装置；FineオイルバスFWB-240又はブロックヒーター (Flow type reactor)
Reaction tube; GL Sciences 3004-28082
SUS-316 stainless steel tubing 1/16(in)*1.0(mm)*10(m) (used in Example 11) or
EYELA PTFE TUBE 1/16(in)*1.0(mm)*10(m) (used in Examples 55 and 56)
Heating device; Fine oil bath FWB-240 or block heater
　本明細書中、室温は１０℃から３５℃である。 In this specification, room temperature is from 10°C to 35°C.
実施例１
３－メトキシ－３－メチルブタナールオキシムの製造 Example 1
Production of 3-methoxy-3-methylbutanal oxime
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９８％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎｏｔ　Ｄｅｔｅｃｔｅｄ（Ｎ.Ｄ．）。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率９６％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2, 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol% ) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 98%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): Not Detected (N.D.).
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 96%.
実施例２
３－メトキシ－３－メチルブタナールオキシムの製造 Example 2
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、臭化鉄（ＩＩＩ）（８９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９３％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：２％。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率８８％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L/mol), iron (III) bromide (89 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.0 mol%) were placed in a 50 mL eggplant-shaped flask. 30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2 , 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 93%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): 2%.
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 88%.
実施例３
３－メトキシ－３－メチルブタナールオキシムの製造 Example 3
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、硝酸鉄（ＩＩＩ）９水和物（１２１ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９１％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率８５％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L/mol), iron (III) nitrate nonahydrate (121 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10 .0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg , 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added and stirred at 60°C under an oxygen atmosphere. The reaction was allowed to proceed for .5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 91%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 85%.
実施例４
３－メトキシ－３－メチルブタナールオキシムの製造 Example 4
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコに酢酸エチル（９．０ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９４％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率８５％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Ethyl acetate (9.0 g, 1.0 L/mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), and 69% nitric acid (27 mg, 0.0 mol%) were added to a 50 mL eggplant-shaped flask. 30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2 , 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 94%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 85%.
実施例５
３－メトキシ－３－メチルブタナールオキシムの製造 Example 5
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、プロピオン酸（７４１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９７％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率９２％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), propionic acid (741 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2 , 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 97%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanal oxime (desired product (5-a)) was obtained with a yield of 92%.
実施例６
３－メトキシ－３－メチルブタナールオキシムの製造 Example 6
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、安息香酸（１２２１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）, ４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９５％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：３％。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率８３％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), benzoic acid (1221 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2 , 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 95%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): 3%.
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 83%.
実施例７
３－メトキシ－３－メチルブタナールオキシムの製造 Example 7
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）, Ｎ－メチルピラゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：８４％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：５％。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率７５％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), N-methylpyrazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2, 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol% ) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methoxy-3-methylbutanal (target product (3-a)): 84%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): 5%.
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanal oxime (desired product (5-a)) was obtained with a yield of 75%.
実施例８
３－メトキシ－３－メチルブタナールの製造 Example 8
Production of 3-methoxy-3-methylbutanal
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％ 硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ，Ｎ－ジメチルアミノピリジン（３７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９１％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), N,N-dimethylaminopyridine (37 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy -2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 91%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
実施例９
３－メトキシ－３－メチルブタナールの製造 Example 9
Production of 3-methoxy-3-methylbutanal
　反応式は実施例８と同じである。 The reaction formula is the same as in Example 8.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％ 硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、ピリジン（２４ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）, ４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９５％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), pyridine (24 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6 , 6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added. under an oxygen atmosphere and stirred at 60° C. for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 95%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
実施例１０
３－メトキシ－３－メチルブタナールオキシムの製造 Example 10
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、硝酸銅（ＩＩ）３水和物（７２ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％ 硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：８９％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率８５％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L / mol), copper (II) nitrate trihydrate (72 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg , 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4- Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol , 100 mol %) was added, and the mixture was stirred at 60° C. in an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 89%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 85%.
実施例１１
３－メトキシ－３－メチルブタナールの製造 Example 11
Production of 3-methoxy-3-methylbutanal
　反応式は実施例８と同じである。　 The reaction formula is the same as in Example 8.　
５０ｍＬナス型フラスコに酢酸ブチル（１０ｍＬ）、塩化鉄（ＩＩＩ）（３２ ｍｇ, ０．２０ｍｍｏｌ, １．０ ｍｏｌ％）、６９％硝酸（１１０ ｍｇ, １．２０ ｍｍｏｌ, ６．０ ｍｏｌ％）、酢酸（１．８０ｇ, ３０．０ ｍｍｏｌ, １５０ ｍｏｌ％）、Ｎ－メチルイミダゾール（４９ ｍｇ, ０．６０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（１３８ ｍｇ, ０．８０ ｍｍｏｌ, ４．０ ｍｏｌ％）及び３－メトキシ－３－メチルブタノール（２．３６ ｇ, ２０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、窒素雰囲気下原料溶液を調製した。その後、連続フロー反応装置（反応管部：内径１ｍｍ，長さ４０ｍ）を用いて、反応管を８０℃に加熱した後、０．６ＭＰａで、原料溶液を流速１ｍＬ／ｍｉｎで、及び酸素ガスを３０ｍＬ／ｍｉｎで、反応管に供給した。反応管の出口に取り付けられた圧力調整弁の出口から反応混合物を採取し、反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９３％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。
　用いられた装置を図１に示す。 Butyl acetate (10 mL), iron (III) chloride (32 mg, 0.20 mmol, 1.0 mol%), 69% nitric acid (110 mg, 1.20 mmol, 6.0 mol%), Acetic acid (1.80 g, 30.0 mmol, 150 mol%), N-methylimidazole (49 mg, 0.60 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethyl Piperidine 1-oxyl (138 mg, 0.80 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (2.36 g, 20.0 mmol, 100 mol%) were added, and the raw material was stirred under a nitrogen atmosphere. A solution was prepared. After that, using a continuous flow reactor (reaction tube part: inner diameter 1 mm, length 40 m), the reaction tube was heated to 80 ° C., and then at 0.6 MPa, the raw material solution was supplied at a flow rate of 1 mL / min, and oxygen gas was supplied. It was supplied to the reaction tube at 30 mL/min. A reaction mixture was sampled from the outlet of a pressure regulating valve attached to the outlet of the reaction tube, and GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 93%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
The apparatus used is shown in FIG.
実施例１２
３－メトキシ－３－メチルブタナールオキシムの製造 Example 12
Production of 3-methoxy-3-methylbutanal oxime
　　反応式は実施例１と同じである。　 The reaction formula is the same as in Example 1.　
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、２，２‘－ビピリジル（４７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、 （２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９８％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：１％。
その後、０ ℃に冷却したのち、撹拌しながら５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率８４％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), 2,2'-bipyridyl (47 mg, 0.30 mmol, 3.0 mol%), (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy- 3-Methylbutanol (1.18 g, 10.0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 98%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): 1%.
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise while stirring.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 84%.
実施例１３
３－メトキシ－３－メチルブタナールオキシムの製造 Example 13
Production of 3-methoxy-3-methylbutanal oxime
　反応式は実施例１と同じである。　 The reaction formula is the same as in Example 1.　
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％ 硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、ピリジン（２４ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）, ４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９４％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。
その後、０ ℃に冷却したのち、撹拌しながら２５％水酸化ナトリウム水溶液（１．６０ｇ、１０．０ｍｍｏｌ、１００ｍｏｌ％）を滴下し、続けて５０ｗ％ヒドロキシルアミン水溶液（７２６ ｍｇ, １１．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。応混合物をＧＣ内部標準法により分析した結果、収率９４．５％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), pyridine (24 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6 , 6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added. under an oxygen atmosphere and stirred at 60° C. for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 94%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
Then, after cooling to 0° C., 25% sodium hydroxide aqueous solution (1.60 g, 10.0 mmol, 100 mol %) was added dropwise with stirring, followed by 50 w % hydroxylamine aqueous solution (726 mg, 11.0 mmol, 110 mol %) was added dropwise. As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanaloxime (desired product (5-a)) was obtained with a yield of 94.5%.
実施例１４
３－メトキシ－３－メチルブタナールの製造 Example 14
Production of 3-methoxy-3-methylbutanal
　反応式は実施例８と同じである。　 The reaction formula is the same as in Example 8.　
２００ｍＬナス型フラスコに酢酸ブチル（９７．９ ｍＬ, ０．７５ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（ ４２０ ｍｇ, ２．６ ｍｍｏｌ, ２．０ ｍｏｌ％）、酢酸（３．９０ ｇ, ６５ ｍｍｏｌ, ５０ ｍｏｌ％）、Ｎ－メチルイミダゾール（３２０ ｍｇ, ３．９ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（９００ ｍｇ, ５．２ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１５．３６ ｇ, １３０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、６０℃で攪拌しながら、６９％ 硝酸（５．９４ ｇ, ６５ ｍｍｏｌ, ５０ ｍｏｌ％）と酢酸（７．８１ ｇ, １３０ ｍｍｏｌ, １００ ｍｏｌ％）混合液を５時間かけて滴下しつつ、５体積％酸素含有窒素を２０ｍＬ／ｍｉｎ．でバブリングした。その後、同温度で４時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：８７％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：６％。 Butyl acetate (97.9 mL, 0.75 L/mol), iron (III) chloride (420 mg, 2.6 mmol, 2.0 mol%), acetic acid (3.90 g, 65 mmol, 50 mol%), N-methylimidazole (320 mg, 3.9 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (900 mg, 5 .2 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (15.36 g, 130 mmol, 100 mol%) were added, and 69% nitric acid (5.94 g , 65 mmol, 50 mol%) and acetic acid (7.81 g, 130 mmol, 100 mol%) was added dropwise over 5 hours, while 5% by volume oxygen-containing nitrogen was added at 20 mL/min. bubbled with After that, the mixture was reacted at the same temperature for 4 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 87%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): 6%.
実施例１５
３－メチル－２－ブテナールの製造 Example 15
Production of 3-methyl-2-butenal
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
５０ｍＬナス型フラスコにアセトニトリル(７．９ ｇ, １．０ Ｌ／ｍｏｌ)、塩化鉄(ＩＩＩ)(４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％)、６９％ 硝酸(５５ ｍｇ, ０．６０ ｍｍｏｌ, ６．０ ｍｏｌ％)、酢酸(６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％)、Ｎ－メチルイミダゾール(２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％), ４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル(６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％)、３－メチル－２－ブテノール(８．６１ ｇ, １００ ｍｍｏｌ, １００ ｍｏｌ％)を加え、酸素雰囲気下、６０℃で攪拌し、１．５時間反応させた。　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：９７％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (55 mg, 0.60 mmol, 6.0 mol%), acetic acid (601 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2, 2,6,6-Tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%) and 3-methyl-2-butenol (8.61 g, 100 mmol, 100 mol%) were added. under an oxygen atmosphere and stirred at 60° C. for 1.5 hours. GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 97%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
実施例１６
３－メチル－２－ブテナールの製造 Example 16
Production of 3-methyl-2-butenal
　反応式は実施例１５と同じである。 The reaction formula is the same as in Example 15.
２００ｍＬ四つ口フラスコに酢酸ブチル（１１２．９ ｍＬ, ０．７５ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９０ ｍｇ, ３．０ ｍｍｏｌ, ２．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（１．０３ ｇ, ６．０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メチル－２－ブテノール（１２．９２ ｇ, １５０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、６０℃で攪拌しながら、６９％ 硝酸（６．８５ ｇ, ７５ ｍｍｏｌ, ５０ ｍｏｌ％）を５時間かけて滴下しつつ、５体積％酸素含有窒素を２０ｍＬ／ｍｉｎ．でバブリングした。その後、同温度で２時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：９４％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。 Butyl acetate (112.9 mL, 0.75 L/mol), iron (III) chloride (490 mg, 3.0 mmol, 2.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) Then, while stirring at 60° C., 69% nitric acid (6.85 g, 75 mmol, 50 mol %) was added dropwise over 5 hours, and 5 vol % oxygen-containing nitrogen was added at 20 mL/min. bubbled with After that, the mixture was reacted at the same temperature for 2 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 94%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
実施例１７
３－メチル－２－ブテナールの製造 Example 17
Production of 3-methyl-2-butenal
　反応式は実施例１５と同じである。　 The reaction formula is the same as in Example 15.　
２０ｍＬ試験管にアセトニトリル（７．５ ｍＬ, ０．７５ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（３２ ｍｇ, ０．２ ｍｍｏｌ, ２．０ ｍｏｌ％）、６９％ 硝酸（２７ ｍｇ, ０．３ ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（９０１ ｍｇ, １５．０ ｍｍｏｌ, １５０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メチル－２－ブテノール（８６１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、１時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：９８％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.5 mL, 0.75 L/mol), iron (III) chloride (32 mg, 0.2 mmol, 2.0 mol%), 69% nitric acid (27 mg, 0.3 mmol, 3.0 mol%), acetic acid (901 mg, 15.0 mmol, 150 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol , 4.0 mol%) and 3-methyl-2-butenol (861 mg, 10.0 mmol, 100 mol%) were added, and the mixture was stirred at 60°C under an oxygen atmosphere and allowed to react for 1 hour.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 98%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
実施例１８～２３
３－メチル－２－ブテナールの製造 Examples 18-23
Production of 3-methyl-2-butenal
　反応式は実施例１５と同じである。　 The reaction formula is the same as in Example 15.　
溶媒及び反応時間を表１に示すように変更した以外は、実施例１７と同じように反応と分析を行った。結果を表１に示す。加えて、実施例１７の結果も表１に要約する。 The reaction and analysis were carried out in the same manner as in Example 17, except that the solvent and reaction time were changed as shown in Table 1. Table 1 shows the results. In addition, the results of Example 17 are also summarized in Table 1.
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
実施例２４
３－メチル－２－ブテナールの製造 Example 24
Production of 3-methyl-2-butenal
　反応式は実施例１５と同じである。　 The reaction formula is the same as in Example 15.　
２００ｍＬ四つ口フラスコに酢酸ブチル（１１２．９ ｍＬ, ０．７５ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９０ ｍｇ, ３．０ ｍｍｏｌ, ２．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（１．０３ ｇ, ６．０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メチル－２－ブテノール（１２．９２ ｇ, １５０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、６０℃で攪拌しながら、６９％ 硝酸（８．２２ ｇ, ９０ ｍｍｏｌ, ６０ ｍｏｌ％）を６時間かけて滴下し、同温度で２時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：９４％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。 Butyl acetate (112.9 mL, 0.75 L/mol), iron (III) chloride (490 mg, 3.0 mmol, 2.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) In addition, 69% nitric acid (8.22 g, 90 mmol, 60 mol %) was added dropwise over 6 hours while stirring at 60°C, and the mixture was reacted at the same temperature for 2 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 94%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
実施例２５～２９
３－メチル－２－ブテナールの製造 Examples 25-29
Production of 3-methyl-2-butenal
　反応式は実施例１５と同じである。　 The reaction formula is the same as in Example 15.　
塩化鉄の使用量、４－ヒドロキシＴＥＭＰＯの使用量（当量（equiv.））、溶媒量及び反応温度を表２に示すように変更した以外は、実施例２４と同じように反応と分析を行った。結果を表２に示す。加えて、実施例２４の結果も表２に要約する。 The reaction and analysis were carried out in the same manner as in Example 24, except that the amount of iron chloride used, the amount of 4-hydroxy TEMPO used (equiv.), the amount of solvent, and the reaction temperature were changed as shown in Table 2. rice field. Table 2 shows the results. In addition, the results of Example 24 are also summarized in Table 2.
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
実施例３０
５，５－ジメチル－４，５－ジヒドロイソキサゾールの製造 Example 30
Production of 5,5-dimethyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
２００ｍｌ四つ口フラスコに酢酸ブチル（７５ｍｌ，０．７５Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（３２４ｍｇ，２ｍｍｏｌ，２ｍｏｌ％）、６９％硝酸（２７４ｍｇ，３ｍｍｏｌ，３ｍｏｌ％）、酢酸（９．０１ｇ，１５０ｍｍｏｌ，１５０ｍｏｌ％）、Ｎ－メチルイミダゾール（２４６ｍｇ，３ｍｍｏｌ，３ｍｏｌ％）, ４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン－１－オキシル（６８９ｍｇ，４ｍｍｏｌ，４ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１１．８ｇ，１００ｍｍｏｌ，１００ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、４．５時間反応させた。　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった。
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ）） ：９１％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ）） ：４％。
　その後、０℃に冷却したのち、撹拌しながら水酸化ナトリウム水溶液（２５ｗｔ％，１６ｇ，１００ｍｍｏｌ，１００ｍｏｌ％）を３０分かけて滴下し、続けて２Ｍ硫酸ヒドロキシルアミン水溶液（３４．８５ｇ，ヒドロキシルアミン（ＮＨ２ＯＨ）として１０４ｍｍｏｌ，ヒドロキシルアミン（ＮＨ２ＯＨ）として１０４ｍｏｌ％）を３０分かけて滴下した。　反応終了後、得られた混合物ろ過したのち、有機層と水層に分配し、２０－２５℃で有機層と水層を分離した。水層を酢酸ブチル（１０ｍｌ，０．１Ｌ／ｍｏｌ）で再抽出し、すべての有機層を合わせた。得られた反応混合物をＧＣ内部標準法による検量線より、反応混合物を分析して収率を求めた。　
３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））：８３％。
上記工程（酸化－オキシム化）で得られた混合物（９５．１４ｇ，８４ｍｍｏｌ，１００ｍｏｌ％）を２００ｍｌの四つ口フラスコへ移し、トリフルオロ酢酸（２．８７ｇ，２５ｍｍｏｌ，３０ｍｏｌ％）を加え、６０－６５℃で７時間攪拌した。反応終了後、飽和食塩水（３５ｍｌ，０．４Ｌ／ｍｏｌ）を加え、有機層と水層に分配し、２０－２５℃で有機層と水層を分離した。有機層を飽和食塩水（３５ｍｌ，０．４Ｌ／ｍｏｌ）で再度洗浄した。ＧＣ内部標準法による検量線より、反応混合物を分析して収率を求めた。
５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（７－ａ））：８３％。 Butyl acetate (75 ml, 0.75 L/mol), iron (III) chloride (324 mg, 2 mmol, 2 mol%), 69% nitric acid (274 mg, 3 mmol, 3 mol%), acetic acid (9.01 g, 150 mmol, 150 mol%), N-methylimidazole (246 mg, 3 mmol, 3 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (689 mg, 4 mmol, 4 mol%), 3-methoxy -3-Methylbutanol (11.8 g, 100 mmol, 100 mol %) was added, stirred at 60° C. under an oxygen atmosphere, and reacted for 4.5 hours. GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows.
3-Methoxy-3-methylbutanal (target product (3-a)): 91%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): 4%.
Then, after cooling to 0° C., an aqueous sodium hydroxide solution (25 wt %, 16 g, 100 mmol, 100 mol %) was added dropwise with stirring over 30 minutes, followed by a 2 M aqueous hydroxylamine sulfate solution (34.85 g, hydroxylamine ( 104 mmol as hydroxylamine (NH 2 OH) and 104 mol % as hydroxylamine (NH 2 OH)) were added dropwise over 30 minutes. After completion of the reaction, the resulting mixture was filtered and partitioned into an organic layer and an aqueous layer, and the organic layer and aqueous layer were separated at 20-25°C. The aqueous layer was re-extracted with butyl acetate (10 ml, 0.1 L/mol) and all organic layers were combined. The obtained reaction mixture was analyzed from the calibration curve by the GC internal standard method to determine the yield.
3-Methoxy-3-methylbutanal oxime (target product (5-a)): 83%.
The mixture (95.14 g, 84 mmol, 100 mol %) obtained in the above step (oxidation-oximation) was transferred to a 200 ml four-necked flask, trifluoroacetic acid (2.87 g, 25 mmol, 30 mol %) was added, and 60 Stirred at -65°C for 7 hours. After completion of the reaction, saturated saline (35 ml, 0.4 L/mol) was added, the mixture was partitioned into an organic layer and an aqueous layer, and the organic layer and aqueous layer were separated at 20-25°C. The organic layer was washed again with saturated brine (35 ml, 0.4 L/mol). The yield was determined by analyzing the reaction mixture from the calibration curve by the GC internal standard method.
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 83%.
実施例３１
５，５－ジメチル－４，５－ジヒドロイソキサゾールの製造 Example 31
Production of 5,5-dimethyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
２００ｍＬ四つ口フラスコに酢酸ブチル（１１２．９ｍｌ，０．７５Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９０ｍｇ，３．０ｍｏｌ，２．０ｍｏｌ％）、酢酸（４．５０ｇ，７５ｍｍｏｌ，５０ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン－１オキシル（１．０３ｇ，６．０ｍｍｏｌ，４．０ｍｏｌ％）、３－メチル－２－ブテノール（１２．９２ｇ，　１５０ｍｍｏｌ，　１００ｍｏｌ％）を加え、６０－６５℃で攪拌しながら、６９％硝酸（６．８５ｇ，　７５ｍｍｏｌ，　５０ｍｏｌ％）と酢酸（９．０１ｇ，　１５０ｍｍｏｌ，　１００ｍｏｌ％）混合液を５時間かけて滴下しつつ、５体積％酸素含有窒素を２０ｍｌ／ｍｉｎ．でバブリングした。その後、同温度で１時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：９１％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ．Ｄ．。
その後、０－５℃に冷却した後、攪拌しながら２５ｗｔ％水酸化ナトリウム水溶液（２４．０ｇ，１５０ｍｏｌ，１００ｍｏｌ％）、２Ｍ硫酸ヒドロキシルアミン水溶液（５１．８ｇ，ヒドロキシルアミン（ＮＨ２ＯＨ）として１５６ｍｍｏｌ，ヒドロキシルアミン（ＮＨ２ＯＨ）として１０４ｍｏｌ％）を滴下した。反応混合物をＧＣ内部標準法により分析して収率を求めた。
３－メチル－２－ブテナールオキシム（目的生成物（６－ａ））：８１％。
上記工程（酸化－オキシム化）で得られた混合物（１２９．６５ｇ，１２０ｍｍｏｌ，１００ｍｏｌ％）を３００ｍｌの四つ口セパラブルフラスコへ移し、６９％硝酸（１．１０ｇ，１２ｍｍｏｌ，１０ｍｏｌ％）を加え、６０－６５℃で１８時間攪拌した。ＧＣ内部標準法による検量線より、反応混合物を分析して収率を求めた。
５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（７－ａ））：８７％。 Butyl acetate (112.9 ml, 0.75 L/mol), iron chloride (III) (490 mg, 3.0 mol, 2.0 mol%), acetic acid (4.50 g, 75 mmol, 50 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1 oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) was added, and while stirring at 60-65 ° C., a mixture of 69% nitric acid (6.85 g, 75 mmol, 50 mol %) and acetic acid (9.01 g, 150 mmol, 100 mol %) was added dropwise over 5 hours, adding 5 volumes. % oxygen containing nitrogen at 20 ml/min. bubbled with After that, the mixture was reacted at the same temperature for 1 hour.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 91%,
3-methyl-2-butenoic acid (side product (10-a)): N.I. D. .
Then, after cooling to 0-5° C., 25 wt % sodium hydroxide aqueous solution (24.0 g, 150 mol, 100 mol %) and 2 M hydroxylamine sulfate aqueous solution (51.8 g, 156 mmol as hydroxylamine (NH 2 OH)) were added while stirring. , 104 mol % as hydroxylamine (NH 2 OH)) was added dropwise. The reaction mixture was analyzed by GC internal standard method to determine the yield.
3-methyl-2-butenaloxime (target product (6-a)): 81%.
The mixture (129.65 g, 120 mmol, 100 mol%) obtained in the above step (oxidation-oximation) was transferred to a 300 ml four-necked separable flask, and 69% nitric acid (1.10 g, 12 mmol, 10 mol%) was added. , 60-65° C. for 18 hours. The yield was determined by analyzing the reaction mixture from the calibration curve by the GC internal standard method.
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 87%.
実施例３２
５，５－ジメチル－４，５－ジヒドロイソキサゾールの製造 Example 32
Production of 5,5-dimethyl-4,5-dihydroisoxazole
　反応式は実施例３１と同じである。　 The reaction formula is the same as in Example 31.　
２００ｍＬ四つ口フラスコに酢酸ブチル（７５．０ ｍＬ, ０．５０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（２４３ ｍｇ, １．５ ｍｍｏｌ, １．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（１．０３ ｇ, ６．０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メチル－２－ブテノール（１２．９２ ｇ, １５０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、６０℃で攪拌しながら、６９％ 硝酸（８．９０ ｇ, ９７．５ ｍｍｏｌ, ６５ ｍｏｌ％）を６.５時間かけて滴下し、同温度で０．５時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物）：９４％、
３－メチル－２－ブテン酸（副生物）：Ｎ.Ｄ．。
その後、０～５℃に冷却した後、攪拌しながら３５ｗｔ％硫酸ヒドロキシルアミン水溶液（３６．１ ｇ, ヒドロキシルアミン（ＮＨ２ＯＨ）として１５０ ｍｍｏｌ, ヒドロキシルアミン（ＮＨ２ＯＨ）として１００ ｍｏｌ％）を０．５時間かけて滴下した。続いて同温度で２５ｗｔ％水酸化ナトリウム水溶液（２４．０ ｇ, １５０ ｍｍｏｌ, １００ ｍｏｌ％）を１時間かけて滴下し、更に同温度で１時間反応させた。
反応混合物をＧＣ内部標準法により分析して収率を求めた。
３－メチル－２－ブテナールオキシム：７５％。
上記工程で得られた混合物（７７．８１ ｇ, １０８．６ ｍｍｏｌ, １００ ｍｏｌ％）を２００ｍＬ四つ口フラスコへ移し、６９％ 硝酸（９９１ ｍｇ, １０．８６ ｍｍｏｌ, １０ ｍｏｌ％）を加え、６０～６５℃の範囲内で１８.５時間攪拌した。
反応混合物をＧＣ内部標準法により分析して収率を求めた。
５,５－ジメチル－４,５－ジヒドロイソキサゾール：９１％ Butyl acetate (75.0 mL, 0.50 L/mol), iron (III) chloride (243 mg, 1.5 mmol, 1.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) In addition, 69% nitric acid (8.90 g, 97.5 mmol, 65 mol %) was added dropwise over 6.5 hours while stirring at 60°C, and the mixture was reacted at the same temperature for 0.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product): 94%,
3-methyl-2-butenoic acid (by-product): N.D. .
Then, after cooling to 0 to 5° C., a 35 wt % hydroxylamine sulfate aqueous solution (36.1 g, 150 mmol as hydroxylamine (NH 2 OH), 100 mol % as hydroxylamine (NH 2 OH)) was added with stirring. It was added dropwise over 0.5 hours. Subsequently, a 25 wt % sodium hydroxide aqueous solution (24.0 g, 150 mmol, 100 mol %) was added dropwise at the same temperature over 1 hour, and the mixture was further reacted at the same temperature for 1 hour.
The reaction mixture was analyzed by GC internal standard method to determine the yield.
3-methyl-2-butenal oxime: 75%.
The mixture (77.81 g, 108.6 mmol, 100 mol%) obtained in the above step was transferred to a 200 mL four-necked flask, 69% nitric acid (991 mg, 10.86 mmol, 10 mol%) was added, The mixture was stirred for 18.5 hours within the range of 60-65°C.
The reaction mixture was analyzed by GC internal standard method to determine the yield.
5,5-dimethyl-4,5-dihydroisoxazole: 91%
実施例３３
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 33
Production of 5,5-dimethyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　３－メチル－２－ブテナール（１５．０ｇ、１７８ｍｍｏｌ、１００ｍｏｌ％）をジクロロメタン（９０ｍｌ、０．５Ｌ／ｍｏｌ）に溶解した。内温が３０～４０℃になるように、そこに５０％ヒドロキシルアミン水溶液（１１．８ｇ、１７８ｍｍｏｌ、１００ｍｏｌ％）を滴下した（発熱反応）。滴下終了後、混合物を室温で４時間撹拌した。反応終了後、食塩水（１０ｍｌ）を加えて、撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離し、有機層を得た。得られた有機層を硫酸マグネシウムで乾燥し、減圧下（４００Ｔｏｒｒ）で４０℃（バス温度）で有機層の量が３６ｇになるまで濃縮して、粗製の３－メチル－２－ブテナールオキシム（収率：定量的、ジクロロメタン約１４ｍｌを含む）を得た。
　上記で得られた３－メチル－２－ブテナールオキシムとジクロロメタンの混合物に、反応系内のジクロロメタンの合計量が約３６ｍｌ（０．２Ｌ／ｍｏｌ）になるように、ジクロロメタン（２２ｍｌ）を加えた。そこにトリフルオロ酢酸（ＴＦＡ、２．０３ｇ、比重：１．４９、１．３６ｍｌ、１７．８ｍｍｏｌ、１０ｍｏｌ％）を加えて、室温で４８時間撹拌した。反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く主な成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソオキサゾール（目的生成物（７－ａ））：９４％、
３－メチル－２－ブテナールオキシム（中間体（６－ａ））：１％。
反応混合物にジエチルエーテル（４０ｍｌ）を加え、得られた混合物を有機層と水層に分配した。有機層と水層を分離し、有機層を得た。炭酸ナトリウム水溶液、食塩水で順次洗浄し、硫酸マグネシウムで乾燥し、減圧で濃縮した。得られた粗生成物を減圧蒸留により精製して、５，５－ジメチル－４，５－ジヒドロイソオキサゾール（７－ａ、無色油状物、１３．７ｇ、純度：９９％（ＧＣ面積百分率）、１３７ｍｍｏｌ、収率：７７％（２工程）、沸点：７５～７７℃／５０Ｔｏｒｒ）を得た。 3-Methyl-2-butenal (15.0 g, 178 mmol, 100 mol %) was dissolved in dichloromethane (90 ml, 0.5 L/mol). A 50% hydroxylamine aqueous solution (11.8 g, 178 mmol, 100 mol %) was added dropwise thereto so that the internal temperature was 30 to 40° C. (exothermic reaction). After the dropwise addition was completed, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, saline (10 ml) was added and stirred. The resulting mixture was partitioned into organic and aqueous layers. The organic layer and aqueous layer were separated to obtain an organic layer. The resulting organic layer was dried over magnesium sulfate and concentrated under reduced pressure (400 Torr) at 40° C. (bath temperature) until the amount of the organic layer was 36 g, yielding crude 3-methyl-2-butenal oxime. (yield: quantitative, containing about 14 ml of dichloromethane).
Dichloromethane (22 ml) was added to the mixture of 3-methyl-2-butenal oxime and dichloromethane obtained above so that the total amount of dichloromethane in the reaction system was about 36 ml (0.2 L/mol). rice field. Trifluoroacetic acid (TFA, 2.03 g, specific gravity: 1.49, 1.36 ml, 17.8 mmol, 10 mol%) was added thereto and stirred at room temperature for 48 hours. As a result of GC analysis (area percentage) of the reaction mixture, the main components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 94%,
3-methyl-2-butenal oxime (intermediate (6-a)): 1%.
Diethyl ether (40 ml) was added to the reaction mixture and the resulting mixture was partitioned between organic and aqueous layers. The organic layer and aqueous layer were separated to obtain an organic layer. The extract was washed successively with an aqueous sodium carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure to give 5,5-dimethyl-4,5-dihydroisoxazole (7-a, colorless oil, 13.7 g, purity: 99% (GC area percentage), 137 mmol, yield: 77% (2 steps), boiling point: 75-77°C/50 Torr).
実施例３４
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 34
Production of 5,5-dimethyl-4,5-dihydroisoxazole
　反応式は実施例３３と同じである。　 The reaction formula is the same as in Example 33.　
　３－メチル－２－ブテナール（１０．０ｇ、１１９ｍｍｏｌ、１００ｍｏｌ％）をジクロロメタン（６０ｍｌ、０．５Ｌ／ｍｏｌ）に溶解した。内温が３０～４０℃になるように、そこに５０％ヒドロキシルアミン水溶液（７．９ｇ、１１９ｍｍｏｌ、１００ｍｏｌ％）を滴下した（発熱反応）。滴下終了後、混合物を室温で４時間撹拌した。反応終了後、食塩水（１０ｍｌ）を加えて、撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離し、有機層を得た。得られた有機層を硫酸マグネシウムで乾燥し、減圧下（４００Ｔｏｒｒ）で４０℃（バス温度）で有機層の量が３１ｇになるまで濃縮して、粗製の３－メチル－２－ブテナールオキシム（収率：定量的、ジクロロメタン約１４ｍｌを含む）を得た。
　上記で得られた３－メチル－２－ブテナールオキシムとジクロロメタンの混合物に、反応系内のジクロロメタンの合計量が約２４ｍｌ（０．２Ｌ／ｍｏｌ）になるように、ジクロロメタン（１０ｍｌ）を加えた。そこにｐ－トルエンスルホン酸一水和物（ＰＴＳ・Ｈ２Ｏ、２．３ｇ、１１．９ｍｍｏｌ、１０ｍｏｌ％）を加えて、室温で６０時間撹拌した。反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く主な成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソオキサゾール（目的生成物（７－ａ））：９５％、
３－メチル－２－ブテナールオキシム（中間体（６－ａ））：３％。
反応混合物にジエチルエーテル（３０ｍｌ）を加え、得られた混合物を有機層と水層に分配した。有機層と水層を分離し、有機層を得た。炭酸ナトリウム水溶液、食塩水で順次洗浄し、硫酸マグネシウムで乾燥し、減圧で濃縮した。得られた粗生成物を減圧蒸留により精製して、５，５－ジメチル－４，５－ジヒドロイソオキサゾール（７－ａ、無色油状物、８．３ｇ、純度：９９％（ＧＣ面積百分率）、８３ｍｍｏｌ、収率：７０％、沸点：７５～７７℃／５０Ｔｏｒｒ）を得た。 3-Methyl-2-butenal (10.0 g, 119 mmol, 100 mol %) was dissolved in dichloromethane (60 ml, 0.5 L/mol). A 50% hydroxylamine aqueous solution (7.9 g, 119 mmol, 100 mol %) was added dropwise thereto so that the internal temperature was 30 to 40° C. (exothermic reaction). After the dropwise addition was completed, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, saline (10 ml) was added and stirred. The resulting mixture was partitioned into organic and aqueous layers. The organic layer and aqueous layer were separated to obtain an organic layer. The resulting organic layer was dried over magnesium sulfate and concentrated under reduced pressure (400 Torr) at 40° C. (bath temperature) until the amount of the organic layer was 31 g, yielding crude 3-methyl-2-butenal oxime. (yield: quantitative, containing about 14 ml of dichloromethane).
Dichloromethane (10 ml) was added to the mixture of 3-methyl-2-butenaloxime and dichloromethane obtained above so that the total amount of dichloromethane in the reaction system was about 24 ml (0.2 L/mol). rice field. p-Toluenesulfonic acid monohydrate (PTS.H 2 O, 2.3 g, 11.9 mmol, 10 mol %) was added thereto and stirred at room temperature for 60 hours. As a result of GC analysis (area percentage) of the reaction mixture, the main components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 95%,
3-methyl-2-butenal oxime (intermediate (6-a)): 3%.
Diethyl ether (30 ml) was added to the reaction mixture and the resulting mixture was partitioned between organic and aqueous layers. The organic layer and aqueous layer were separated to obtain an organic layer. The extract was washed successively with an aqueous sodium carbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure to give 5,5-dimethyl-4,5-dihydroisoxazole (7-a, colorless oil, 8.3 g, purity: 99% (GC area percentage), 83 mmol, yield: 70%, boiling point: 75-77°C/50 Torr).
実施例３５
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 35
Production of 5,5-dimethyl-4,5-dihydroisoxazole
　反応式は実施例３３と同じである。　 The reaction formula is the same as in Example 33.　
　２５ｍｌナスフラスコ中で塩酸ヒドロキシルアミン（８．９１g、１２８ｍｍｏｌ、１１０ｍｏｌ％）に水（１２ｍｌ）とジクロロメタン（１２ｍｌ、０．１Ｌ／ｍｏｌ）を加えた後、氷冷下で撹拌しながらアンモニア水（７．８０ｇ、純度２８％、１２８ｍｍｏｌ、１１０ｍｏｌ％）を加えた。３０℃を超えないように、そこに３－メチル－２－ブテナール（１０．０ｇ、純度９８％（ＧＣ面積％）、１１７ｍｍｏｌ、１００ｍｏｌ％）を加え、室温で１時間撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離した。水層を少量のジクロロメタンで抽出した。この時、水層のｐＨは６．６であった。
　５０ｍｌナスフラスコ中で、上記で得られた有機層を合わせた（用いたジクロロメタンは合計２３ｍｌ、合計０．２Ｌ/ｍｏｌ）。そこにマレイン酸（１．３５ｇ、１１．７ｍｍｏｌ、１０ｍｏｌ％）を加え、３０℃で４８時間撹拌した。反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く成分は次の通りであった；５，５－ジメチル－４，５－ジヒドロイソオキサゾール（目的生成物（７－ａ））：９６％。
　反応終了後、飽和炭酸水素ナトリウム水溶液（１２ｍｌ）を加えて、撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離した。水層を少量のジクロロメタンで抽出し、合わせた有機層を減圧下で濃縮した。得られた粗生成物を減圧蒸留により精製して、５，５－ジメチル－４，５－ジヒドロイソオキサゾール（７－ａ、無色油状物、９．５ｇ、収率：８２％，沸点：７５～７７℃／５０Ｔｏｒｒ）を得た。 After adding water (12 ml) and dichloromethane (12 ml, 0.1 L/mol) to hydroxylamine hydrochloride (8.91 g, 128 mmol, 110 mol %) in a 25 ml round-bottom flask, ammonia water (7 .80 g, 28% pure, 128 mmol, 110 mol %) was added. 3-Methyl-2-butenal (10.0 g, purity 98% (GC area %), 117 mmol, 100 mol %) was added thereto so as not to exceed 30° C., and stirred at room temperature for 1 hour. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane. At this time, the pH of the aqueous layer was 6.6.
The organic layers obtained above were combined in a 50 ml round-bottomed flask (the amount of dichloromethane used was 23 ml in total, 0.2 L/mol in total). Maleic acid (1.35 g, 11.7 mmol, 10 mol %) was added thereto and stirred at 30° C. for 48 hours. As a result of GC analysis (area percentage) of the reaction mixture, the components other than the solvent etc. in the reaction mixture were as follows; 5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a )): 96%.
After completion of the reaction, saturated aqueous sodium hydrogencarbonate solution (12 ml) was added and stirred. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane and the combined organic layers were concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure to give 5,5-dimethyl-4,5-dihydroisoxazole (7-a, colorless oil, 9.5 g, yield: 82%, boiling point: 75- 77° C./50 Torr).
実施例３６
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 36
Production of 5,5-dimethyl-4,5-dihydroisoxazole
　反応式は実施例３３と同じである。　 The reaction formula is the same as in Example 33.　
　２５ｍｌナスフラスコ中で硫酸ヒドロキシルアミン（１０．５ｇ、ヒドロキシルアミン（ＮＨ２ＯＨ）として１２８ｍｍｏｌ、ヒドロキシルアミン（ＮＨ２ＯＨ）として１１０ｍｏｌ％）に水（５ｍｌ）とジクロロメタン（１２ｍｌ、０．１Ｌ／ｍｏｌ）を加えた後、氷冷下で撹拌しながら、ｐＨが６．９になるまで、２５％水酸化ナトリウム水溶液（約２０ｇ、１２８ｍｍｏｌ、１１０ｍｏｌ％）を加えた。３０℃を超えないように、そこに３－メチル－２－ブテナール（１０．０ｇ、純度９８％（ＧＣ面積％）、１１７ｍｍｏｌ、１００ｍｏｌ％）を加え、室温で１時間撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離した。水層を少量のジクロロメタンで抽出した。
　５０ｍｌナスフラスコ中で、上記で得られた有機層を合わせた（用いたジクロロメタンは合計２３ｍｌ、合計０．２Ｌ/ｍｏｌ）。そこに７０％硝酸（１．０５g、１１．７ｍｍｏｌ、１０ｍｏｌ％）を加え、３０℃で４８時間撹拌した。反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソオキサゾール（目的生成物（７－ａ））：８４％。
　反応終了後、飽和炭酸水素ナトリウム水溶液（１２ｍｌ）を加えて、撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離した。水層を少量のジクロロメタンで抽出し、合わせた有機層を減圧下で濃縮した。得られた粗生成物を減圧蒸留により精製して、５，５－ジメチル－４，５－ジヒドロイソオキサゾール（７－ａ、無色油状物、９．２ｇ、収率：８０％，沸点：７５～７７℃／５０Ｔｏｒｒ）を得た。　 Hydroxylamine sulfate (10.5 g, 128 mmol as hydroxylamine (NH 2 OH), 110 mol% as hydroxylamine (NH 2 OH)) was added to water (5 ml) and dichloromethane (12 ml, 0.1 L/mol) in a 25 ml eggplant flask. was added, and then a 25% sodium hydroxide aqueous solution (about 20 g, 128 mmol, 110 mol %) was added while stirring under ice-cooling until the pH reached 6.9. 3-Methyl-2-butenal (10.0 g, purity 98% (GC area %), 117 mmol, 100 mol %) was added thereto so as not to exceed 30° C., and stirred at room temperature for 1 hour. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane.
The organic layers obtained above were combined in a 50 ml round-bottomed flask (the amount of dichloromethane used was 23 ml in total, 0.2 L/mol in total). 70% Nitric acid (1.05 g, 11.7 mmol, 10 mol %) was added thereto and stirred at 30°C for 48 hours. As a result of GC analysis (area percentage) of the reaction mixture, the components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 84%.
After completion of the reaction, saturated aqueous sodium hydrogencarbonate solution (12 ml) was added and stirred. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane and the combined organic layers were concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure to give 5,5-dimethyl-4,5-dihydroisoxazole (7-a, colorless oil, 9.2 g, yield: 80%, boiling point: 75- 77° C./50 Torr).
実施例３７
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 37
Production of 5,5-dimethyl-4,5-dihydroisoxazole
　反応式は実施例３３と同じである。 The reaction formula is the same as in Example 33.
　２５ｍｌナスフラスコ中で硫酸ヒドロキシルアミン（９．５６ｇ、ヒドロキシルアミン（ＮＨ２ＯＨ）として１１７ｍｍｏｌ，ヒドロキシルアミン（ＮＨ２ＯＨ）として１００ｍｏｌ％）に水（１２ｍｌ）とジクロロメタン（１２ｍｌ、０．１Ｌ／ｍｏｌ）を加えた後、氷冷下で撹拌しながらアンモニア水（７．０９ｇ、純度２８％、１１７ｍｍｏｌ、１００ｍｏｌ％）を加えた。３０℃を超えないように、そこに３－メチル－２－ブテナール（１０．２ｇ、純度９８％（ＧＣ面積％）、１１９ｍｍｏｌ、１０２ｍｏｌ％）を加え、室温で１時間撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離した。水層を少量のジクロロメタンで抽出した。 Hydroxylamine sulfate (9.56 g, 117 mmol as hydroxylamine (NH 2 OH), 100 mol% as hydroxylamine (NH 2 OH)) was added to water (12 ml) and dichloromethane (12 ml, 0.1 L/mol) in a 25 ml eggplant flask. was added, and aqueous ammonia (7.09 g, purity 28%, 117 mmol, 100 mol %) was added while stirring under ice-cooling. 3-Methyl-2-butenal (10.2 g, purity 98% (GC area %), 119 mmol, 102 mol %) was added thereto so as not to exceed 30°C, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane.
　５０ｍｌナスフラスコ中で、上記で得られた有機層を合わせた（用いたジクロロメタンは合計２３ｍｌ、合計０．２Ｌ/ｍｏｌ）。そこにマレイン酸（４０６ｍｇ、３．５０ｍｍｏｌ、３ｍｏｌ％）とＮ－メチルアニリン（１２６μｌ、比重０．９９（２０℃）、１２５ｍｇ、１．１７ｍｍｏｌ、１ｍｏｌ％）を加え、３０℃で４８時間撹拌した。反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソオキサゾール（目的生成物（７－ａ））：９３％。
　反応終了後、飽和炭酸水素ナトリウム水溶液（１２ｍｌ）を加えて、撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離した。水層を少量のジクロロメタンで抽出し、合わせた有機層を減圧下で濃縮した。得られた粗生成物を減圧蒸留により精製して、５，５－ジメチル－４，５－ジヒドロイソオキサゾール（７－ａ、無色油状物、８．９ｇ、収率：７５％，沸点：７５～７７℃／５０Ｔｏｒｒ）を得た。 The organic layers obtained above were combined in a 50 ml round-bottomed flask (the amount of dichloromethane used was 23 ml in total, 0.2 L/mol in total). Maleic acid (406 mg, 3.50 mmol, 3 mol%) and N-methylaniline (126 µl, specific gravity 0.99 (20°C), 125 mg, 1.17 mmol, 1 mol%) were added thereto and stirred at 30°C for 48 hours. . As a result of GC analysis (area percentage) of the reaction mixture, the components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 93%.
After completion of the reaction, saturated aqueous sodium hydrogencarbonate solution (12 ml) was added and stirred. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane and the combined organic layers were concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure to give 5,5-dimethyl-4,5-dihydroisoxazole (7-a, colorless oil, 8.9 g, yield: 75%, boiling point: 75- 77° C./50 Torr).
実施例３８
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 38
Production of 5,5-dimethyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　５０ｍｌナスフラスコ中でプレナール（１０．０ｇ，純度：９８％（ＧＣ面積％），１１６．５ｍｍｏｌ，１００ｍｏｌ％）をジクロロメタン（１１．７ｍｌ，０．１Ｌ／ｍｏｌ）に溶解した後、氷冷下でトリフルオロ酢酸（０．８９ｍｌ，比重：１．４９（２０℃）），１．３３ｇ，１１．７ｍｍｏｌ，１０ｍｏｌ％）を加えた。氷冷下、そこに３０℃を超えないようにヒドロキシルアミン水溶液（７．５５ｇ，純度：５２％（１．０Ｍ塩酸で滴定），１１８．８ｍｍｏｌ，１０２ｍｏｌ％）を加え、４５℃で２０時間撹拌した（熟成）。反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソオキサゾール（目的生成物（７－ａ））：９６％。
　反応終了後、飽和炭酸水素ナトリウム水溶液（１２ｍｌ）を加えて、撹拌した。得られた混合物を有機層と水層に分配した。有機層と水層を分離した。水層を少量のジクロロメタンで抽出し、合わせた有機層を減圧下で濃縮した。得られた粗生成物を減圧蒸留により精製して、５，５－ジメチル－４，５－ジヒドロイソオキサゾール（７－ａ，無色油状物，９．３ｇ，９３．８ｍｍｏｌ，収率：８１％，沸点：７５～７７℃／５０Ｔｏｒｒ）を得た。 After dissolving prenal (10.0 g, purity: 98% (GC area %), 116.5 mmol, 100 mol%) in dichloromethane (11.7 ml, 0.1 L/mol) in a 50 ml eggplant flask, Trifluoroacetic acid (0.89 ml, specific gravity: 1.49 (20°C)), 1.33 g, 11.7 mmol, 10 mol%) was added. Under ice-cooling, an aqueous hydroxylamine solution (7.55 g, purity: 52% (titration with 1.0 M hydrochloric acid), 118.8 mmol, 102 mol%) was added so as not to exceed 30°C, and the mixture was stirred at 45°C for 20 hours. (ripened). As a result of GC analysis (area percentage) of the reaction mixture, the components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 96%.
After completion of the reaction, saturated aqueous sodium hydrogencarbonate solution (12 ml) was added and stirred. The resulting mixture was partitioned into organic and aqueous layers. The organic and aqueous layers were separated. The aqueous layer was extracted with a small amount of dichloromethane and the combined organic layers were concentrated under reduced pressure. The resulting crude product was purified by distillation under reduced pressure to give 5,5-dimethyl-4,5-dihydroisoxazole (7-a, colorless oil, 9.3 g, 93.8 mmol, yield: 81%, boiling point: 75-77°C/50 Torr).
実施例３９～４４
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Examples 39-44
Production of 5,5-dimethyl-4,5-dihydroisoxazole
　反応式は実施例３８と同じである。　 The reaction formula is the same as in Example 38.　
有機溶媒、ヒドロキシルアミンの使用量、触媒並びに撹拌条件（熟成条件）を表３に示すように変更した以外は、実施例３８と同じように反応と分析を行った。結果を表３に示す。加えて、実施例３８の結果も表３に要約する。 The reaction and analysis were carried out in the same manner as in Example 38, except that the organic solvent, amount of hydroxylamine used, catalyst and stirring conditions (aging conditions) were changed as shown in Table 3. Table 3 shows the results. In addition, the results of Example 38 are also summarized in Table 3.
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
実施例４５
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 45
Production of 5,5-dimethyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　５０ｍｌ試験管に３－ａ（８．４６ｍｍｏｌ，１００ｍｏｌ％）のジクロロメタン溶液（１１．８３ｇ）、水（４．２３ｍｌ，０．５Ｌ／ｍｏｌ）、硫酸ヒドロキシルアミン（０．６９ｇ，ヒドロキシルアミン（ＮＨ２ＯＨ）として４．２３ｍｍｏｌ，ヒドロキシルアミン（ＮＨ２ＯＨ）として１００ｍｏｌ％）を加えた。１０～２０℃の範囲内で４８％水酸化ナトリウム水溶液（０．７１ｇ，８．４６ｍｍｏｌ，１００ｍｏｌ％）を滴下した後、１時間撹拌した。ＧＣ内部標準法による検量線より収率を求めた結果、５－ａのＧＣ収率は８５．６％であった。トリフルオロ酢酸（０．２９ｇ，２．５３ｍｍｏｌ，３５ｍｏｌ％）、Ｎ－メチルアニリン（０．０９ｇ，０．８７ｍｍｏｌ，１２ｍｏｌ％）を加え、５０℃で２４時間撹拌した。
反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く目的成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（７－ａ））：８０％。 Dichloromethane solution (11.83 g) of 3-a (8.46 mmol, 100 mol %), water (4.23 ml, 0.5 L/mol), hydroxylamine sulfate (0.69 g, hydroxylamine (NH 2 4.23 mmol as OH) and 100 mol % as hydroxylamine (NH 2 OH)) were added. A 48% sodium hydroxide aqueous solution (0.71 g, 8.46 mmol, 100 mol %) was added dropwise within the range of 10 to 20° C., followed by stirring for 1 hour. As a result of obtaining the yield from the calibration curve by the GC internal standard method, the GC yield of 5-a was 85.6%. Trifluoroacetic acid (0.29 g, 2.53 mmol, 35 mol%) and N-methylaniline (0.09 g, 0.87 mmol, 12 mol%) were added and stirred at 50°C for 24 hours.
As a result of GC analysis (area percentage) of the reaction mixture, the target components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 80%.
　反応終了後、得られた混合物を有機層と水層に分配し、有機層と水層を分離した。ＧＣ内部標準法による検量線より収率を求めた；
５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（７－ａ））：７９％（３－ａから算出）。 After completion of the reaction, the obtained mixture was partitioned into an organic layer and an aqueous layer, and the organic layer and the aqueous layer were separated. The yield was determined from the calibration curve by the GC internal standard method;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 79% (calculated from 3-a).
実施例４６～４８
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Examples 46-48
Production of 5,5-dimethyl-4,5-dihydroisoxazole
　反応式は実施例４５と同じである。　 The reaction formula is the same as in Example 45.　
　オキシム化剤及び中和剤の添加を変更した以外は、実施例４５と同様に反応及び分析を行った。実施例４５～４８の結果を表４に示す。 The reaction and analysis were carried out in the same manner as in Example 45, except that the addition of the oximating agent and neutralizing agent was changed. The results of Examples 45-48 are shown in Table 4.
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
実施例４９
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 49
Production of 5,5-dimethyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　５０ｍｌ試験管に５－ａ（１．２１ｇ，７．３５ｍｍｏｌ，１００ｍｏｌ％）、マレイン酸（０．０９ｇ，０．７３ｍｍｏｌ，１０ｍｏｌ％）を加え、５０℃で１２時間撹拌した。
反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く目的成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（７－ａ））：８２％。 5-a (1.21 g, 7.35 mmol, 100 mol%) and maleic acid (0.09 g, 0.73 mmol, 10 mol%) were added to a 50 ml test tube and stirred at 50°C for 12 hours.
As a result of GC analysis (area percentage) of the reaction mixture, the target components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 82%.
　反応終了後、得られた混合物をＧＣ内部標準法による検量線より収率を求めた；
５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（７－ａ））：８４％。 After completion of the reaction, the yield of the resulting mixture was determined from the calibration curve by the GC internal standard method;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 84%.
　反応式は実施例３３と同じである。 The reaction formula is the same as in Example 33.
実施例５０～５４ Examples 50-54
　酸触媒、塩基触媒、溶媒、温度及び反応時間を変更した以外は、実施例４９と同様に反応及び分析を行った。実施例４９～５４の結果を表５に示す。 The reaction and analysis were carried out in the same manner as in Example 49, except that the acid catalyst, base catalyst, solvent, temperature and reaction time were changed. The results of Examples 49-54 are shown in Table 5.
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
実施例５４
５，５－ジメチル－４，５－ジヒドロイソオキサゾールの製造 Example 54
Production of 5,5-dimethyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　５０ｍｌ試験管に３－ａ（１１．８３ｇ，８．４６ｍｍｏｌ，１００ｍｏｌ％）のジクロロメタン溶液、水（４．２３ｍｌ，０．５０Ｌ／ｍｏｌ）、アセトンオキシム（０．６２ｇ，８．４５ｍｍｏｌ，１００ｍｏｌ％）、トリフルオロ酢酸（０．２７ｇ，２．４０ｍｍｏｌ，２８ｍｏｌ％）、Ｎ－メチルアニリン（０．０９ｇ，０．８３ｍｍｏｌ，１０ｍｏｌ％）を加え、５０℃で２４時間撹拌した。
反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く目的成分は次の通りであった；
５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（７－ａ））：８６％。 Dichloromethane solution of 3-a (11.83 g, 8.46 mmol, 100 mol%) in a 50 ml test tube, water (4.23 ml, 0.50 L/mol), acetone oxime (0.62 g, 8.45 mmol, 100 mol%) , trifluoroacetic acid (0.27 g, 2.40 mmol, 28 mol %) and N-methylaniline (0.09 g, 0.83 mmol, 10 mol %) were added and stirred at 50° C. for 24 hours.
As a result of GC analysis (area percentage) of the reaction mixture, the target components excluding the solvent etc. in the reaction mixture were as follows;
5,5-dimethyl-4,5-dihydroisoxazole (target product (7-a)): 86%.
実施例５５
３－メチル－２－ブテナールの製造 Example 55
Production of 3-methyl-2-butenal
　反応式は実施例１５と同じである。 The reaction formula is the same as in Example 15.
窒素雰囲気下、３－メチル－２－ブテノール（１１．４５ｇ，１３３ｍｍｏｌ，１００ｍｏｌ％）、塩化鉄（ＩＩＩ）（２１５ｍｇ，１．３３ｍｍｏｌ，１ｍｏｌ％）及び４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（９１６ｍｇ，５．３２ｍｍｏｌ，４ｍｏｌ％）を１００ｍＬの酢酸ブチルに溶解させ、原料溶液を調製した。その後、連続フロー反応装置（反応管部：内径１ｍｍ，長さ１０ｍ）を用いて、次のように反応を行った：当該原料溶液を流速０．９７ｍＬ／ｍｉｎで、６９％硝酸水溶液を流速０．０５ｍＬ／ｍｉｎで、Y字管混合器（Y-tube mixer）に供給して混合した後、当該混合溶液を６０℃に加熱した反応管に供給して反応させた。反応混合物を採取し、反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：８３％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。
ＧＣ内部標準法による検量線より、反応混合物を分析して収率を求めた。
３－メチル－２－ブテナール（目的生成物（４－ａ））：７５％。
　用いられた装置を図２に示す。 Under a nitrogen atmosphere, 3-methyl-2-butenol (11.45 g, 133 mmol, 100 mol%), iron (III) chloride (215 mg, 1.33 mmol, 1 mol%) and 4-hydroxy-2,2,6,6- Tetramethylpiperidine 1-oxyl (916 mg, 5.32 mmol, 4 mol %) was dissolved in 100 mL of butyl acetate to prepare a raw material solution. Then, using a continuous flow reactor (reaction tube: inner diameter 1 mm, length 10 m), the reaction was carried out as follows: the raw material solution was flowed at a flow rate of 0.97 mL/min, and the 69% nitric acid aqueous solution was flowed at a flow rate of 0. After being supplied to a Y-tube mixer and mixed at 0.05 mL/min, the mixed solution was supplied to a reaction tube heated to 60° C. and allowed to react. The reaction mixture was sampled and subjected to GC analysis (area percentage) of the reaction mixture. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 83%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
The yield was determined by analyzing the reaction mixture from the calibration curve by the GC internal standard method.
3-methyl-2-butenal (target product (4-a)): 75%.
The apparatus used is shown in FIG.
実施例５６
３－メチル－２－ブテナールの製造 Example 56
Production of 3-methyl-2-butenal
　反応式は実施例１５と同じである。 The reaction formula is the same as in Example 15.
　窒素雰囲気下、３－メチル－２－ブテノール（１１．４５ｇ，１３３ｍｍｏｌ，１００ｍｏｌ％）と４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（９１６ｍｇ，５．３２ｍｍｏｌ，４ｍｏｌ％）を５０ｍＬの酢酸ブチルに溶解させた溶液を調製した。別に、窒素雰囲気下、塩化鉄（ＩＩＩ）（２１５ｍｇ，１．３３ｍｍｏｌ，１ｍｏｌ％）と６９％硝酸水溶液（６０７ｍｇ，６．６４ｍｍｏｌ，５．０ｍｏｌ％）を５０ｍＬの酢酸ブチルに溶解させた溶液を調製した。その後、連続フロー反応装置（反応管部：内径１ｍｍ，長さ２０ｍ）を用いて、次のように反応を行った：０．５ＭＰａの圧力下で、上記で調製した２つの原料溶液をそれぞれ流速０．０５ｍＬ／ｍｉｎでY字管混合器（Y-tube mixer）に供給して混合した後、８０℃に加熱した反応管に供給し、及び同時に、酸素ガスを３．１５ｍＬ／ｍｉｎで供給した。反応管の出口に取り付けられた圧力調整弁の出口から反応混合物を採取し、反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：９６％。
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。
　用いられた装置を図３に示す。 Under a nitrogen atmosphere, 3-methyl-2-butenol (11.45 g, 133 mmol, 100 mol%) and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (916 mg, 5.32 mmol, 4 mol%) was dissolved in 50 mL of butyl acetate to prepare a solution. Separately, a solution was prepared by dissolving iron (III) chloride (215 mg, 1.33 mmol, 1 mol%) and 69% nitric acid aqueous solution (607 mg, 6.64 mmol, 5.0 mol%) in 50 mL of butyl acetate under a nitrogen atmosphere. bottom. Then, using a continuous flow reactor (reaction tube part: inner diameter 1 mm, length 20 m), the reaction was carried out as follows: Under a pressure of 0.5 MPa, the two raw material solutions prepared above were flowed at a flow rate of After being fed to a Y-tube mixer at 0.05 mL/min and mixed, it was fed to a reaction tube heated to 80° C., and oxygen gas was supplied at 3.15 mL/min at the same time. . A reaction mixture was sampled from the outlet of a pressure regulating valve attached to the outlet of the reaction tube, and GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 96%.
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
The apparatus used is shown in FIG.
参考例１
５，５－ジメチル－４，５－ジヒドロイソキサゾール－３－チオカルボキサミジン塩酸塩の製造 Reference example 1
Preparation of 5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride
Figure JPOXMLDOC01-appb-C000053
３００ｍｌの四つ口フラスコに酢酸ブチル（８５ｍｌ，０．８５Ｌ／ｍｏｌ）を入れて、そこへ０－５℃で塩素（７．８１ｇ，１１０ｍｍｏｌ，１１０ｍｏｌ％）をバブリングしながら、実施例３１にて得られた混合物（１２３．７５ｇ，１００ｍｍｏｌ，１００ｍｏｌ％）を１時間かけて滴下し、同温度で１時間攪拌した。ＧＣ内部標準法による検量線より、反応混合物を分析して収率を求めた。
３－クロロ－５，５－ジメチル－４，５－ジヒドロイソキサゾール（目的生成物（１１））：９４．１％。
　反応終了後、得られた反応混合物へチオウレア（７．８８ｇ，１０４ｍｍｏｌ，１１０ｍｏｌ％）を加え、０－５℃で２３時間攪拌した。反応終了後、水（２８．３ｍｌ，０．３Ｌ／ｍｏｌ）を加え、得られた混合物を有機層と水層に分配し、２０－２５℃で有機層と水層を分離した。有機層を水（９．４１ｍｌ，０．１Ｌ／ｍｏｌ）で再抽出し、すべての水層を合わせた。ＬＣ絶対検量線法による検量線より、水層を分析して収率を求めた。
５，５－ジメチル－４，５－ジヒドロイソキサゾール－３－チオカルボキサミジン塩酸塩（目的生成物（１２））：９５％。
Figure JPOXMLDOC01-appb-C000053
Put butyl acetate (85 ml, 0.85 L / mol) in a 300 ml four-necked flask, and while bubbling chlorine (7.81 g, 110 mmol, 110 mol%) there at 0-5 ° C., The resulting mixture (123.75 g, 100 mmol, 100 mol %) was added dropwise over 1 hour and stirred at the same temperature for 1 hour. The yield was determined by analyzing the reaction mixture from the calibration curve by the GC internal standard method.
3-chloro-5,5-dimethyl-4,5-dihydroisoxazole (target product (11)): 94.1%.
After completion of the reaction, thiourea (7.88 g, 104 mmol, 110 mol %) was added to the resulting reaction mixture and stirred at 0-5°C for 23 hours. After completion of the reaction, water (28.3 ml, 0.3 L/mol) was added, the resulting mixture was partitioned into organic and aqueous layers, and the organic and aqueous layers were separated at 20-25°C. The organic layer was re-extracted with water (9.41 ml, 0.1 L/mol) and all aqueous layers were combined. The yield was determined by analyzing the water layer from the calibration curve by the LC absolute calibration curve method.
5,5-dimethyl-4,5-dihydroisoxazole-3-thiocarboxamidine hydrochloride (target product (12)): 95%.
参考例２
　酸素の発生確認 Reference example 2
Oxygen generation confirmation
　２００ｍＬ四つ口フラスコに酢酸ブチル（３８．０ ｍＬ, ０．３８ Ｌ／ｍｏｌ）、６９％ 硝酸（９．１３ ｇ, １００ ｍｍｏｌ, １００ ｍｏｌ％）を加え、６０℃で攪拌しながら、塩化鉄（ＩＩＩ）（１６２ ｍｇ, １．０ ｍｍｏｌ, １．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（３４５ ｍｇ, ２．０ ｍｍｏｌ, ２．０ ｍｏｌ％）、３－メチル－２－ブテノール（８．６１ ｇ, １００ ｍｍｏｌ, １００ ｍｏｌ％）を順番に加えた。その後、同温度で発生したガスを捕集した。得らえた２リットルのガスをＧＡＳＴＥＣ製 気体採取器セットＧＶ－１００Ｓにより分析したところ、７体積％の酸素が含まれていた。本発明の反応において、酸素が発生することが確認された。
　ガスの分析方法：ＧＡＳＴＥＣ製 気体採取器セットＧＶ－１００Ｓ及びＧＡＳＴＥＣ製 酸素ガス検知管　Ｎｏ．３１Ｂ 測定範囲３～２４ｖ％を使用して、ＧＡＳＴＥＣ　Ｎｏ．３１Ｂの取扱説明書の通り分析を行った。 Butyl acetate (38.0 mL, 0.38 L/mol) and 69% nitric acid (9.13 g, 100 mmol, 100 mol%) were added to a 200 mL four-necked flask, and iron chloride was added while stirring at 60°C. (III) (162 mg, 1.0 mmol, 1.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (345 mg, 2.0 mmol, 2.0 mol %) and 3-methyl-2-butenol (8.61 g, 100 mmol, 100 mol %) were added in order. After that, the gas generated at the same temperature was collected. 2 liters of the obtained gas was analyzed with a gas extractor set GV-100S manufactured by GASTEC and found to contain 7% by volume of oxygen. It was confirmed that oxygen is generated in the reaction of the present invention.
Gas analysis method: Gas extractor set GV-100S manufactured by GASTEC and oxygen gas detector tube No. manufactured by GASTEC. 31B Using a measurement range of 3-24 v%, GASTEC No. Analysis was performed as per the 31B instruction manual.
比較例１
３－ヒドロキシ－３－メチルブタナールの製造 Comparative example 1
Production of 3-hydroxy-3-methylbutanal
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　１Ｌナスフラスコ中で３－メチル－１，３－ブタンジオール（１－ａ）（５０．００ｇ，４８０．０８ｍｍｏｌ，１００ｍｏｌ％）をジクロロメタン（２４０．０５ｍｌ、０．５Ｌ／ｍｏｌ）に溶解させた後、テトラブチルアンモニウムブロミド（１．５５ｇ，４．８０ｍｍｏｌ，１ｍｏｌ％）、２，２，６，６－テトラメチルピペリジン１－オキシル（０．１５ｇ，０．９６ｍｍｏｌ，０．２ｍｏｌ％）、リン酸（５．５４ｇ，４８．０１ｍｍｏｌ，１０ｍｏｌ％）を加えた。０～１０℃まで冷却し、次亜塩素酸ナトリウム水溶液（１２．６３ｗｔ％，３１１．２５ｇ，５２８．０８ｍｍｏｌ，１１０ｍｏｌ％）を４時間かけて滴下し、１時間撹拌した。
　反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く成分は次の通りであった；
３－ヒドロキシ－３－メチルブタナール（目的生成物（３－ｂ））：７７％、
３－ヒドロキシ－３－メチルブタン酸（副生物（９－ｂ））：５％、
エステル体Ａ（副生物（１３－ａ））：４％、
エステル体Ｂ（副生物（１３－ｂ））：１０％。 After dissolving 3-methyl-1,3-butanediol (1-a) (50.00 g, 480.08 mmol, 100 mol%) in dichloromethane (240.05 ml, 0.5 L/mol) in a 1 L eggplant flask , tetrabutylammonium bromide (1.55 g, 4.80 mmol, 1 mol%), 2,2,6,6-tetramethylpiperidine 1-oxyl (0.15 g, 0.96 mmol, 0.2 mol%), phosphoric acid ( 5.54 g, 48.01 mmol, 10 mol %) was added. After cooling to 0 to 10° C., an aqueous sodium hypochlorite solution (12.63 wt %, 311.25 g, 528.08 mmol, 110 mol %) was added dropwise over 4 hours and stirred for 1 hour.
As a result of GC analysis (area percentage) of the reaction mixture, the components excluding the solvent etc. in the reaction mixture were as follows;
3-hydroxy-3-methylbutanal (target product (3-b)): 77%,
3-hydroxy-3-methylbutanoic acid (by-product (9-b)): 5%,
Ester A (byproduct (13-a)): 4%,
Ester B (by-product (13-b)): 10%.
比較例２
３－メトキシ－３－メチルブタナールの製造 Comparative example 2
Production of 3-methoxy-3-methylbutanal
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　５００ｍＬ四つ口フラスコ中で３－メトキシ－３－メチルブタノール（２０．００ｇ，１６９．２３ｍｍｏｌ，１００ｍｏｌ％）をジクロロメタン（１６９．２３ｍｌ，１．０Ｌ／ｍｏｌ）に溶解させた後、テトラブチルアンモニウムブロミド（０．５５ｇ，１．６９ｍｍｏｌ，１ｍｏｌ％）、２，２，６，６－テトラメチルピペリジン１－オキシル（０．０２６ｇ，０．１７ｍｍｏｌ，０．１ｍｏｌ％）、リン酸（１．９５ｇ，１６．９２ｍｍｏｌ，１０ｍｏｌ％）を加えた。０～１０℃で次亜塩素酸ナトリウム水溶液（１３．９５ｗｔ％，９９．３４ｇ，１８６．１６ｍｍｏｌ，１１０ｍｏｌ％）を４時間かけて滴下後、１時間撹拌した。
　反応混合物のＧＣ分析（面積百分率）の結果、反応混合物中の溶媒等を除く目的成分は次の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：９１％、
エステル体Ａ（副生物（１３－ａ））：７％。 3-Methoxy-3-methylbutanol (20.00 g, 169.23 mmol, 100 mol%) was dissolved in dichloromethane (169.23 ml, 1.0 L/mol) in a 500 mL four-necked flask, followed by tetrabutylammonium bromide. (0.55 g, 1.69 mmol, 1 mol%), 2,2,6,6-tetramethylpiperidine 1-oxyl (0.026 g, 0.17 mmol, 0.1 mol%), phosphoric acid (1.95 g, 16 .92 mmol, 10 mol %) was added. An aqueous sodium hypochlorite solution (13.95 wt %, 99.34 g, 186.16 mmol, 110 mol %) was added dropwise at 0 to 10° C. over 4 hours, and then stirred for 1 hour.
As a result of GC analysis (area percentage) of the reaction mixture, the target components excluding the solvent etc. in the reaction mixture were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 91%,
Ester form A (by-product (13-a)): 7%.
比較例３
３－メトキシ－３－メチルブタナールの製造 Comparative example 3
Production of 3-methoxy-3-methylbutanal
　反応式は実施例８と同じである。　 The reaction formula is the same as in Example 8.　
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、硝酸マグネシウム（ＩＩ）６水和物（７７ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L/mol), magnesium (II) nitrate hexahydrate (77 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10 .0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg , 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added and stirred at 60°C under an oxygen atmosphere. The reaction was allowed to proceed for .5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): N.D. .
比較例４
３－メトキシ－３－メチルブタナールの製造 Comparative example 4
Production of 3-methoxy-3-methylbutanal
　反応式は実施例８と同じである。 The reaction formula is the same as in Example 8.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、硝酸コバルト（ＩＩ）６水和物（８７ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L/mol), cobalt (II) nitrate hexahydrate (87 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10 .0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg , 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added and stirred at 60°C under an oxygen atmosphere. The reaction was allowed to proceed for .5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): N.D. .
比較例５
３－メトキシ－３－メチルブタナールの製造 Comparative example 5
Production of 3-methoxy-3-methylbutanal
　反応式は実施例８と同じである。　 The reaction formula is the same as in Example 8.　
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、硝酸マンガン（ＩＩ）６水和物（８６ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L/mol), manganese (II) nitrate hexahydrate (86 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10 .0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg , 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added and stirred at 60°C under an oxygen atmosphere. The reaction was allowed to proceed for .5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): N.D. .
比較例６
３－メトキシ－３－メチルブタナールの製造 Comparative example 6
Production of 3-methoxy-3-methylbutanal
　反応式は実施例８と同じである。　 The reaction formula is the same as in Example 8.　
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、硝酸ニッケル（ＩＩ）６水和物（８６ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、酢酸（６０１ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L/mol), nickel (II) nitrate hexahydrate (86 mg, 0.30 mmol, 3.0 mol%), acetic acid (601 mg, 10 .0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg , 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added and stirred at 60°C under an oxygen atmosphere. The reaction was allowed to proceed for .5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): N.D. .
比較例７
３－メトキシ－３－メチルブタナールの製造（酢酸を用いないていない以外実施例１と同様にして行った） Comparative example 7
Preparation of 3-methoxy-3-methylbutanal (performed in the same manner as in Example 1 except that acetic acid was not used)
　反応式は実施例８と同じである。 The reaction formula is the same as in Example 8.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：２４％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg , 0.40 mmol, 4.0 mol%) and 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol%) were added and stirred at 60°C under an oxygen atmosphere. The reaction was allowed to proceed for .5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methoxy-3-methylbutanal (target product (3-a)): 24%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
比較例８
３－メトキシ－３－メチルブタナールの製造（酢酸の代わりに水を用いた以外実施例１と同様にして行った） Comparative example 8
Preparation of 3-methoxy-3-methylbutanal (performed in the same manner as in Example 1 except water was used instead of acetic acid)
　反応式は実施例８と同じである。　 The reaction formula is the same as in Example 8.　
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、水（１８ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：２９％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), water (18 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy-2, 2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1.18 g, 10.0 mmol, 100 mol% ) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methoxy-3-methylbutanal (target product (3-a)): 29%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
比較例９
３－メトキシ－３－メチルブタナールの製造（酢酸の代わりにtert-ブタノールを用いた以外実施例１と同様にして行った） Comparative example 9
Preparation of 3-methoxy-3-methylbutanal (performed in the same manner as in Example 1 except that tert-butanol was used instead of acetic acid)
　　反応式は実施例８と同じである。 The reaction formula is the same as in Example 8.
５０ｍＬナス型フラスコにアセトニトリル（７．９ ｇ, １．０ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９ ｍｇ, ０．３０ｍｍｏｌ, ３．０ ｍｏｌ％）、６９％硝酸（２７ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、tert-ブタノール（７４ ｍｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）、Ｎ－メチルイミダゾール（２５ ｍｇ, ０．３０ ｍｍｏｌ, ３．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（６９ ｍｇ, ０．４０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メトキシ－３－メチルブタノール（１－ｂ）（１．１８ ｇ, １０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、酸素雰囲気下、６０℃で攪拌し、６．５時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：１８％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。 Acetonitrile (7.9 g, 1.0 L / mol), iron (III) chloride (49 mg, 0.30 mmol, 3.0 mol%), 69% nitric acid (27 mg, 0.30 mmol, 3.0 mol%), tert-butanol (74 mg, 10.0 mmol, 100 mol%), N-methylimidazole (25 mg, 0.30 mmol, 3.0 mol%), 4-hydroxy- 2,2,6,6-tetramethylpiperidine 1-oxyl (69 mg, 0.40 mmol, 4.0 mol%), 3-methoxy-3-methylbutanol (1-b) (1.18 g, 10 .0 mmol, 100 mol %) was added, and the mixture was stirred at 60° C. under an oxygen atmosphere and reacted for 6.5 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methoxy-3-methylbutanal (target product (3-a)): 18%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
比較例１０
３－メトキシ－３－メチルブタナールオキシムの製造（先行技術文献３の国際公開第２００５／０８２８２５号の例ＩＩＩの反応条件を本願基質に適用させた） Comparative example 10
Preparation of 3-methoxy-3-methylbutanal oxime (the reaction conditions of Example III of WO2005/082825 of prior art document 3 were applied to the substrate of the present application)
　反応式は実施例１と同じである。 The reaction formula is the same as in Example 1.
５０ｍＬナス型フラスコに、硝酸鉄（ＩＩＩ）９水和物（１０１ ｍｇ, ０．２５ｍｍｏｌ, ０．５ ｍｏｌ％）、２，２‘－ビピリジル（３９ ｍｇ, ０．２５ ｍｍｏｌ, ０．５ ｍｏｌ％）、２，２，６，６－テトラメチルピペリジン１－オキシル（５５ ｍｇ, ０．３５ ｍｍｏｌ, ０．７ ｍｏｌ％）及びＮ－ブロモスクシンイミド（５３ ｍｇ, ０．３０ ｍｍｏｌ, ０．６ ｍｏｌ％）を氷酢酸（５ｍＬ）中に溶解させた。反応容器に５回酸素パージし、撹拌下４５℃に加温し、同温度で３－メトキシ－３－メチルブタノール（５．９１ ｇ, ５０．０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、２５０分反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：６５．３％、
３－メトキシ－３－メチルブタン酸（副生物（９－ａ））：Ｎ.Ｄ．。
その後、０ ℃に冷却したのち、５０ｗ％ヒドロキシルアミン水溶液（３．３ｇ, ５５．０ ｍｍｏｌ, １１０ ｍｏｌ％）を滴下した。
反応混合物をＧＣ内部標準法により分析した結果、収率６３％で３－メトキシ－３－メチルブタナールオキシム（目的生成物（５－ａ））を得た。 Iron (III) nitrate nonahydrate (101 mg, 0.25 mmol, 0.5 mol%) and 2,2'-bipyridyl (39 mg, 0.25 mmol, 0.5 mol%) were added to a 50 mL eggplant-shaped flask. ), 2,2,6,6-tetramethylpiperidine 1-oxyl (55 mg, 0.35 mmol, 0.7 mol%) and N-bromosuccinimide (53 mg, 0.30 mmol, 0.6 mol% ) was dissolved in glacial acetic acid (5 mL). The reaction vessel was purged with oxygen five times, heated to 45°C with stirring, 3-methoxy-3-methylbutanol (5.91 g, 50.0 mmol, 100 mol%) was added at the same temperature, and reacted for 250 minutes. let me
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methoxy-3-methylbutanal (target product (3-a)): 65.3%,
3-Methoxy-3-methylbutanoic acid (side product (9-a)): N.D. .
Then, after cooling to 0° C., a 50 w % hydroxylamine aqueous solution (3.3 g, 55.0 mmol, 110 mol %) was added dropwise.
As a result of analyzing the reaction mixture by GC internal standard method, 3-methoxy-3-methylbutanal oxime (desired product (5-a)) was obtained with a yield of 63%.
比較例１１
３－メトキシ－３－メチルブタナールの製造（先行技術文献４の中国特許出願第１０１７０９０２６号の実施例１の反応条件を本願基質に適用させた） Comparative example 11
Preparation of 3-methoxy-3-methylbutanal (the reaction conditions of Example 1 of Chinese Patent Application No. 101709026 of Prior Art Document 4 were applied to the substrate of the present application)
　反応式は実施例８と同じである。 The reaction formula is the same as in Example 8.
５０ｍＬナス型フラスコに、３－メトキシ－３－メチルブタノール（５．９１ ｇ, ５０．０ ｍｍｏｌ, １００ ｍｏｌ％）、硝酸鉄（ＩＩＩ）９水和物（１０１ ｍｇ, ０．３ｍｍｏｌ, ０．３ ｍｏｌ％）、２，２，６，６－テトラメチルピペリジン１－オキシル（５５ ｍｇ, ０．３５ ｍｍｏｌ, ０．７ ｍｏｌ％）をジクロロメタン（６．５ｍL）中に溶解させた。反応容器に酸素を置換し、室温で６時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：３％。 3-Methoxy-3-methylbutanol (5.91 g, 50.0 mmol, 100 mol%), iron (III) nitrate nonahydrate (101 mg, 0.3 mmol, 0.3 mol%), 2,2,6,6-tetramethylpiperidine 1-oxyl (55 mg, 0.35 mmol, 0.7 mol%) was dissolved in dichloromethane (6.5 mL). Oxygen was replaced in the reaction vessel, and the reaction was allowed to proceed at room temperature for 6 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 3%.
比較例１２
３－メトキシ－３－メチルブタナールの製造（先行技術文献４の中国特許出願第１０１７０９０２６号の実施例９の反応条件を本願基質に適用させた） Comparative example 12
Preparation of 3-methoxy-3-methylbutanal (the reaction conditions of Example 9 of Chinese Patent Application No. 101709026 of Prior Art Document 4 were applied to the substrate of the present application)
　反応式は実施例８と同じである。 The reaction formula is the same as in Example 8.
５０ｍＬナス型フラスコに、３－メトキシ－３－メチルブタノール（５．９１ ｇ, ５０．０ ｍｍｏｌ, １００ ｍｏｌ％）、硝酸鉄（ＩＩＩ）９水和物（１０１ ｍｇ, ０．３ｍｍｏｌ, ０．３ ｍｏｌ％）、２，２，６，６－テトラメチルピペリジン１－オキシル（５５ ｍｇ, ０．３５ ｍｍｏｌ, ０．７ ｍｏｌ％）をアセトニトリル（６．５ｍL）中に溶解させた。反応容器に酸素を置換し、５０℃で６時間反応させた。
反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メトキシ－３－メチルブタナール（目的生成物（３－ａ））：３５％。 3-Methoxy-3-methylbutanol (5.91 g, 50.0 mmol, 100 mol%), iron (III) nitrate nonahydrate (101 mg, 0.3 mmol, 0.3 mol%), 2,2,6,6-tetramethylpiperidine 1-oxyl (55 mg, 0.35 mmol, 0.7 mol%) was dissolved in acetonitrile (6.5 mL). Oxygen was replaced in the reaction vessel, and reaction was carried out at 50° C. for 6 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-Methoxy-3-methylbutanal (target product (3-a)): 35%.
比較例１３
３－メチル－２－ブテナールの製造（実施例２４で使用している４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシルを用いない以外は、実施例２４と同じように反応と分析を行った） Comparative example 13
Preparation of 3-methyl-2-butenal (Reaction in the same manner as in Example 24 except that 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl used in Example 24 is not used and analyzed)
　　反応式は実施例１５と同じである。　 The reaction formula is the same as in Example 15.　
２００ｍＬ四つ口フラスコに酢酸ブチル（１１２．９ ｍＬ, ０．７５ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９０ ｍｇ, ３．０ ｍｍｏｌ, ２．０ ｍｏｌ％）、３－メチル－２－ブテノール（１２．９２ ｇ, １５０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、６０℃で攪拌しながら、６９％ 硝酸（６．８５ ｇ, ７５ ｍｍｏｌ, ５０ ｍｏｌ％）を５時間かけて滴下しつつ、５体積％酸素含有窒素を２０ｍＬ／ｍｉｎ．でバブリングした。その後、同温度で２時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：８％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。 Butyl acetate (112.9 mL, 0.75 L / mol), iron chloride (III) (490 mg, 3.0 mmol, 2.0 mol%), 3-methyl-2-butenol in a 200 mL four-neck flask (12.92 g, 150 mmol, 100 mol%) was added, and while stirring at 60°C, 69% nitric acid (6.85 g, 75 mmol, 50 mol%) was added dropwise over 5 hours to add 5 volumes. % oxygen containing nitrogen at 20 mL/min. bubbled with After that, the mixture was reacted at the same temperature for 2 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 8%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
比較例１４
３－メチル－２－ブテナールの製造（実施例２４で使用している塩化鉄（ＩＩＩ）を用いない以外は、実施例２４と同じように反応と分析を行った） Comparative example 14
Preparation of 3-methyl-2-butenal (reaction and analysis were carried out in the same manner as in Example 24, except that the iron (III) chloride used in Example 24 was not used)
　　反応式は実施例１５と同じである。　 The reaction formula is the same as in Example 15.　
２００ｍＬ四つ口フラスコに酢酸ブチル（１１２．９ ｍＬ, ０．７５ Ｌ／ｍｏｌ）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（１．０３ ｇ, ６．０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メチル－２－ブテノール（１２．９２ ｇ, １５０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、６０℃で攪拌しながら、６９％ 硝酸（６．８５ ｇ, ７５ ｍｍｏｌ, ５０ ｍｏｌ％）を５時間かけて滴下しつつ、５体積％酸素含有窒素を２０ｍＬ／ｍｉｎ．でバブリングした。その後、同温度で２時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：６３％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。 Butyl acetate (112.9 mL, 0.75 L/mol) and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol) were added to a 200 mL four-necked flask. , 4.0 mol%) and 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) were added, and 69% nitric acid (6.85 g, 75 mmol, 50 mol %) was added dropwise over 5 hours, while 5 vol % oxygen-containing nitrogen was added at 20 mL/min. bubbled with After that, the mixture was reacted at the same temperature for 2 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 63%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
比較例１５
３－メチル－２－ブテナールの製造 Comparative example 15
Production of 3-methyl-2-butenal
　　反応式は実施例１５と同じである。（実施例２４の反応温度を２０℃に変更した以外は、実施例２４と同じように反応と分析を行った）　 The reaction formula is the same as in Example 15. (The reaction and analysis were performed in the same manner as in Example 24, except that the reaction temperature in Example 24 was changed to 20°C.)
２００ｍＬ四つ口フラスコに酢酸ブチル（１１２．９ ｍＬ, ０．７５ Ｌ／ｍｏｌ）、塩化鉄（ＩＩＩ）（４９０ ｍｇ, ３．０ ｍｍｏｌ, ２．０ ｍｏｌ％）、４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシル（１．０３ ｇ, ６．０ ｍｍｏｌ, ４．０ ｍｏｌ％）、３－メチル－２－ブテノール（１２．９２ ｇ, １５０ ｍｍｏｌ, １００ ｍｏｌ％）を加え、２０℃で攪拌しながら、６９％ 硝酸（６．８５ ｇ, ７５ ｍｍｏｌ, ５０ ｍｏｌ％）を５時間かけて滴下しつつ、５体積％酸素含有窒素を２０ｍＬ／ｍｉｎ．でバブリングした。その後、同温度で２時間反応させた。
　反応混合物のＧＣ分析（面積百分率）を行った。分析の結果は以下の通りであった；
３－メチル－２－ブテナール（目的生成物（４－ａ））：７９％、
３－メチル－２－ブテン酸（副生物（１０－ａ））：Ｎ.Ｄ．。 Butyl acetate (112.9 mL, 0.75 L/mol), iron (III) chloride (490 mg, 3.0 mmol, 2.0 mol%), 4-hydroxy-2,2 were placed in a 200 mL four-necked flask. , 6,6-tetramethylpiperidine 1-oxyl (1.03 g, 6.0 mmol, 4.0 mol%), 3-methyl-2-butenol (12.92 g, 150 mmol, 100 mol%) Then, while stirring at 20° C., 69% nitric acid (6.85 g, 75 mmol, 50 mol %) was added dropwise over 5 hours, and 5 vol % oxygen-containing nitrogen was added at 20 mL/min. bubbled with After that, the mixture was reacted at the same temperature for 2 hours.
GC analysis (area percentage) of the reaction mixture was performed. The results of the analysis were as follows;
3-methyl-2-butenal (target product (4-a)): 79%,
3-methyl-2-butenoic acid (side product (10-a)): N.D. .
　本発明により、医薬及び農薬等の製造中間体として有用な式（３）の化合物、式（４）の化合物及び式（７）の化合物の新規な製造方法が提供される。本発明の製造方法は、経済的であり、そして環境にも優しく、高い工業的な利用価値を有する。
　従って、本発明は高い産業上の利用可能性を有する。 INDUSTRIAL APPLICABILITY The present invention provides novel methods for producing compounds of formula (3), compounds of formula (4), and compounds of formula (7), which are useful as intermediates for the production of pharmaceuticals, agricultural chemicals, and the like. The production method of the present invention is economical and environmentally friendly, and has high industrial utility value.
Therefore, the present invention has high industrial applicability.

Claims (8)

  1. 　式（７）の化合物の製造方法であって、以下の工程を含む製造方法；
    　工程（ｉ）　金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）の化合物又は式（２）の化合物を反応させて、それぞれ対応する式（３）の化合物又は式（４）の化合物を得る：
    Figure JPOXMLDOC01-appb-C000001
    （式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）。
    　工程（ｉｉ）　式（３）の化合物又は式（４）の化合物をオキシム化剤と反応させて、それぞれ対応する式（５）の化合物又は式（６）の化合物を得る：
    Figure JPOXMLDOC01-appb-C000002
    （式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）。
    　工程（ｉｉｉ）　酸触媒の存在下で、又は酸触媒と塩基触媒の存在下で、式（５）の化合物又は式（６）の化合物を反応させて、式（７）の化合物を得る：
    Figure JPOXMLDOC01-appb-C000003
    （式中、Ｒ１、Ｒ２及びＲ３は上記で定義した通りである。）。     A method for producing a compound of formula (7), comprising the steps of;
    Step (i) reacting the compound of formula (1) or the compound of formula (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound to give the corresponding compound of formula (3) or formula ( 4) to obtain the compound:
    Figure JPOXMLDOC01-appb-C000001
    (wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. ).
    Step (ii) reacting a compound of formula (3) or a compound of formula (4) with an oximating agent to give the corresponding compound of formula (5) or compound of formula (6) respectively:
    Figure JPOXMLDOC01-appb-C000002
    (wherein R 1 , R 2 and R 3 are as defined above).
    Step (iii) reacting a compound of formula (5) or a compound of formula (6) in the presence of an acid catalyst or in the presence of an acid catalyst and a base catalyst to give a compound of formula (7):
    Figure JPOXMLDOC01-appb-C000003
    (wherein R 1 , R 2 and R 3 are as defined above).
  2. 　請求項１に記載の製造方法であって、金属触媒が鉄触媒又は銅触媒である製造方法。 The production method according to claim 1, wherein the metal catalyst is an iron catalyst or a copper catalyst.
  3. 　請求項１に記載の製造方法であって、金属触媒が塩化鉄（ＩＩＩ）である製造方法。 The production method according to claim 1, wherein the metal catalyst is iron (III) chloride.
  4. 　請求項１に記載の製造方法であって、ニトロキシルラジカル化合物が４－ヒドロキシ－２，２，６，６－テトラメチルピペリジン１－オキシルである製造方法。 The production method according to claim 1, wherein the nitroxyl radical compound is 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl.
  5. 　請求項１に記載の化合物の置換基がＲ１、Ｒ２及びＲ３がメチルである製造方法。 2. A process for producing the compound according to claim 1, wherein the substituents R1 , R2 and R3 are methyl.
  6. 　式（３）の化合物又は式（４）の化合物の製造方法であって、金属触媒、硝酸、酸素及びニトロキシルラジカル化合物の存在下で、式（１）又は式（２）の化合物を反応させて、それぞれ対応する式（３）の化合物又は式（４）の化合物を得ることを含む製造方法：
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ１及びＲ２は、それぞれ独立して、置換されていてもよい（Ｃ１－Ｃ６）アルキルであり、Ｒ３は、水素原子；置換されていてもよい（Ｃ１－Ｃ６）アルキル；置換されていてもよい（Ｃ３－Ｃ６）シクロアルキル；置換されていてもよい（Ｃ６－Ｃ１０）アリール；又は置換されていてもよい（Ｃ６－Ｃ１０）アリール（Ｃ１－Ｃ４）アルキルである。）。     A method for producing a compound of formula (3) or a compound of formula (4), comprising reacting a compound of formula (1) or (2) in the presence of a metal catalyst, nitric acid, oxygen and a nitroxyl radical compound. to obtain the corresponding compound of formula (3) or compound of formula (4):
    Figure JPOXMLDOC01-appb-C000004
     (wherein R 1 and R 2 are each independently optionally substituted (C1-C6) alkyl; R 3 is a hydrogen atom; optionally substituted (C1-C6) alkyl optionally substituted (C3-C6) cycloalkyl; optionally substituted (C6-C10) aryl; or optionally substituted (C6-C10) aryl(C1-C4) alkyl. ).
  7. 　請求項６に記載の製造方法であって、金属触媒が鉄触媒又は銅触媒である製造方法。 The production method according to claim 6, wherein the metal catalyst is an iron catalyst or a copper catalyst.
  8. 　請求項６に記載の製造方法であって、金属触媒が塩化鉄（ＩＩＩ）である製造方法。 The production method according to claim 6, wherein the metal catalyst is iron (III) chloride.
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