WO2013021949A1 - Procédé de fabrication d'un composé 4,4-difluoro-2-butén-1-one substitué et procédé de fabrication d'un composé isoxazoline substitué - Google Patents

Procédé de fabrication d'un composé 4,4-difluoro-2-butén-1-one substitué et procédé de fabrication d'un composé isoxazoline substitué Download PDF

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WO2013021949A1
WO2013021949A1 PCT/JP2012/069867 JP2012069867W WO2013021949A1 WO 2013021949 A1 WO2013021949 A1 WO 2013021949A1 JP 2012069867 W JP2012069867 W JP 2012069867W WO 2013021949 A1 WO2013021949 A1 WO 2013021949A1
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alkyl
group
substituted
phenyl
atom
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祐二 森山
一隆 的場
学 八尾坂
賢一 外山
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日産化学工業株式会社
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

Definitions

  • the present invention relates to a method for producing a substituted 4,4-difluoro-2-buten-1-one compound and a substituted isoxazoline compound useful as functional materials such as medical and agricultural chemicals or electronic materials, or as production intermediates thereof. .
  • substituted isoxazoline compounds are known to be used as pest control agents, in particular insecticides / acaricides, or as internal or external parasite control agents for mammals and birds (see, for example, Patent Documents 1 and 2).
  • Substituted 4,4-difluoro-2-buten-1-one compounds are known as intermediates for the production of substituted isoxazoline compounds.
  • a method for producing substituted 4,4-difluoro-2-buten-1-one compounds Is known by reacting a substituted 3-hydroxybutan-1-one compound with a dehydrating agent in the presence of a base (see, for example, Patent Document 3).
  • a substituted ketone compound and a substituted acetyl compound can be prepared by using a base of A method of reacting in the presence (for example, see Patent Document 3), a method of reacting a substituted ketone compound and a substituted acetyl compound while removing water from the reaction system by azeotropic dehydration in the presence of a base (for example, Patent Document 4) And Patent Document 5) are known.
  • the production method using a dehydrating agent described in Patent Document 3 includes dehydration.
  • the agent was required to be 1 equivalent or more with respect to the substituted 3-hydroxybutan-1-one compound as a raw material.
  • a long reaction such as more than an hour was required.
  • a substituted 4,4-difluoro-2-buten-1-one compound produced from a substituted ketone compound and a substituted acetyl compound in one step is added with hydroxylamine and a basic compound without isolation or post-treatment.
  • a method for producing a substituted isoxazoline compound has not been known so far, and there remains room for improvement in terms of shortening the production process of the substituted isoxazoline compound.
  • the present inventors conducted substitutions from substituted 4,4-difluoro-3-hydroxybutan-1-one compounds by performing a dehydration reaction in the presence of a phase transfer catalyst. It has been found that 4,4-difluoro-2-buten-1-one compounds can be produced. Furthermore, it has been found that a substituted 4,4-difluoro-2-buten-1-one compound can be produced from a substituted ketone compound and a substituted acetyl compound in one step in the presence of a phase transfer catalyst.
  • the present invention relates to the following [1] to [20].
  • the phase transfer catalyst has the general formula (6): [Wherein M 1 represents a nitrogen atom or a phosphorus atom, V 1 , V 2 , V 3 and V 4 are each independently C 1 -C 18 alkyl, C 1 -C 4 alkyl optionally substituted with V 5 , C 3 -C 6 cycloalkyl, benzyl, benzene In the ring represents (V 6 ) r1 substituted benzyl, phenyl, (V 6 ) r1 substituted phenyl, ferrocenylmethyl or 1-naphthylmethyl, or V 1 and V 2 together Represents a C 4 -C 6 alkylene chain, and may form a 5- to 7-membered ring with M 1 to which they are bonded, in which case the alkylene chain may contain one oxygen atom, sulfur atom or nitrogen atom; V 5 represents a halogen atom, —OH, —OC (O) V 7
  • the phase transfer catalyst has the general formula (6): [Wherein M 1 represents a nitrogen atom or a phosphorus atom, V 1 , V 2 , V 3 and V 4 are each independently C 1 -C 18 alkyl, C 1 -C 4 alkyl optionally substituted with V 5 , C 3 -C 6 cycloalkyl, benzyl, benzene In the ring represents (V 6 ) r1 substituted benzyl, phenyl, (V 6 ) r1 substituted phenyl, ferrocenylmethyl or 1-naphthylmethyl, or V 1 and V 2 together Represents a C 4 -C 6 alkylene chain, and may form a 5- to 7-membered ring with M 1 to which they are bonded, in which case the alkylene chain may contain one oxygen atom, sulfur atom or nitrogen atom; V 5 represents
  • V 1 , V 2 , V 3 and V 4 each independently represent C 1 -C 4 alkyl, benzyl or phenyl, the production method according to [5-1].
  • V 1 , V 2 , V 3 and V 4 each independently represent C 1 -C 4 alkyl, benzyl or phenyl, the production method according to [5-2].
  • the phase transfer catalyst has the general formula (7): [Wherein M 1 represents a nitrogen atom or a phosphorus atom, V 1 , V 2 , V 3 and V 4 are each independently C 1 -C 18 alkyl, C 1 -C 4 alkyl optionally substituted with V 5 , C 3 -C 6 cycloalkyl, benzyl, benzene In the ring represents (V 6 ) r1 substituted benzyl, phenyl, (V 6 ) r1 substituted phenyl, ferrocenylmethyl or 1-naphthylmethyl, or V 1 and V 2 together Represents a C 4 -C 6 alkylene chain, and may form a 5- to 7-membered ring with M 1 to which they are bonded, in which case the alkylene chain may contain one oxygen atom, sulfur atom or nitrogen atom; V 5 represents a halogen atom, —OH, —OC (O) V 7
  • the phase transfer catalyst has the general formula (7): [Wherein M 1 represents a nitrogen atom or a phosphorus atom, V 1 , V 2 , V 3 and V 4 are each independently C 1 -C 18 alkyl, C 1 -C 4 alkyl optionally substituted with V 5 , C 3 -C 6 cycloalkyl, benzyl, benzene In the ring represents (V 6 ) r1 substituted benzyl, phenyl, (V 6 ) r1 substituted phenyl, ferrocenylmethyl or 1-naphthylmethyl, or V 1 and V 2 together Represents a C 4 -C 6 alkylene chain, and may form a 5- to 7-membered ring with M 1 to which they are bonded, in which case the alkylene chain may contain one oxygen atom, sulfur atom or
  • the basic compound is represented by the general formula (8): [Wherein M 2 represents an alkali metal.
  • the basic compound is represented by the general formula (8): [Wherein M 2 represents the same meaning as defined in [8-1].
  • a salt represented by the general formula (11) [Wherein M 2 represents the same meaning as defined in [8-1].
  • a salt represented by the general formula (12) [Wherein M 2 represents the same meaning as defined in [8-1].
  • a salt represented by the general formula (13) [Wherein M 2 represents the same meaning as defined in [8-1].
  • the manufacturing method of [8-1] which is a salt represented by this.
  • the basic compound is represented by the general formula (8): [Wherein M 2 represents the same meaning as defined in [8-2].
  • a salt represented by the general formula (11) [Wherein M 2 represents the same meaning as defined in [8-2].
  • a salt represented by the general formula (12) [Wherein M 2 represents the same meaning as defined in [8-2].
  • a salt represented by the general formula (13) [Wherein M 2 represents the same meaning as defined in [8-2].
  • the phase transfer catalyst is a compound represented by the general formula (7) in which V 1 , V 2 , V 3 and V 4 each independently represent C 1 -C 4 alkyl, benzyl or phenyl. Or a crown ether selected from the group consisting of 18-crown-6-ether, dibenzo-18-crown-6-ether and 15-crown-5-ether,
  • the basic compound is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium sulfite, dipotassium hydrogen phosphate, phthalimide potassium, or potassium acetate.
  • the phase transfer catalyst is a compound represented by the general formula (7) in which V 1 , V 2 , V 3 and V 4 each independently represent C 1 -C 4 alkyl, benzyl or phenyl. Or a crown ether selected from the group consisting of 18-crown-6-ether, dibenzo-18-crown-6-ether and 15-crown-5-ether,
  • the basic compound is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium sulfite, dipotassium hydrogen phosphate, potassium phthalimide, or potassium acetate.
  • the phase transfer catalyst has the general formula (7): [Wherein M 1 represents a nitrogen atom or a phosphorus atom, V 1 , V 2 , V 3 and V 4 are each independently C 1 -C 18 alkyl, C 1 -C 4 alkyl optionally substituted with V 5 , C 3 -C 6 cycloalkyl, benzyl, benzene In the ring represents (V 6 ) r1 substituted benzyl, phenyl, (V 6 ) r1 substituted phenyl, ferrocenylmethyl or 1-naphthylmethyl, or V 1 and V 2 together Represents a C 4 -C 6 alkylene chain and may form a 5- to 7-membered ring together with M 1 to which they are bonded, in which case the alkylene chain may contain one oxygen atom, sulfur atom or nitrogen atom, V 5 represents a halogen atom, —OH, —OC (O) V 7
  • the phase transfer catalyst has the general formula (7): [Wherein M 1 represents a nitrogen atom or a phosphorus atom, V 1 , V 2 , V 3 and V 4 are each independently C 1 -C 18 alkyl, C 1 -C 4 alkyl optionally substituted with V 5 , C 3 -C 6 cycloalkyl, benzyl, benzene In the ring represents (V 6 ) r1 substituted benzyl, phenyl, (V 6 ) r1 substituted phenyl, ferrocenylmethyl or 1-naphthylmethyl, or V 1 and V 2 together Represents a C 4 -C 6 alkylene chain and may form a 5- to 7-membered ring together with M 1 to which they are bonded, in which case the alkylene chain may contain one oxygen atom, sulfur atom or nitrogen atom, V 5 represents a halogen atom, —OH, —OC (O) V 7 ,
  • the phase transfer catalyst is a compound represented by the general formula (7) in which V 1 , V 2 , V 3 and V 4 each independently represent C 1 -C 4 alkyl, benzyl or phenyl. Or a crown ether selected from the group consisting of 18-crown-6-ether and dibenzo-18-crown-6-ether, The production method according to [13-1], wherein the fluoride salt is potassium fluoride.
  • the phase transfer catalyst is a compound represented by the general formula (7) in which V 1 , V 2 , V 3 and V 4 each independently represent C 1 -C 4 alkyl, benzyl or phenyl. Or a crown ether selected from the group consisting of 18-crown-6-ether and dibenzo-18-crown-6-ether, The production method according to [13-2], wherein the fluoride salt is potassium fluoride.
  • [15] The dehydration reaction of the substituted 4,4-difluoro-3-hydroxybutan-1-one compound represented by the general formula (2) in the presence of a phase transfer catalyst is performed by azeotropic dehydration using a solvent. The production method according to any one of [1] and [5-1] to [14-1].
  • [15-2] The dehydration reaction of the substituted 4,4-difluoro-3-hydroxybutan-1-one compound represented by the general formula (2) in the presence of a phase transfer catalyst is performed by azeotropic dehydration using a solvent.
  • [3] The production method according to any one of [5-2] to [14-2].
  • [16] [16-1] The dehydration reaction of the ketone compound represented by the general formula (3) and the acetyl compound represented by the formula (4) in the presence of a phase transfer catalyst is performed by azeotropic dehydration using a solvent. The method according to any one of [2] and [5-1] to [14-1].
  • T is the general formula (16): [Where X 1 Is a hydrogen atom, halogen atom, cyano, nitro, -SF 5 , C 1 ⁇ C 4 Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio, A Five Is N or CX 2 Represents X 2 Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Alkyl, C 1 ⁇ C Four Haloalkyl or C 1 ⁇ C Four Represents haloalkoxy, X Three Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio.
  • Y is the general formula (17): [Where A 1 , A 2 , A Three And A Four Each independently represents N or CJ; R is C 1 ⁇ C 6 Alkyl, halogen atom, cyano, nitro, -NH 2 , -N (R Five ) R Four , -OH, -OR Three , Benzyloxy, -OSO 2 R Three , Phenylsulfonyloxy, (Z) p1 Phenylsulfonyloxy substituted by -C (O) OH, -C (O) OR Three , -C (O) NH 2 , -C (O) N (R 1b ) R 1a , -C (S) N (R 1b ) R 1a , -LQ, -LN (R 1c ) R 1d , C 1 ⁇ C 6 Alkylsulfonyl, C 1
  • R 6 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C Three ⁇ C 6 Cycloalkyl, C Three ⁇ C 6 Halocycloalkyl, C Three ⁇ C 6 Alkenyl, C Three ⁇ C 6 Haloalkenyl, C Three ⁇ C 6 Alkynyl, C Three ⁇ C 6 Haloalkynyl, phenyl, (Z) p1 Represents phenyl, D-42, D-45 to D-49, E-1 to E-4 or E-7, substituted by R 7 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C 1 ⁇ C 6 Alkoxy (C 1 ⁇ C 6 ) Alkyl, C 1 ⁇ C 6 Alkylthio (C 1
  • a substituted 4,4-difluoro-3-hydroxybutan-1-one compound which is a substituted aryl or substituted heteroaryl represented by the formula: [1] and [3] and [5-1] to [16- 1].
  • the production method according to any one of 1).
  • T is the general formula (16): [Where X 1 Is a hydrogen atom, halogen atom, cyano, nitro, -SF 5 , C 1 ⁇ C 4 Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio, A Five Is N or CX 2 Represents X 2 Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Alkyl, C 1 ⁇ C Four Haloalkyl or C 1 ⁇ C Four Represents haloalkoxy, X Three Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio.
  • Y is the general formula (17): [Where A 1 , A 2 , A Three And A Four Each independently represents N or CJ; R is C 1 ⁇ C 6 Alkyl, halogen atom, cyano, nitro, -NH 2 , -N (R Five ) R Four , -OH, -OR Three , Benzyloxy, -OSO 2 R Three , Phenylsulfonyloxy, (Z) p1 Phenylsulfonyloxy substituted by -C (O) OH, -C (O) OR Three , -C (O) NH 2 , -C (O) N (R 1b ) R 1a , -C (S) N (R 1b ) R 1a , -LQ, -LN (R 1c ) R 1d , C 1 ⁇ C 6 Alkylsulfonyl, C 1
  • R 6 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C Three ⁇ C 6 Cycloalkyl, C Three ⁇ C 6 Halocycloalkyl, C Three ⁇ C 6 Alkenyl, C Three ⁇ C 6 Haloalkenyl, C Three ⁇ C 6 Alkynyl, C Three ⁇ C 6 Haloalkynyl, phenyl, (Z) p1 Represents phenyl, D-42, D-45 to D-49, E-1 to E-4 or E-7, substituted by R 7 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C 1 ⁇ C 6 Alkoxy (C 1 ⁇ C 6 ) Alkyl, C 1 ⁇ C 6 Alkylthio (C 1
  • a substituted 4,4-difluoro-3-hydroxybutan-1-one compound which is a substituted aryl or substituted heteroaryl represented by the formula: [1] and [3] and [5-2] to [16- 2].
  • the production method according to any one of [2].
  • X 1 and X 3 each independently represent a halogen atom, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy
  • a 5 represents CH
  • a 1 , A 2 and A 3 represent CH
  • a 4 represents C-J 2 J 2 represents a hydrogen atom, a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl
  • R represents a halogen atom, cyano, nitro, —C (O) OR 3 , —C (O) NH 2 , —C (O) N (R 1b ) R 1a or —LN (R 1c ) R 1d ;
  • R 3 , R 1a , R 1b , L, R 1c and R 1d have the same meanings as defined
  • X 1 and X 3 each independently represent a halogen atom, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy
  • a 5 represents CH
  • a 1 , A 2 and A 3 represent CH
  • a 4 represents C-J 2 J 2 represents a hydrogen atom, a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl
  • R represents a halogen atom, cyano, nitro, —C (O) OR 3 , —C (O) NH 2 , —C (O) N (R 1b ) R 1a or —LN (R 1c ) R 1d ;
  • R 3 , R 1a , R 1b , L, R 1c and R 1d have the same meanings as defined in [17
  • T is the general formula (16): [Where X 1 Is a hydrogen atom, halogen atom, cyano, nitro, -SF 5 , C 1 ⁇ C 4 Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio, A Five Is N or CX 2 Represents X 2 Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Alkyl, C 1 ⁇ C Four Haloalkyl or C 1 ⁇ C Four Represents haloalkoxy, X Three Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio.
  • Y is the general formula (17): [Where A 1 , A 2 , A Three And A Four Each independently represents N or CJ; R is C 1 ⁇ C 6 Alkyl, halogen atom, cyano, nitro, -NH 2 , -N (R Five ) R Four , -OH, -OR Three , Benzyloxy, -OSO 2 R Three , Phenylsulfonyloxy, (Z) p1 Phenylsulfonyloxy substituted by -C (O) OH, -C (O) OR Three , -C (O) NH 2 , -C (O) N (R 1b ) R 1a , -C (S) N (R 1b ) R 1a , -LQ, -LN (R 1c ) R 1d , C 1 ⁇ C 6 Alkylsulfonyloxy
  • R 6 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C Three ⁇ C 6 Cycloalkyl, C Three ⁇ C 6 Halocycloalkyl, C Three ⁇ C 6 Alkenyl, C Three ⁇ C 6 Haloalkenyl, C Three ⁇ C 6 Alkynyl, C Three ⁇ C 6 Haloalkynyl, phenyl, (Z) p1 Represents phenyl, D-42, D-45 to D-49, E-1 to E-4 or E-7, substituted by R 7 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C 1 ⁇ C 6 Alkoxy (C 1 ⁇ C 6 ) Alkyl, C 1 ⁇ C 6 Alkylthio (C 1
  • a substituted 4,4-difluoro-3-hydroxybutan-1-one compound which is a substituted aryl or a substituted heteroaryl represented by the formula: [2] and [4] and [5-1] to [16- 1].
  • the production method according to any one of 1).
  • T is the general formula (16): [Where X 1 Is a hydrogen atom, halogen atom, cyano, nitro, -SF 5 , C 1 ⁇ C 4 Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio, A Five Is N or CX 2 Represents X 2 Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Alkyl, C 1 ⁇ C Four Haloalkyl or C 1 ⁇ C Four Represents haloalkoxy, X Three Is a hydrogen atom, halogen atom, C 1 ⁇ C Four Haloalkyl, C 1 ⁇ C 4 Haloalkoxy or C 1 ⁇ C 4 Represents haloalkylthio.
  • Y is the general formula (17): [Where A 1 , A 2 , A Three And A Four Each independently represents N or CJ; R is C 1 ⁇ C 6 Alkyl, halogen atom, cyano, nitro, -NH 2 , -N (R Five ) R Four , -OH, -OR Three , Benzyloxy, -OSO 2 R Three , Phenylsulfonyloxy, (Z) p1 Phenylsulfonyloxy substituted by -C (O) OH, -C (O) OR Three , -C (O) NH 2 , -C (O) N (R 1b ) R 1a , -C (S) N (R 1b ) R 1a , -LQ, -LN (R 1c ) R 1d , C 1 ⁇ C 6 Alkylsulfonyloxy
  • R 6 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C Three ⁇ C 6 Cycloalkyl, C Three ⁇ C 6 Halocycloalkyl, C Three ⁇ C 6 Alkenyl, C Three ⁇ C 6 Haloalkenyl, C Three ⁇ C 6 Alkynyl, C Three ⁇ C 6 Haloalkynyl, phenyl, (Z) p1 Represents phenyl, D-42, D-45 to D-49, E-1 to E-4 or E-7, substituted by R 7 Is a hydrogen atom, C 1 ⁇ C 6 Alkyl, C 1 ⁇ C 6 Haloalkyl, C 1 ⁇ C 6 Alkoxy (C 1 ⁇ C 6 ) Alkyl, C 1 ⁇ C 6 Alkylthio (C 1
  • a substituted 4,4-difluoro-3-hydroxybutan-1-one compound which is a substituted aryl or a substituted heteroaryl represented by the formula [2], [4] and [5-2] to [16- 2].
  • the production method according to any one of [2].
  • X 1 and X 3 each independently represent a halogen atom, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy
  • a 5 represents CH
  • a 1 , A 2 and A 3 represent CH
  • a 4 represents C-J 2 J 2 represents a hydrogen atom, a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl
  • R represents a halogen atom, cyano, nitro, —C (O) OR 3 , —C (O) NH 2 , —C (O) N (R 1b ) R 1a or —LN (R 1c ) R 1d ;
  • R 3 , R 1a , R 1b , L, R 1c and R 1d have the same meanings as defined
  • X 1 and X 3 each independently represent a halogen atom, C 1 -C 4 haloalkyl or C 1 -C 4 haloalkoxy
  • a 5 represents CH
  • a 1 , A 2 and A 3 represent CH
  • a 4 represents C-J 2 J 2 represents a hydrogen atom, a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl
  • R represents a halogen atom, cyano, nitro, —C (O) OR 3 , —C (O) NH 2 , —C (O) N (R 1b ) R 1a or —LN (R 1c ) R 1d ;
  • R 3 , R 1a , R 1b , L, R 1c and R 1d have the same meanings as defined in [19
  • a substituted 4,4-difluoro-2-buten-1-one compound and a substituted isoxazoline compound useful as functional materials such as medical and agricultural chemicals or electronic materials or as production intermediates thereof can be substituted. It can be produced from a hydroxybutan-1-one compound or from a substituted ketone compound and a substituted acetyl compound in a short reaction time, in a high yield and in one pot, and can provide a production method useful for industrial production.
  • the substituted 4,4-difluoro-2-buten-1-one compound represented by the general formula (1) has geometric isomers of E-form and Z-form. -A body or a mixture containing E- body and Z- body in an arbitrary ratio is included. Next, specific examples of each substituent shown in the present specification are shown below. Here, n- represents normal, i- represents iso, s- represents secondary, and t- represents tertiary, and Ph represents phenyl.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the notation “halo” also represents these halogen atoms.
  • C a -C b alkyl represents a linear or branched saturated hydrocarbon group having a carbon number of a to b, for example, methyl group, ethyl group, n-propyl group.
  • aryl examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • substituted aryl refers to a group that is unsubstituted or has at least one non-hydrogen substituent with respect to aryl in the definitions of substituents T and Y. Since the substituents T and Y are the end of the part of the molecule involved in the reaction in the method according to the invention, both a very wide range of numbers and types of substituents are compatible with the method according to the invention. Unless otherwise indicated, the optionally substituted group may have a substituent at each substitutable position of the group and each substitution is independent of the other.
  • heteroaryl is represented by 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyranyl group, 3-pyranyl group, 4-pyranyl group, 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2 -Benzothienyl group, 3-benzothienyl group, 4-benzothienyl group, 5-benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group, 5 -Isobenzothienyl group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group, 5-chromenyl group,
  • substituted heteroaryl refers to a group that is unsubstituted or has at least one non-hydrogen substituent with respect to heteroaryl in the definition of substituents T and Y. Since the substituents T and Y are the end of the part of the molecule involved in the reaction in the method according to the invention, both a very wide range of numbers and types of substituents are compatible with the method according to the invention. Unless otherwise indicated, the optionally substituted group may have a substituent at each substitutable position of the group and each substitution is independent of the other.
  • C a -C b haloalkyl in this specification is a linear or branched chain consisting of a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom.
  • a saturated hydrocarbon group, which is substituted with two or more halogen atoms, may be the same as or different from each other.
  • fluoromethyl group chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, chlorofluoromethyl group, dichloromethyl group, bromofluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, dichlorofluoromethyl group, trichloromethyl Group, bromodifluoromethyl group, bromochlorofluoromethyl group, dibromofluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl Group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2 -Fl group, 2-chloro-2,2-
  • cyano (C a -C b ) alkyl is a straight or branched chain having a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a cyano group
  • a cyano group represents a chain-like alkyl group, for example, cyanomethyl group, 1-cyanoethyl group, 2-cyanoethyl group, 2-cyanopropyl group, 3-cyanopropyl group, 2-cyanobutyl group, and the like. Selected in the range of the number of carbon atoms.
  • C a -C b cycloalkyl represents a cyclic saturated hydrocarbon group having a to b carbon atoms, and represents a monocyclic or complex ring structure having 3 to 6 members. Can be formed. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms.
  • cyclopropyl group 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2- Specific examples include methylcyclopentyl group, 3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, bicyclo [2.2.1] heptan-2-yl group and the like. , Each selected range of carbon atoms.
  • C a -C b halocycloalkyl is a cyclic saturated hydrocarbon group having a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom.
  • Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the substitution with a halogen atom may be a ring structure part, a side chain part, It may be both, and when it is substituted by two or more halogen atoms, these halogen atoms may be the same as or different from each other.
  • 2,2-difluorocyclopropyl group, 2,2-dichlorocyclopropyl group, 2,2-dibromocyclopropyl group, 2,2-difluoro-1-methylcyclopropyl group, 2,2-dichloro-1-methyl Cyclopropyl group, 2,2-dibromo-1-methylcyclopropyl group, 2,2,3,3-tetrafluorocyclobutyl group, 2- (trifluoromethyl) cyclohexyl group, 3- (trifluoromethyl) cyclohexyl group , 4- (trifluoromethyl) cyclohexyl group and the like are listed as specific examples, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b alkenyl is a linear or branched chain composed of a to b carbon atoms and has one or more double bonds in the molecule.
  • Represents a saturated hydrocarbon group for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 2-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2 -Pentenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 2-ethyl-2-propenyl group, 1,1-dimethyl-2-propenyl group, 2-hexenyl group, 2-methyl Specific examples include 2-pentenyl group, 2,4-dimethyl-2,6-heptadienyl group, 3,7-dimethyl-2,6-octadienyl group, etc. Is done.
  • C a -C b haloalkenyl is a linear or branched chain having a carbon number of a to b in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. And an unsaturated hydrocarbon group having one or more double bonds in the molecule. At this time, when substituted by two or more halogen atoms, these halogen atoms may be the same as or different from each other.
  • C a -C b alkynyl represents a linear or branched chain having a carbon number of a to b and an unsaturated group having one or more triple bonds in the molecule.
  • Specific examples include a 1-dimethyl-2-propynyl group, a 2-hexynyl group, and the like, and each is selected within the specified number of carbon atoms.
  • C a -C b alkoxy in the present specification represents an alkyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methoxy group, ethoxy group, n-propyloxy group, Specific examples include i-propyloxy group, n-butyloxy group, i-butyloxy group, s-butyloxy group, t-butyloxy group, n-pentyloxy group, n-hexyloxy group, etc. It is selected in the range of the number of atoms.
  • C a -C b haloalkoxy represents a haloalkyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, for example, a difluoromethoxy group, a trifluoromethoxy group, a chlorodifluoro Methoxy group, bromodifluoromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2, -tetrafluoroethoxy group, 2-chloro-1 , 1,2-trifluoroethoxy group, 2-bromo-1,1,2-trifluoroethoxy group, pentafluoroethoxy group, 2,2-dichloro-1,1,2-trifluoroethoxy group, 2,2 , 2-trichloro-1,1-difluoroethoxy group, 2-bromo-1,1,2,2-tetrafluoroeth
  • benzyloxy in the present specification represents a phenyl-CH 2 O— group.
  • C a -C b alkylthio in the present specification represents an alkyl-S-group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylthio group, ethylthio group, n-propylthio group, i Specific examples include -propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group, n-pentylthio group, n-hexylthio group, etc. Selected.
  • C a -C b haloalkylthio in the present specification represents a haloalkyl-S-group having the above-mentioned meaning comprising a to b carbon atoms, for example, difluoromethylthio group, trifluoromethylthio group, chlorodifluoro Methylthio group, bromodifluoromethylthio group, 2,2,2-trifluoroethylthio group, 1,1,2,2-tetrafluoroethylthio group, 2-chloro-1,1,2-trifluoroethylthio group, Pentafluoroethylthio group, 2-bromo-1,1,2,2-tetrafluoroethylthio group, 1,1,2,3,3,3-hexafluoropropylthio group, heptafluoropropylthio group, 1, Specific examples include 2,2,2-tetrafluoro-1- (trifluoromethyl) ethy
  • C a -C b alkylsulfinyl in the present specification represents an alkyl-S (O) — group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylsulfinyl group, ethylsulfinyl group, Specific examples include n-propylsulfinyl group, i-propylsulfinyl group, n-butylsulfinyl group, i-butylsulfinyl group, s-butylsulfinyl group, t-butylsulfinyl group and the like. The range is selected.
  • C a -C b haloalkylsulfinyl represents a haloalkyl-S (O) -group having the above-mentioned meaning consisting of a to b carbon atoms, for example, difluoromethylsulfinyl group, trifluoromethyl Sulfinyl group, chlorodifluoromethylsulfinyl group, bromodifluoromethylsulfinyl group, 2,2,2-trifluoroethylsulfinyl group, 2-bromo-1,1,2,2-tetrafluoroethylsulfinyl group, 1,2,2 Specific examples include 2-tetrafluoro-1- (trifluoromethyl) ethylsulfinyl group, nonafluorobutylsulfinyl group, and the like, each selected within the range of the designated number of carbon atoms.
  • C a -C b alkylsulfonyl in the present specification represents an alkyl-SO 2 — group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylsulfonyl group, ethylsulfonyl group, n- Specific examples include propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group, s-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group and the like. Each of which is selected for each specified number of carbon atoms.
  • C a -C b haloalkylsulfonyl in the present specification represents a haloalkyl-SO 2 — group having the above-mentioned meaning consisting of a to b carbon atoms, such as a difluoromethylsulfonyl group, a trifluoromethylsulfonyl group.
  • Chlorodifluoromethylsulfonyl group bromodifluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group, 1,1,2,2-tetrafluoroethylsulfonyl group, 2-chloro-1,1,2-trimethyl
  • Specific examples include a fluoroethylsulfonyl group, a 2-bromo-1,1,2,2-tetrafluoroethylsulfonyl group, and the like, and each is selected within the range of the designated number of carbon atoms.
  • phenylsulfonyloxy in the present specification represents a phenylsulfonyl-O— group (phenyl-SO 2 —O-group).
  • C a -C b alkylsulfonyloxy in the present specification represents an alkylsulfonyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylsulfonyloxy group, ethylsulfonyloxy group N-propylsulfonyloxy group, i-propylsulfonyloxy group, n-butylsulfonyloxy group, i-butylsulfonyloxy group, s-butylsulfonyloxy group, t-butylsulfonyloxy group, n-pentylsulfonyloxy group, Specific examples include n-hexylsulfonyloxy group and the like, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b haloalkylsulfonyloxy in the present specification represents a haloalkylsulfonyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, such as a difluoromethylsulfonyloxy group, trifluoro Methylsulfonyloxy group, chlorodifluoromethylsulfonyloxy group, bromodifluoromethylsulfonyloxy group, 2,2,2-trifluoroethylsulfonyloxy group, 1,1,2,2-tetrafluoroethylsulfonyloxy group, 2-chloro Specific examples include -1,1,2-trifluoroethylsulfonyloxy group, 2-bromo-1,1,2,2-tetrafluoroethylsulfonyloxy group, etc. Selected.
  • C a -C b alkylcarbonyl represents an alkyl-C (O) -group having the above-mentioned meanings having a to b carbon atoms, for example, acetyl group (ethanoyl group), propionyl.
  • Specific examples include groups (propanoyl group), butyryl group (butanoyl group), isobutyryl group, valeryl group (pentanoyl group), isovaleryl group, 2-methylbutanoyl group, pivaloyl group, hexanoyl group, heptanoyl group, etc. Is selected within the range of the specified number of carbon atoms.
  • C a -C b haloalkylcarbonyl in the present specification represents a haloalkyl-C (O) — group having the above-mentioned meaning consisting of a to b carbon atoms, such as a fluoroacetyl group, a chloroacetyl group, Difluoroacetyl group, dichloroacetyl group, trifluoroacetyl group, chlorodifluoroacetyl group, bromodifluoroacetyl group, trichloroacetyl group, pentafluoropropionyl group, heptafluorobutanoyl group, 3-chloro-2,2-dimethylpropanoyl group Etc. are given as specific examples, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b alkoxycarbonyl in the present specification represents an alkoxy-C (O) — group having the above-mentioned meaning consisting of a to b carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, Specific examples include n-propyloxycarbonyl group, i-propyloxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, t-butoxycarbonyl group, etc., each selected within the range of the specified number of carbon atoms Is done.
  • C a -C b (alkylthio) carbonyl represents an alkylthio-C (O) — group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylthio-C (O) -Group, ethylthio-C (O)-group, n-propylthio-C (O)-group, i-propylthio-C (O)-group, n-butylthio-C (O)-group, i-butylthio-C Specific examples include (O) -group, t-butylthio-C (O) -group, and the like, and each is selected within the range of the designated number of carbon atoms.
  • C a -C b alkoxythiocarbonyl represents an alkoxy-C (S) — group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methoxy-C (S) — Specific examples include groups, ethoxy-C (S) -groups, n-propyloxy-C (S) -groups, i-propyloxy-C (S) -groups, etc. Selected by range.
  • C a -C b (alkylthio) thiocarbonyl represents an alkylthio-C (S) — group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylthio-C (S ) -Group, ethylthio-C (S) -group, n-propylthio-C (S) -group, i-propylthio-C (S) -group, etc. Selected by range.
  • C a -C b alkylaminocarbonyl is represented by a carbamoyl group (H 2) in which one of the hydrogen atoms of the amino group is substituted with an alkyl group having the above-mentioned meaning consisting of a to b carbon atoms.
  • NC (O)-) for example, methylcarbamoyl group, ethylcarbamoyl group, n-propylcarbamoyl group, i-propylcarbamoyl group, n-butylcarbamoyl group, i-butylcarbamoyl group, s-butylcarbamoyl group, t- Specific examples include a butylcarbamoyl group and the like, and each butylcarbamoyl group is selected within the range of the designated number of carbon atoms.
  • di (C a -C b alkyl) aminocarbonyl refers to the case where the number of carbon atoms in which both of the hydrogen atoms of the amino group may be the same or different from each other consists of a to b.
  • C a -C b alkylaminosulfonyl refers to a sulfamoyl group (H 2) in which one of the hydrogen atoms of the amino group is substituted with an alkyl group having the above-mentioned meaning consisting of a to b carbon atoms.
  • NS (O) 2- for example, methylsulfamoyl group, ethylsulfamoyl group, n-propylsulfamoyl group, i-propylsulfamoyl group, n-butylsulfamoyl group, i-butyl
  • Specific examples include a sulfamoyl group, a s-butylsulfamoyl group, a t-butylsulfamoyl group, and the like, and each sulfamoyl group is selected within the range of the designated number of carbon atoms.
  • di (C a -C b alkyl) aminosulfonyl is the above-mentioned wherein the number of carbon atoms in which both of the hydrogen atoms of the amino group may be the same or different from each other consists of a to b.
  • a hydrogen atom bonded to a carbon atom is optionally substituted by any C a -C b cycloalkyl group, C a -C b alkoxy group or C a -C b alkylthio group each having the above-mentioned meaning. It represents a linear or branched saturated hydrocarbon group comprising d to e carbon atoms, and is selected within the range of the respective designated number of carbon atoms.
  • the notation [(C a -C b ) alkyl optionally substituted with V 5 ] means that the number of carbon atoms in which a hydrogen atom bonded to a carbon atom is arbitrarily substituted with an arbitrary V 5 is a It represents a linear or branched saturated hydrocarbon group composed of ⁇ b, and is selected in the range of the designated number of carbon atoms. At this time, when two or more substituents V 5 on each (C a -C b ) alkyl group are present, each V 5 may be the same as or different from each other.
  • the notation [(C a -C b ) alkyl optionally substituted with R 8 ] means that the number of carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with any R 8 is a It represents a linear or branched saturated hydrocarbon group composed of ⁇ b, and is selected in the range of the designated number of carbon atoms. At this time, when there are two or more substituents R 8 on each (C a -C b ) alkyl group, each R 8 may be the same as or different from each other.
  • the notation [(C a -C b ) alkyl optionally substituted with R 3d ] means that the number of carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with any R 3d is a It represents a linear or branched saturated hydrocarbon group composed of ⁇ b, and is selected in the range of the designated number of carbon atoms.
  • each R 3d may be the same as or different from each other.
  • the notation [(C a -C b ) alkyl optionally substituted with R 4a ] indicates that the number of carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with any R 4a is a It represents a linear or branched saturated hydrocarbon group composed of ⁇ b, and is selected within the range of the designated number of carbon atoms. At this time, when there are two or more substituents R 4a on each (C a -C b ) alkyl group, each R 4a may be the same as or different from each other.
  • the expression [benzyl substituted with (V 6 ) r1 in the benzene ring] [phenyl substituted with (V 6 ) r1 ] represents hydrogen bonded to a carbon atom of the benzene ring by any V 6 . It represents a benzyl group or phenyl group in which atoms are optionally substituted. At this time, when two or more substituents V 6 on the phenyl group are present (that is, when r1 is 2 to 5), each V 6 may be the same as or different from each other.
  • the expression [phenyl substituted by (Z) p1 ] represents a phenyl group in which a hydrogen atom bonded to a carbon atom is optionally substituted by an arbitrary Z.
  • each Z may be the same as or different from each other.
  • the expression [(V) phenyl substituted by p1 ] represents a phenyl group in which a hydrogen atom bonded to a carbon atom is optionally substituted by an arbitrary V.
  • each V may be the same as or different from each other.
  • C a -C b cycloalkyl optionally condensed by a benzene ring is a carbon atom in which a hydrogen atom bonded to two adjacent carbon atoms is optionally substituted by a benzene ring. It represents a cyclic hydrocarbon group having a to b atoms and can form a complex ring structure having 3 to 6 members.
  • 1-indanyl group, 2-indanyl group, 1,2,3,4-tetrahydro-1-naphthyl group, 1,2,3,4-tetrahydro-2-naphthyl group and the like can be mentioned as specific examples. Selected within the specified number of carbon atoms.
  • Specific examples of the ring represented by] may include one oxygen atom, sulfur atom or nitrogen atom, for example, pyrrolidine, pyrrolidin-2-one, oxazolidine-2-one, oxazolidine-2-thione, thiazolidine , Thiazolidine-2-one, thiazolidine-2-thione, imidazolidine, imidazolidine-2-one, imidazolidine-2-thione, piperidine, piperidin-2-one, piperidine-2-thione, 2H-3,4, 5,6-tetrahydro-1,3-oxazin-2-one, 2H-3,4,5,6-tetrahydro-1,3-oxazin-2-thione, morpholine, 2H-3,4,5,6- Tetrahydro-1,3-thiazin
  • [R 1b and R 1a together represent a C 2 to C 6 alkylene chain, and may form a 3 to 7 membered ring together with the nitrogen atom to which they are bonded.
  • Specific examples of the ring represented by the notation] may include one oxygen atom, sulfur atom or nitrogen atom, for example, aziridine, azetidine, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine, homo Piperidine, heptamethyleneimine and the like can be mentioned, and each is selected within the range of the designated number of atoms.
  • [R 1c and R 1d together represent a C 4 to C 6 alkylene chain, and they may form a 5- to 7-membered ring together with the nitrogen atom to which they are bonded. It may contain one oxygen atom, sulfur atom or nitrogen atom, and C 1 -C 6 alkyl group, —CHO group, C 1 -C 6 alkylcarbonyl group, C 1 -C 6 haloalkylcarbonyl group, C 1 -C Optionally substituted by a 6 alkoxycarbonyl group, a C 1 -C 6 haloalkoxycarbonyl group, a C 1 -C 6 alkylaminocarbonyl group, a C 1 -C 6 haloalkylaminocarbonyl group, an oxo group or a thioxo group, ]
  • the ring represented by the notation of, ON, imidazolidine, imidazolidine-2-one, imidazolidine-2-thioxo group As specific
  • Specific examples of the ring represented by the notation] may include, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a pyrrolidine ring, A cyclohexane ring, a tetrahydropyran ring, a tetrahydrothiopyran ring, a piperidine ring, an oxepane ring, a thiepan ring, an azepane ring, etc. are mentioned, and each is selected in the range of the designated number of atoms.
  • phase transfer catalyst for example, a compound represented by the general formula (6), a compound represented by the general formula (7), these formula (6) or formula (7) And other quaternary ammonium salts and other quaternary phosphonium salts, pyridinium salts, and crown ethers.
  • a compound represented by the general formula (7), crown ether, or pyridinium salt (chloride salt, bromide salt, fluoride salt) as a phase transfer catalyst, a basic compound described later is used in combination. Then, dehydration reaction is performed.
  • M 1 represents a nitrogen atom
  • X 4 represents a fluorine atom
  • r2 represents 1 as a quaternary ammonium fluoride, for example, tetrabutylammonium fluoride , Tetraethylammonium fluoride, tetramethylammonium fluoride, benzyltrimethylammonium fluoride, benzyltriethylammonium fluoride, benzyltripropylammonium fluoride, benzyltributylammonium fluoride, methyltributylammonium fluoride, trimethylphenylammonium fluoride, tetra Examples include decyltrimethylammonium fluoride and tetraoctylammonium fluoride, and preferably tetrabutylammonium fluoride.
  • M 1 represents a phosphorus atom
  • X 4 represents a fluorine atom
  • r 2 represents 1.
  • Examples of the quaternary phosphonium fluoride include tetraphenylphosphonium fluoride.
  • Tetrabutylphosphonium fluoride Tetrabutylphosphonium fluoride, methyltriphenylphosphonium fluoride, ethyltriphenylphosphonium fluoride, propyltriphenylphosphonium fluoride, benzyltriphenylphosphonium fluoride, dodecyltriphenylphosphonium fluoride, hexadecyltributylphosphonium fluoride and tetra Examples include decyltriphenylphosphonium fluoride, preferably tetrabutylphosphonium fluoride.
  • phase transfer catalyst represented by the general formula (6), quaternary ammonium hydroxide in which M 1 represents a nitrogen atom, X 5 represents —OH, and r 2 represents 1, for example, benzyltriethylammonium hydroxide , Benzyltrimethylammonium hydroxide, choline [(2-hydroxyethyl) trimethylammonium], hexadecyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, tetraethylammonium hydroxide, tetrahexylammonium hydroxide, tetramethylammonium hydroxide, tetra Propyl ammonium hydroxide, 3- (trifluoromethyl) phenyltrimethylammonium hydroxide, trimethylphenylammonium hydroxide and tris (2-hydroxyethyl) methyl Ammonium hydroxide and the like, preferably benzyl trimethylammonium hydroxide,
  • phase transfer catalyst represented by the general formula (6), quaternary phosphonium hydroxide in which M 1 represents a phosphorus atom, X 5 represents —OH, and r 2 represents 1, for example, tetrabutylphosphonium hydroxide Tetraethylphosphonium hydroxide, tetraphenylphosphonium hydroxide, methyltriphenylphosphonium hydroxide, ethyltriphenylphosphonium hydroxide, propyltriphenylphosphonium hydroxide, butyltriphenylphosphonium hydroxide, benzyltriphenylphosphonium hydroxide, etc.
  • tetrabutylphosphonium hydroxide and tetraphenylphosphonium hydroxide are used.
  • the quaternary ammonium acetate in which M 1 represents a nitrogen atom, X 5 represents —OC (O) CH 3 , and r 2 represents 1 is, for example, Examples include tetrabutylammonium acetate, tetraethylammonium acetate, and tetramethylammonium acetate, and preferably tetrabutylammonium acetate.
  • Examples include tetrabutylphosphonium acetate, ethyltriphenylphosphonium acetate, and tetramethylammonium acetate, and preferably tetrabutylphosphonium acetate.
  • the quaternary ammonium sulfate in which M 1 represents a nitrogen atom, X 5 represents —OS (O) 2 O—, and r 2 represents 2 is, for example, , Tetrabutylammonium sulfate, tetramethylammonium sulfate, tetraethylammonium sulfate, bis (dodecyltrimethylammonium) sulfate, and the like, preferably tetrabutylammonium sulfate.
  • phase transfer catalyst represented by the general formula (6), the quaternary phosphonium sulfate in which M 1 represents a phosphorus atom, X 5 represents —OS (O) 2 O—, and r 2 represents 2, And tetrakis (hydroxymethyl) phosphonium sulfate.
  • examples of the quaternary ammonium chloride in which M 1 represents a nitrogen atom and X 5 represents a chlorine atom include acetylcholine chloride and (3-acrylamidopropyl) trimethylammonium chloride.
  • Benzalkonium chloride benzoylcholine chloride, benzylcetyldimethylammonium chloride, benzyldimethylphenylammonium chloride, benzyldimethylstearylammonium chloride, benzyldimethyltetradecylammonium chloride, benzyltributylammonium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, 1-butyl-1-methylpyrrolidinium chloride, carbamylcholine chloride, chlorocholine chloride, (3-chloro-2-hydride Xylpropyl) trimethylammonium chloride, choline chloride, decyltrimethylammonium chloride, dimethyldistearylammonium chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, methacholine chloride, ⁇ -methyl
  • examples of the quaternary phosphonium chloride in which M 1 represents a phosphorus atom and X 5 represents a chlorine atom include benzyltriphenylphosphonium chloride, (4-chlorobenzyl) Triphenylphosphonium chloride, (2-chlorobenzyl) triphenylphosphonium chloride, triphenyl (2-chlorobenzyl) phosphonium chloride, (chloromethyl) triphenylphosphonium chloride, (2,4-dichlorobenzyl) triphenylphosphonium chloride, ( 1-naphthylmethyl) triphenylphosphonium chloride, tetrabutylphosphonium chloride, tetrakis (hydroxymethyl) phosphonium chloride, tetraphenylphosphonium chloride and the like, preferably tetrabutylphosphonium chloride, tetraphenyl Suho chloride, and
  • examples of the quaternary ammonium bromide in which M 1 represents a nitrogen atom and X 5 represents a bromine atom include acetylcholine bromide, benzoylcholine bromide, benzyltributylammonium bromide, Benzyltriethylammonium bromide, benzyltrimethylammonium bromide, bromocholine bromide, 1-butyl-1-methylpiperidinium bromide, choline bromide, decyltrimethylammonium bromide, didecyldimethylammonium bromide, dilauryldimethylammonium bromide, dimethyldimyristylammonium Bromide, dimethyl dioctadecyl ammonium bromide, dimethyl dioctyl ammonium bromide, dimethyl dipalmityl ammonium bromide, dodecy Tri
  • examples of the quaternary phosphonium bromide in which M 1 represents a phosphorus atom and X 5 represents a bromine atom include amyltriphenylphosphonium bromide, benzyltriphenylphosphonium bromide, (Bromomethyl) triphenylphosphonium bromide, 3-bromopropyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide, cyclopropyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, heptyltriphenylphosphonium bromide, hexyltriphenylphosphonium bromide, (2 -Hydroxybenzyl) triphenylphosphonium bromide, methyltriphenylphosphonium bromide, (4-nitrobenzyl) triphenylphosphonium bromide, Raethylphosphon
  • examples of the quaternary ammonium iodide in which M 1 represents a nitrogen atom and X 5 represents an iodine atom include acetylcholine iodide, acetylthiocholine iodide, benzoyl Choline iodide, benzoylthiocholine iodide, benzyltriethylammonium iodide, ethyltrimethylammonium iodide, ethyltripropylammonium iodide, (ferrocenylmethyl) trimethylammonium iodide, (2-hydroxyethyl) triethylammonium iodide , ⁇ -methylcholine iodide, tetraamylammonium iodide, tetrabutylammonium iodide, tetraethylammonium
  • examples of the quaternary phosphonium iodide in which M 1 represents a phosphorus atom and X 5 represents an iodine atom include ethyltriphenylphosphonium iodide and isopropyltriphenylphosphonium. Examples include iodide, methyltriphenylphosphonium iodide, tetraphenylphosphonium iodide, and tributylmethylphosphonium iodide, preferably tetraphenylphosphonium iodide.
  • quaternary ammonium salts include, for example, acetylcholine perchlorate, amyltriethylammonium bis (trifluoromethanesulfonyl) imide, benzyltriethylammonium borohydride, benzyltrimethylammonium dichloroiodate, benzyltrimethylammonium tetrachloroiodate, benzyl Trimethylammonium tribromide, anhydrous betaine, betaine hydrochloride, bis (tetrabutylammonium dichromate), bis (tetrabutylammonium) tetracyanodiphenoquinodimethanide, 1-butyl-1-methylpyrrolidinium bis (trifluoromethane (Sulfonyl) imide, L-carnitine, 3-[(3-colamidopropyl) dimethylammonio] -1-propanesulfonate, choline bitartrate, 1-cyclohe
  • quaternary phosphonium salts include, for example, di-tert-butylmethylphosphonium tetraphenylborate, ⁇ -oxo-bis [tris (dimethylamino) phosphonium] bis (tetrafluoroborate), tetrabutylphosphonium benzotriazo , Tetraethylphosphonium tetrafluoroborate, tetrakis (hydroxymethyl) phosphonium sulfate, tetraphenylphosphonium tetraphenylborate, tetraphenylphosphonium tetra-p-tolylborate, tributyl (2-methoxyethyl) phosphonium bis (trifluoromethanesulfonyl) imide , Tri-tert-butylphosphonium tetrafluoroborate, tri-tert-butylphosphonium tetraphenylborate, tricyclohexyl
  • pyridinium salt examples include 1-acetonylpyridinium chloride, 2-benzyloxy-1-methylpyridinium trifluoromethanesulfonate, 1,1 ′-[biphenyl-4,4′-diylbis (methylene)] bis (4, 4'-bipyridinium) bis (hexafluorophosphate), 1,1 '-[biphenyl-4,4'-diylbis (methylene)] bis (4,4'-bipyridinium) dibromide, 1,1'-bis (2 , 4-dinitrophenyl) -4,4'-bipyridinium dichloride, 2-bromo-1-ethylpyridinium tetrafluoroborate, 1-butyl-4-methylpyridinium bromide, 1-butyl-3-methylpyridinium bromide, 1- Butyl-3-methylpyridinium chloride, 1-butyl-4-methylpyridinium chloride, 1-but
  • crown ether examples include 4′-acetylbenzo-15-crown-5, 4′-acetylbenzo-18-crown-6, 2- (allyloxymethyl) -18-crown-6, 4′-aminobenzo- 15-crown-5, 1-aza-15-crown-5, 1-aza-18-crown-6, 1-aza-12-crown-4, benzo-15-crown-5, benzo-12-crown- 4, benzo-18-crown-6, bis (1,4-phenylene) -34-crown-10, 4'-bromobenzo-18-crown-6, 4'-bromobenzo-15-crown-5, 4'- Carboxybenzo-15-crown-5, 4'-carboxybenzo-18-crown-6, 15-crown-4 [4- (2,4-dinitrophenylazo) phenol], 18-crown-5 [4- ( 2,4-dinitrophenylazo) phenol], 12-crown-4
  • the phase transfer catalyst may be in a hydrate state, in a solid state, or in a solution state dissolved in water, methanol, tetrahydrofuran, or a solvent used in the reaction.
  • the amount of the phase transfer catalyst used is usually 0.0001 to 1 mol, preferably 0.0005 to 1 mol of the compound represented by the general formula (2) or 1 mol of the compound represented by the general formula (4).
  • the amount is 0.8 times mol, particularly preferably 0.001 to 0.5 times mol.
  • the compound represented by the general formula (2) is first obtained by the aldol reaction between the compound represented by the general formula (3) and the compound represented by the general formula (4). Although it occurs in the reaction system, the dehydration reaction proceeds immediately and becomes a compound represented by the general formula (1).
  • the reaction can be carried out in the absence or presence of a basic compound.
  • basic compounds that can be used at this time include hydroxide salts, carbonates, hydrogen carbonates, sulfites, phosphates, hydrogen phosphates, tungstates, nitrogen-containing organic compounds, and organic acid salts.
  • the salt means an alkali metal salt, and examples of the alkali metal include sodium and potassium.
  • Specific examples of these basic compounds include, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium sulfite, potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate.
  • Dipotassium, sodium tungstate, pyridine, 2-methyl-5-ethylpyridine, piperidine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5-diazabicyclo Examples include [4,3,0] -5-nonene, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium phenoxide, sodium benzoate, potassium t-butoxide, and potassium phthalimide.
  • preferred basic compounds include a hydroxide salt represented by the formula (8), a carbonate represented by the formula (9), a bicarbonate represented by the formula (10), and the formula ( 11), bisulfite represented by the formula (12), phthalimide salt represented by the formula (13), and organic acid salt represented by the formula (14).
  • a hydroxide salt represented by the formula (8) a carbonate represented by the formula (9), a bicarbonate represented by the formula (10), and the formula ( 11), bisulfite represented by the formula (12), phthalimide salt represented by the formula (13), and organic acid salt represented by the formula (14).
  • sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium sulfite, dipotassium hydrogen phosphate, potassium phthalimide, and potassium acetate are used, and more preferable bases include sodium hydroxide and potassium hydroxide. .
  • the amount of the basic compound used is usually 0.0001 to 1 times mol, preferably 0.0005 to 1 mol of the compound represented by the general formula (2) or 1 mol of the compound represented by the general formula (4).
  • the amount is 0.8 times mol, particularly preferably 0.001 to 0.5 times mol.
  • reaction can be performed in presence of the fluoride salt represented by General formula (15).
  • Specific examples of the fluoride salt represented by the general formula (15) include, for example, lithium fluoride, sodium fluoride, potassium fluoride, rubidium fluoride, cesium fluoride, ammonium fluoride, and preferably , Potassium fluoride, cesium fluoride, and ammonium fluoride.
  • the amount of the fluoride salt used is usually 0.0001 to 1 times mol, preferably 0.0005 to 1 mol of the compound represented by the general formula (2) or 1 mol of the compound represented by the general formula (4).
  • the amount is 0.8 times mol, particularly preferably 0.001 to 0.5 times mol.
  • the reaction may be performed in the presence of a solvent, if necessary.
  • the solvent that can be used in the reaction of the present invention is not particularly limited as long as it does not inhibit the progress of the reaction.
  • it is substituted with a halogen atom such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, or mesitylene.
  • Aromatic hydrocarbons which may be substituted; substituted with halogen atoms such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride or 1,2-dichloroethane
  • Aliphatic ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and butyl acetate; Nitromethane, nitroethane, Methyl sulfoxide, water, supercritical fluid, etc., even if these are used singly or may be used by mixing two or more kinds.
  • toluene, n-heptane, cyclopentyl methyl ether, cyclohexane, methylene chloride, chlorobenzene, acetonitoyl, and ethyl acetate are preferable, and toluene and cyclopentyl methyl ether are more preferable.
  • the amount of the solvent may be an amount that can sufficiently stir the reaction system. 0.1 to 100 parts by mass, preferably 0.5 to 50 parts by mass, particularly preferably 1 to 15 parts by mass.
  • the reaction temperature can be set at an arbitrary temperature in the range of ⁇ 20 ° C. to the reflux temperature of the reaction mixture, and preferably 0 to 150 ° C.
  • reaction may be performed while removing water by azeotropic dehydration with a solvent.
  • Azeotropic dehydration may be performed at normal pressure or under reduced pressure.
  • reaction time varies depending on the concentration of the reaction substrate and the reaction temperature, it can usually be arbitrarily set within the range of 0.1 to 48 hours, preferably 0.1 to 24 hours. It is preferable to set 5 to 10 hours.
  • a predetermined amount of a phase transfer catalyst represented by 4-difluoro-3-hydroxybutan-1-one compound, tetrabutylammonium hydroxide (and a basic compound such as sodium hydroxide if necessary) and a solvent represented by toluene The reaction is usually carried out at 0 to 150 ° C. with stirring, usually for 0.1 to 48 hours, preferably 0.1 to 24 hours, particularly preferably 0.5 to 10 hours, with azeotropic dehydration as necessary. Just do it.
  • ketone compounds represented by the general formula (3) used in the present invention are known compounds, and some of them are available as commercial products. Others can be easily synthesized according to known methods described in the literature, for example, the methods described in Journal of Fluorine Chemistry, 18 (2), 29117-29; 1981, and the like.
  • acetyl compounds represented by the general formula (4) used in the present invention are known compounds, and some are available as commercial products. Others can be easily synthesized according to known synthesis methods described in the literature.
  • the step of producing the compound represented by the general formula (1) from the compound represented by the general formula (2) using a phase transfer catalyst is performed in the absence or presence of a basic compound.
  • a basic compound examples include hydroxide salts, carbonates, hydrogen carbonates, sulfites, phosphates, hydrogen phosphates, tungstates, nitrogen-containing organic compounds, and organic acid salts. It is done.
  • the salt means an alkali metal salt, and examples of the alkali metal include sodium and potassium.
  • these basic compounds include, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium sulfite, potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate.
  • Dipotassium, sodium tungstate, pyridine, 2-methyl-5-ethylpyridine, piperidine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5-diazabicyclo Examples include [4,3,0] -5-nonene, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium phenoxide, sodium benzoate, potassium t-butoxide, and potassium phthalimide.
  • preferred basic compounds include a hydroxide salt represented by the formula (8), a carbonate represented by the formula (9), a bicarbonate represented by the formula (10), and the formula ( 11), bisulfite represented by the formula (12), phthalimide salt represented by the formula (13), and organic acid salt represented by the formula (14).
  • sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium sulfite, dipotassium hydrogen phosphate, potassium phthalimide, and potassium acetate are used, and more preferable bases include sodium hydroxide and potassium hydroxide.
  • the amount of the basic compound used is usually 0.0001 to 1 times mol, preferably 0.0005 to 0.8 times mol, particularly preferably 0.001 mol, per mol of the compound represented by the general formula (2). 001 to 0.5 times mol.
  • the reaction may be performed in the presence of a solvent, if necessary.
  • the solvent that can be used in this production method is not particularly limited as long as it does not inhibit the progress of the reaction.
  • Good aromatic hydrocarbons Fats that may be substituted with halogen atoms such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride or 1,2-dichloroethane Group hydrocarbons; ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether and t-butyl methyl ether; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and butyl acetate; and nitromethane and nitroethane , Jime Rusuruhokishido,
  • the amount of the solvent is not particularly limited as long as the reaction system can be sufficiently stirred, but is usually 0.1 to 100 parts by mass, preferably 0.1 to 1 part by mass of the compound represented by the general formula (2). 5 to 50 parts by mass, particularly preferably 1 to 15 parts by mass.
  • the step of producing the compound represented by the general formula (1) from the compound represented by the general formula (2) is performed while removing water by azeotropic dehydration with a solvent as necessary. Also good. Azeotropic dehydration may be carried out at normal pressure or under reduced pressure.
  • a hydroxylamine compound is added to a reaction solution containing the compound represented by the general formula (1) obtained by the reaction from the compound represented by the general formula (2), and the general formula (5) ) Is produced in one pot.
  • the hydroxylamine compound used at this time may be a salt such as hydroxylamine hydrochloride, sulfate, phosphate, oxalate, nitrate or acetate, or an aqueous hydroxylamine solution.
  • the amount of the hydroxylamine compound used is usually 0.5 to 100 times mol, preferably 1 to 10 times mol, particularly preferably 1 to 2 times mol, per mol of the compound represented by the general formula (2). is there.
  • a basic compound may be used in combination with the hydroxylamine compound in the step of producing the compound represented by the general formula (5) from the compound represented by the general formula (1).
  • Examples of basic compounds that can be used at this time include sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, sodium methoxide, potassium-t- Butoxide, pyridine, 2-methyl-5-ethylpyridine, piperidine, triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5- Diazabicyclo [4,3,0] -5-nonene, triethylenediamine, N, N, N ′, N′-tetramethylethylenediamine, 1,4-diazabicyclo [2,2,2] octane,
  • More preferred bases include sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5-diazabicyclo [4,3,0] -5-nonene.
  • the amount used is usually 0.01 to 10 moles, preferably 0.1 to 5 moles per mole of the compound represented by the general formula (1).
  • a phase transfer catalyst in the step of producing the compound represented by the general formula (5) from the compound represented by the general formula (1), can be arbitrarily added.
  • examples include quaternary ammonium salts and crown ethers, preferably quaternary ammonium salts.
  • the quaternary ammonium salts include benzyltrimethylammonium hydroxide, tributylammonium hydroxide, tributylammonium bromide, and methyltrimethyl. -N-octylammonium chloride and the like.
  • the amount used in the case of adding a phase transfer catalyst is usually 0.0001 to 1 times mol, preferably 0.001 to 0.8 times mol for 1 mol of the compound represented by the general formula (1). .
  • the reaction temperature is any temperature within the range of ⁇ 20 ° C. to the reflux temperature of the reaction mixture in the step of producing the compound represented by the general formula (1) from the compound represented by the general formula (2).
  • it in the step of producing the compound represented by the general formula (5) from the compound represented by the general formula (1), it can be usually set to ⁇ 70 to 100 ° C., preferably ⁇ 40 to 50 ° C.
  • the total reaction time required to produce the compound represented by the general formula (5) from the reaction represented by the above reaction formula (3), that is, the compound represented by the general formula (2) is the concentration of the reaction substrate, although it varies depending on the reaction temperature, it can usually be arbitrarily set in the range of 0.1 to 120 hours, preferably 0.1 to 72 hours, more preferably 1 to 48 hours. I can do it.
  • a reactor is represented by the general formula (2).
  • a predetermined amount is charged and stirred, usually at 0 to 150 ° C., usually for 0.1 to 48 hours, preferably 0.1 to 24 hours, particularly preferably 0.5 to 10 hours, and azeotropically dehydrated as necessary.
  • reaction usually at ⁇ 70 to 100 ° C., preferably at ⁇ 40 to 50 ° C., separately, a solution in which a basic compound, water and a hydroxylamine compound are mixed is dropped, and usually from 10 minutes to 20 hours, preferably the reaction can be about 1 to 48 hours.
  • the compound represented by the general formula (5) is produced in one pot from the compound represented by the general formula (3) and the compound represented by the general formula (4).
  • the method of performing will be described in detail.
  • the step of producing the compound represented by the general formula (1) from the compound represented by the general formula (3) and the compound represented by the general formula (4) using a phase transfer catalyst can be performed in the absence or presence of a basic compound.
  • basic compounds that can be used at this time include hydroxide salts, carbonates, hydrogen carbonates, sulfites, phosphates, hydrogen phosphates, tungstates, nitrogen-containing organic compounds, and organic acid salts. It is done.
  • the salt means an alkali metal salt, and examples of the alkali metal include sodium and potassium.
  • these basic compounds include, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium sulfite, potassium phosphate, disodium hydrogen phosphate, hydrogen phosphate.
  • Dipotassium, sodium tungstate, pyridine, 2-methyl-5-ethylpyridine, piperidine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5-diazabicyclo Examples include [4,3,0] -5-nonene, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium phenoxide, sodium benzoate, potassium t-butoxide, and potassium phthalimide.
  • preferred basic compounds include a hydroxide salt represented by the formula (8), a carbonate represented by the formula (9), a bicarbonate represented by the formula (10), and the formula ( 11), bisulfite represented by the formula (12), phthalimide salt represented by the formula (13), and organic acid salt represented by the formula (14).
  • sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium sulfite, dipotassium hydrogen phosphate, potassium phthalimide, and potassium acetate are used, and more preferable bases include sodium hydroxide and potassium hydroxide.
  • the amount of the basic compound used is usually 0.0001 to 1 times mol, preferably 0.0005 to 0.8 times mol, particularly preferably 0.001 mol, per mol of the compound represented by the general formula (4). 001 to 0.5 times mol.
  • the reaction may be performed in the presence of a solvent, if necessary.
  • the solvent that can be used in this production method is not particularly limited as long as it does not inhibit the progress of the reaction.
  • it may be substituted with a halogen atom such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, or mesitylene.
  • Fats that may be substituted with halogen atoms such as n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride or 1,2-dichloroethane Group hydrocarbons; ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether and t-butyl methyl ether; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and butyl acetate; and nitromethane, nitroethane , Jime Rusuruhokishido, water, supercritical fluid, etc.
  • halogen atoms such as n-pentane, n-hexane, n-heptane, n-octane, cyclopen
  • the amount of the solvent is not particularly limited as long as the reaction system can be sufficiently stirred, but is usually 0.1 to 100 parts by mass, preferably 0.1 to 1 part by mass of the compound represented by the general formula (4). 5 to 50 parts by mass, particularly preferably 1 to 15 parts by mass.
  • the step of producing the compound represented by the general formula (1) from the compound represented by the general formula (3) and the compound represented by the general formula (4) includes, as necessary, a solvent and It may be carried out while removing water by azeotropic dehydration. Azeotropic dehydration may be carried out at normal pressure or under reduced pressure.
  • a reaction solution containing the compound represented by the general formula (1) obtained by reacting the compound represented by the general formula (3) with the compound represented by the general formula (4) is used.
  • a hydroxylamine compound is added to produce the compound represented by the general formula (5) in one pot.
  • the hydroxylamine compound used at this time may be a salt such as hydroxylamine hydrochloride, sulfate, phosphate, oxalate, nitrate or acetate, or an aqueous hydroxylamine solution.
  • the amount of the hydroxylamine compound used is usually 0.5 to 100 times mol, preferably 1 to 10 times mol, particularly preferably 1 to 2 times mol, based on 1 mol of the compound represented by the general formula (4). is there.
  • a basic compound may be used in combination with the hydroxylamine compound in the step of producing the compound represented by the general formula (5) from the compound represented by the general formula (1).
  • Examples of basic compounds that can be used at this time include sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, sodium methoxide, potassium-t- Butoxide, pyridine, 2-methyl-5-ethylpyridine, piperidine, triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5- Diazabicyclo [4,3,0] -5-nonene, triethylenediamine, N, N, N ′, N′-tetramethylethylenediamine, 1,4-diazabicyclo [2,2,2] octane,
  • More preferable bases include sodium hydroxide, potassium hydroxide, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5-diazabicyclo [4,3,0] -5-nonene.
  • the amount used is usually 0.01 to 10 moles, preferably 0.1 to 5 moles per mole of the compound represented by the general formula (1).
  • a phase transfer catalyst in the step of producing the compound represented by the general formula (5) from the compound represented by the general formula (1), can be arbitrarily added.
  • examples include quaternary ammonium salts and crown ethers, preferably quaternary ammonium salts.
  • the quaternary ammonium salts include benzyltrimethylammonium hydroxide, tributylammonium hydroxide, tributylammonium bromide, and methyltrimethyl. -N-octylammonium chloride and the like.
  • the amount used in the case of adding a phase transfer catalyst is usually 0.0001 to 1 times mol, preferably 0.001 to 0.8 times mol for 1 mol of the compound represented by the general formula (1). .
  • the reaction temperature in this production method is ⁇ 20 ° C. in the step of producing the compound represented by the general formula (1) from the compound represented by the general formula (3) and the compound represented by the general formula (4).
  • ⁇ Arbitrary temperature can be set within the reflux temperature range of the reaction mixture, preferably 0 to 150 ° C.
  • it in the step of producing the compound represented by the general formula (5) from the compound represented by the general formula (1), it can be usually set to ⁇ 70 to 100 ° C., preferably ⁇ 40 to 50 ° C.
  • the reaction represented by the above reaction formula (4) that is, the compound represented by the general formula (1) is produced from the compound represented by the general formula (3) and the compound represented by the general formula (4),
  • the total reaction time required to produce the compound represented by the general formula (5) from the compound represented by the general formula (1) varies depending on the concentration of the reaction substrate and the reaction temperature.
  • the time can be arbitrarily set in the range of up to 120 hours, preferably 0.1 to 72 hours, and more preferably 1 to 48 hours.
  • a ketone compound represented by general formula (3), an acetyl compound represented by general formula (4), a phase transfer catalyst represented by tetrabutylammonium hydroxide, and a basic compound such as sodium hydroxide if desired And a predetermined amount of a solvent typified by toluene, and after stirring, reacting with azeotropic dehydration as necessary, usually at ⁇ 70 to 100 ° C., preferably at ⁇ 40 to 50 ° C., separately with a basic compound
  • a solution prepared by mixing water and a hydroxylamine compound may be dropped and reacted.
  • T is a substituted aryl or substituted heteroaryl represented by the general formula (16)
  • Y is a substituted aryl or substituted represented by the general formula (17).
  • the compound represented by the general formula (5-1) which is heteroaryl and X is a fluorine atom can also be synthesized as follows.
  • Some substituted 4,4-difluoro-2-buten-1-one compounds represented by the following general formula (1-1) are known compounds.
  • phase transfer catalyst to be added examples include quaternary ammonium salts and crown ethers, preferably quaternary ammonium salts.
  • the salt include tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, tributylammonium hydroxide, tributylammonium bromide, methyltri-n-octylammonium chloride and the like.
  • the amount used in the case of adding a phase transfer catalyst is usually 0.0001 to 1 times mol, preferably 0.001 to 0.8 times mol for 1 mol of the compound represented by the general formula (1). .
  • Examples 4 to 7 In the same experimental procedure as in Example 3, the reaction was carried out by changing the phase transfer catalyst from benzyltributylammonium chloride. The relative area percentages of the phase transfer catalyst used and the target product are shown in Table 1 below.
  • Example 8 to 12 In the same experimental operation as in Example 3, the reaction was carried out by changing the solvent from toluene. Table 2 below shows the solvent used, the reaction time, and the relative area percentage of the target product from which the solvent used was omitted. In the table, “DMSO” represents “dimethyl sulfoxide”.
  • the area percentage of the target product was 86.0%.
  • One drop of 40 mass% benzyltrimethylammonium hydroxide aqueous solution was added to this reaction liquid, and it heated up at 105 degreeC, and also continued stirring for 2 hours. After completion of stirring, a part of the reaction solution was extracted and analyzed by HPLC under the same analysis conditions as in Example 1. As a result, the relative area percentage of the target product was 90.0%.
  • a Dean-Stark apparatus in which the trap portion was filled with toluene was attached to the reaction vessel, and 2.00 g of 4-acetyl-2-methylbenzoic acid amide, 20.0 g of toluene, 0.774 g of an aqueous solution of the above phase transfer catalyst, and 3 ′ , 5′-dichloro-2,2,2-trifluoroacetophenone 2.80 g was added and heated to 90 ° C.
  • the relative area percentage of 2-butenoyl] -2-methylbenzoic acid amide was 97.2%.
  • the pressure in the reaction vessel was returned to normal pressure, 25.4 g of toluene and 0.364 g of tetrabutylammonium bromide were added, and the reaction solution was cooled to 10 ° C.
  • a mixed solution of 1.18 g of hydroxylamine hydrochloride, 2.24 g of water and 2.26 mL of 10N aqueous sodium hydroxide solution separately prepared in a reaction vessel was added dropwise to the reaction solution. After completion of dropping, the mixture was stirred at the same temperature for 20 hours.
  • the pressure was reduced to 20 kPa, and the mixture was heated to reflux for 2.5 hours for azeotropic dehydration.
  • the reaction solution was analyzed under the same analysis conditions as in Example 1. As a result, the relative area percentage of the target product was 95.5%.
  • Example 26 to 29 In the same experimental operation as in Example 23, the basic compound was changed from potassium bicarbonate to carry out the reaction.
  • the basic compound used and the relative area percentage of the target product are shown in Table 3 below.
  • reaction solution was cooled to 10 ° C., and the whole amount of the toluene solution of 4-acetyl-2-methylbenzoic acid chloride obtained in the above step was added dropwise and stirred at room temperature for 2 hours. After completion of the reaction, 30 mL of water was added dropwise, and the organic layer obtained after liquid separation was washed with 50 mL of 1N hydrochloric acid and 50 mL of water in this order, dehydrated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure .
  • Step 2 4- [5- (3,5-Dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methyl-N-[(2,2,2- Synthesis of (trifluoroethyl) carbamoylmethyl] benzoic acid amide
  • 0.10 g of 85 mass% potassium hydroxide and 2.5 mL of water were added to prepare an aqueous solution of a phase transfer catalyst.
  • reaction solution was allowed to cool, 6 mL of toluene was added, and the mixture was cooled to 5 ° C. And an aqueous solution of 0.84 mL of water was added dropwise, followed by an aqueous solution of 0.44 g of sodium hydroxide and 1 mL of water. After completion of dropping, the mixture was stirred at room temperature for 14 hours. After completion of the reaction, 15 mL of ethyl acetate was added to the reaction solution, liquid separation operation was performed, and the organic layer was separated.
  • the obtained organic layer was washed twice with 10 mL of 1N hydrochloric acid and once with 10 mL of water, dehydrated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue is purified by silica gel column chromatography eluting with n-hexane: ethyl acetate [1: 2 (volume ratio)], and then crystallized with a mixed solvent of 5 mL of toluene and 1 mL of ethyl acetate. Gave 0.66 g of the desired product as a pale yellow solid.
  • the analysis conditions by HPLC are shown below.
  • the production method of the present invention is a method for producing substituted 4,4-difluoro-2-buten-1-one compounds and substituted isoxazoline compounds that are useful as functional materials such as medical pesticides or electronic materials, or as production intermediates thereof. Useful.

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Abstract

La présente invention a pour but de proposer un procédé de fabrication d'un composé 4,4-difluoro-2-butén-1-one substitué et un procédé de fabrication d'un composé isoxazoline substitué. A cet effet, l'invention concerne un procédé de fabrication d'un composé 4,4-difluoro-2-butén-1-one substitué représenté par la formule générale (1) à partir d'un composé représenté par la formule générale (2) par la conduite d'une réaction de déshydratation en présence d'un catalyseur de transfert de phase. L'invention concerne également un procédé de fabrication d'un composé représenté par la formule générale (1) à partir d'un composé représenté par la formule générale (3) et d'un composé représenté par la formule générale (4) par la conduite d'une réaction de condensation et de déshydratation en présence d'un catalyseur de transfert de phase. L'invention concerne aussi un procédé de fabrication d'un composé isoxazoline substitué représenté par la formule générale (5) par l'addition d'un composé hydroxylamine après les procédés de fabrication d'un composé représenté par la formule générale (1).
PCT/JP2012/069867 2011-08-05 2012-08-03 Procédé de fabrication d'un composé 4,4-difluoro-2-butén-1-one substitué et procédé de fabrication d'un composé isoxazoline substitué WO2013021949A1 (fr)

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WO2016151990A1 (fr) * 2015-03-24 2016-09-29 Okinawa Institute Of Science And Technology School Corporation Dérivés de 5-hydroxy-5-aryl-3-oxo-pentanoate substitués en 5 et leurs formes énantiopures
CN113354551A (zh) * 2020-03-04 2021-09-07 东莞市东阳光动物保健药品有限公司 一种酰胺化合物的制备方法
CN113461653A (zh) * 2020-03-30 2021-10-01 洛阳惠中兽药有限公司 一种制备氟雷拉纳中间体的方法以及其制备中间体和应用
CN115594645A (zh) * 2022-11-08 2023-01-13 世华合创生物技术开发（山东）有限公司（Cn） 一种氟雷拉纳的合成方法

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