Classifications

• • 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
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
  • B01J31/0231—Halogen-containing compounds
  • B01J31/0232—Halogen-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0228
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
  • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
  • B01J31/0235—Nitrogen containing compounds
  • B01J31/0237—Amines
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
  • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
  • B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
  • B01J2231/348—1,4-additions, e.g. conjugate additions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
  • B01J2531/001—General concepts, e.g. reviews, relating to catalyst systems and methods of making them, the concept being defined by a common material or method/theory
  • B01J2531/002—Materials
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B61/00—Other general methods

Definitions

• the present invention has the formula (3):
• Patent Document 1 discloses a useful herbicide. Among them, pyroxasulfone is well known as a herbicide having excellent herbicidal activity. Furthermore, JP 2013-512202 (Patent Document 2) shows that 5,5-disubstituted-4,5-dihydroisoxazole of the formula (3) is an important intermediate of the herbicide described in Patent Document 1. Disclose.
• Patent Document 2 JP 2013-512202 discloses a method for producing 5,5-disubstituted-4,5-dihydroisoxazole.
• the oxime of the formula (II) is converted to the carbonyl compound of the formula (III) ( ⁇ -disubstituted- ⁇ , ⁇ - Unsaturated aldehyde) to give 5,5-disubstituted-4,5-dihydroisoxazole of formula (I).
• the present inventor has diligently studied a method for producing the compound of formula (3). As a result, it was surprisingly found that the above problem can be solved by providing the following production method of the compound of formula (3). The present inventor has completed the present invention based on this finding.
• the present invention is as follows.
• R 1 and R 2 are each independently an optionally substituted (C1-C6) alkyl; an optionally substituted (C3-C6) cycloalkyl; Optionally (C2-C6) alkenyl; optionally substituted (C2-C6) alkynyl; optionally substituted (C1-C6) alkoxy; or optionally substituted phenyl; or R 1 and R 2 , together with the carbon atom to which they are attached, forms a 4 to 12 membered carbocyclic ring, where the ring formed here may be substituted.
• 1 and R 2 are as defined above).
• the acid catalyst is one or more selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids, and phosphoric acids (preferably 1 to 3, more preferably 1 or 2, more preferably 1). ), The method according to [I-20].
• the acid catalyst is one or more (preferably 1 to 3, more preferably 1 or 2 and even more preferably 1) acids selected from the group consisting of mineral acids, carboxylic acids and sulfonic acids. The method according to [I-20].
• Acid catalyst is nitric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid, maleic anhydride, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphor
• One or more (preferably 1 to 3) acid catalysts are selected from the group consisting of nitric acid, trifluoroacetic acid, trichloroacetic acid, maleic acid, maleic anhydride, benzenesulfonic acid and p-toluenesulfonic acid.
• the method according to [I-20] which is more preferably 1 or 2 acids, and still more preferably 1 acid.
• the acid catalyst is one or more selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and p-toluenesulfonic acid (preferably 1 to 3, more preferably 1 or 2, more preferably Is an acid), the method according to [I-20].
• the acid catalyst is 1 to 3, preferably 1 or 2, more preferably 1 acid selected from the group consisting of trifluoroacetic acid, maleic acid and maleic anhydride. I-20].
• the amount of the acid catalyst used is 0.01 to 0.30 mol per mol of the compound of formula (1), and any one of [I-20] to [I-28] The method according to item.
• the acid of the acid-base catalyst is at least one selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids, and phosphoric acids (preferably 1 to 3, more preferably 1 or 2, more preferably Is a single acid). The method according to [I-32].
• the acid of the acid-base catalyst is one or more selected from the group consisting of mineral acids, carboxylic acids and sulfonic acids (preferably 1 to 3, more preferably 1 or 2, more preferably 1). ), The method according to [I-32].
• Acid-base catalyst acid is nitric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid, maleic anhydride, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1- or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) acid selected from the group consisting of 10-camphorsulfonic acid and diphenyl phosphate [I-32] The method described in 1.
• the acid of the acid-base catalyst is one or more selected from the group consisting of nitric acid, trifluoroacetic acid, trichloroacetic acid, maleic acid, maleic anhydride, benzenesulfonic acid and p-toluenesulfonic acid (preferably 1
• the method according to [I-32], wherein the acid is ⁇ 3, more preferably 1 or 2, more preferably 1.
• the acid-base catalyst acid is one or more selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and p-toluenesulfonic acid (preferably 1 to 3, more preferably 1 or 2)
• the method according to [I-32], more preferably 1 acid is one or more selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and p-toluenesulfonic acid (preferably 1 to 3, more preferably 1 or 2)
• the method according to [I-32] more preferably 1 acid.
• the acid of the acid-base catalyst is 1 to 3, preferably 1 or 2, more preferably 1 selected from the group consisting of trifluoroacetic acid, maleic acid and maleic anhydride.
• the amount of acid used in the acid-base catalyst is 0.005 to 0.10 mol per mol of the compound of formula (1), from [I-32] to [I-40] The method according to any one of the above.
• the base of the acid-base catalyst is one or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) secondary amines, [I-32] To [I-41].
• the base of the acid-base catalyst is one or more selected from the group consisting of N-methylaniline, morpholine and pyrrolidine (preferably 1 to 3, more preferably 1 or 2, more preferably 1). ), The method according to any one of [I-32] to [I-41].
• the amount of the base of the acid-base catalyst used is 0.005 to 0.10 mol with respect to 1 mol of the compound of formula (1), from [I-32] to [I-44] The method according to any one of the above.
• the neutralizing agent is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or ammonia, according to [I-53] or [I-54] Method.
• reaction is carried out in the presence of one or more (preferably 1 or 2, more preferably 1) solvent selected from acetonitrile, toluene, xylene, chlorobenzene, dichlorobenzene and dichloromethane, and an aqueous solvent.
• solvent selected from acetonitrile, toluene, xylene, chlorobenzene, dichlorobenzene and dichloromethane, and an aqueous solvent.
• reaction is carried out in the presence of one or more (preferably 1 or 2, more preferably 1) solvent selected from toluene, xylene, chlorobenzene, dichlorobenzene and dichloromethane, and an aqueous solvent.
• solvent selected from toluene, xylene, chlorobenzene, dichlorobenzene and dichloromethane, and an aqueous solvent.
• R 1 and R 2 are each independently (C1-C6) alkyl; (C1-C6) haloalkyl; (C3-C6) cycloalkyl; (C2-C6) alkenyl; (C2-C6) ) Alkynyl; (C1-C6) alkoxy; or phenyl optionally substituted by 1 to 5 substituents independently selected from halogen atoms, (C1-C4) alkyl and (C1-C4) haloalkyl Or R 1 and R 2 together with the carbon atom to which they are attached form a 4-6 membered carbocycle, any of [I-1] to [I-64] 2.
• R 1 and R 2 are each independently (C1-C4) alkyl; (C1-C4) haloalkyl; (C3-C6) cycloalkyl; (C2-C4) alkenyl; (C2-C4 ) Alkynyl; (C1-C4) alkoxy; or phenyl optionally substituted by 1 to 5 substituents independently selected from halogen atoms, (C1-C4) alkyl and (C1-C4) haloalkyl Yes; or R 1 and R 2 together with the carbon atom to which they are attached form a 4-6 membered carbocycle, any one of [I-1] to [I-64] The method according to item.
• R 1 and R 2 are each independently (C1-C4) alkyl or (C1-C4) haloalkyl. The method described.
• the present invention is as follows.
• R 1 and R 2 are each independently an optionally substituted (C1-C6) alkyl; an optionally substituted (C3-C6) cycloalkyl; Optionally (C2-C6) alkenyl; optionally substituted (C2-C6) alkynyl; optionally substituted (C1-C6) alkoxy; or optionally substituted phenyl; or R 1 and R 2 , together with the carbon atom to which they are attached, forms a 4 to 12 membered carbocyclic ring, where the ring formed here may be substituted.
• 1 and R 2 are as defined above).
• [II-6] One or more (preferably 1 to 3, more preferably 1 or 2 and even more preferably 1) acids selected from the group consisting of mineral acids, carboxylic acids and sulfonic acids. The method according to [II-5].
• the acid catalyst is one or more selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and p-toluenesulfonic acid (preferably 1 to 3, more preferably 1 or 2, more preferably Is a single acid) according to [II-5].
• the acid of the acid-base catalyst is at least one selected from the group consisting of mineral acids, carboxylic acids and sulfonic acids (preferably 1 to 3, more preferably 1 or 2, more preferably 1). ), The method according to [II-9].
• the acid of the acid-base catalyst is one or more selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and p-toluenesulfonic acid (preferably 1 to 3, more preferably 1 or 2)
• the base of the acid-base catalyst is one or more selected from the group consisting of N-methylaniline, morpholine and pyrrolidine (preferably 1 to 3, more preferably 1 or 2, more preferably 1). ), The method according to any one of [II-9] to [II-12].
• the hydroxylamine is hydroxylamine hydrochloride or hydroxylamine sulfate, and the reaction is further performed in the presence of a neutralizing agent, according to any one of [II-1] to [II-14] the method of.
• the neutralizing agent is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or ammonia, according to [II-17] or [II-18] Method.
• reaction is carried out in the presence of one or more (preferably 1 or 2, more preferably 1) solvent selected from acetonitrile, toluene, xylene, chlorobenzene, dichlorobenzene and dichloromethane, and an aqueous solvent.
• solvent selected from acetonitrile, toluene, xylene, chlorobenzene, dichlorobenzene and dichloromethane, and an aqueous solvent.
• the present invention provides a novel method for producing a compound of formula (3). According to this invention, the manufacturing method of the compound of Formula (3) more preferable industrially is provided. Moreover, according to this invention, the compound of Formula (3) can be manufactured by simple operation and efficiently.
• Non-Patent Document 2 Special Table 2013-512202 (Patent Document 2) and Synlett 2008, No. 6, 827-830 (Non-Patent Document 1) and Chem. Eur. J. 2010, Vol. 16, 11325-11339 (Non-Patent Document 2)
• a ketone oxime that produces a ketone such as acetone or diethyl ketone as a by-product is used as a raw material.
• ketone oximes are unnecessary. Therefore, the method of the present invention does not produce ketones as by-products and / or waste.
• the raw material having the minimum structure necessary for introducing the oximino moiety (—O—N ⁇ ) of the target compound was hydroxylamine (HO—NH 2 ).
• the present inventor succeeded in producing the target compound without using ketone oxime.
• the method for producing the compound of formula (3) using the hydroxylamine of the present invention suppresses the generation of by-products and / or waste and improves the atomic efficiency. Therefore, the production method of the present invention is industrially preferable, economical, and environmentally friendly.
• the compound of formula (3) is produced in the presence of water.
• a highly safe 50% aqueous hydroxylamine solution can be used instead of highly explosive and dangerous anhydrous hydroxylamine.
• the compound of formula (3) is produced under non-aqueous conditions.
• the reaction intermediate of the process, oxime is expected to hydrolyze back to aldehyde and hydroxylamine in the presence of water.
• the acid as a catalyst is diluted and inactivated, so the reaction is expected to hardly proceed.
• the target compound can be produced efficiently by a simple operation. Furthermore, by the present invention, the production of by-products and / or waste can be suppressed, and the atomic efficiency can be improved. As a result, the present invention provides a method by which an intermediate for producing herbicides such as pyroxasulfone can be produced easily and inexpensively on an industrial scale. Therefore, the method of the present invention is industrially favorable, economical, environmentally friendly and has high industrial utility value.
• halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom.
• (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.
• specific terms such as “butyl” are used, this is specific for “normal butyl”, ie “n-butyl”.
• the specific term “butyl” means linear “normal butyl”.
• branched isomers such as “tert-butyl” are specifically mentioned when intended.
• Me means methyl.
• Et means ethyl.
• Pr 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.
• T-Bu and “Bu-t” mean tert-butyl.
• Pen pentyl (ie, normal pentyl).
• Hex n-Hex and Hex-n
• 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.
• Ms means methylsulfonyl (CH 3 SO 2 —).
• Ts means tosyl (4-CH 3 —C 6 H 4 SO 2 —).
• Tf means trifluoromethylsulfonyl (CF 3 SO 2 —).
• Ac means acetyl (CH 3 CO—).
• (C1-C6) alkyl means straight-chain 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 straight or branched alkyl having 1 to 4 carbon atoms.
• Examples of (C1-C4) alkyl are suitable examples of the above (C1-C6) alkyl examples.
• (C1-C6) haloalkyl means a linear or branched alkyl having 1 to 6 carbon atoms, which is substituted with 1 to 13 halogen atoms which are the same or different (where halogen atoms are Has the same meaning as defined above).
• Examples of (C1-C6) haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoro Propyl, 3-chloropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,2-trifluoro-1-trifluoromethylethyl, heptafluoropropyl, 1,2,2,2-tetra Fluoro-1-trifluoromethylethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2,2,3,3,4,4,4-heptafluorobutyl, 5-fluoropentyl, 6-fluorohexyl However, it is not limited to these.
• (C1-C4) haloalkyl means a linear or branched alkyl having 1 to 4 carbon atoms, which is substituted with 1 to 9 halogen atoms which are the same or different (wherein the halogen atom is the above) Has the same meaning as the definition of Examples of (C1-C4) haloalkyl include, but are not limited to, suitable examples of the above (C1-C6) haloalkyl examples.
• (C3-C6) cycloalkyl means cycloalkyl having 3 to 6 carbon atoms.
• Examples of (C3-C6) cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
• (C2-C6) alkenyl means straight or branched alkenyl having 2 to 6 carbon atoms.
• Examples of (C2-C6) alkenyl are vinyl, 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-butenyl, 1,3 -Including but not limited to butadienyl, 1-pentenyl, 1-hexenyl and the like.
• (C2-C4) alkenyl means straight or branched alkenyl having 2 to 4 carbon atoms.
• Examples of C2-C6 alkenyl include, but are not limited to, suitable examples of the above (C2-C6) alkenyl examples.
• (C2-C6) alkynyl means a straight-chain or branched alkynyl having 2 to 6 carbon atoms.
• Examples of (C2-C6) alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 1-pentynyl, 1-hexynyl and the like It is not limited.
• (C2-C4) alkynyl means straight or branched alkynyl having 2 to 4 carbon atoms.
• Examples of (C2-C4) alkynyl include, but are not limited to, suitable examples of the above (C2-C6) alkynyl examples.
• (C1-C6) alkoxy means (C1-C6) alkyl-O- (wherein the (C1-C6) alkyl moiety has the same meaning as defined above).
• Examples of (C1-C6) alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc. It is not limited to.
• (C1-4) alkoxy means (C1-C4) alkyl-O— (where the (C1-C4) alkyl moiety has the same meaning as defined above).
• Examples of (C1-C4) alkoxy include, but are not limited to, suitable examples of the above (C1-C6) alkoxy examples.
• the cyclic hydrocarbon group means an aromatic or non-aromatic monocyclic or polycyclic cyclic group in which all atoms constituting the ring are carbon atoms.
• examples of cyclic hydrocarbon groups include aromatic or non-aromatic monocyclic, bicyclic or tricyclic 3-14 membered (preferably 5-14 membered, more preferably 5-10 membered) cyclic hydrocarbon groups, but not limited thereto.
• examples of cyclic hydrocarbon groups include aromatic or non-aromatic monocyclic or bicyclic (preferably monocyclic) 4 to 8 members (preferably 5 to 6 members). These cyclic hydrocarbon groups include, but are not limited to:
• 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 (eg monocyclic or spirocyclic) and fused cyclic cyclic groups where possible. .
• the 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 carbocycle is a ring corresponding to a cyclic hydrocarbon group as defined or exemplified above.
• examples of the “substituent” relating to the term “optionally substituted” include one or more substituents (preferably 1 to 4) independently selected from the substituent group (a). But not limited to these.
• Substituent group (a) includes halogen atom; nitro group; cyano group; hydroxy group; amino group; (C1-C6) alkyl; (C1-C6) haloalkyl; (C3-C6) cycloalkyl; (C2-C6). (C2-C6) alkynyl; (C1-C6) alkoxy; phenyl; phenoxy and the like.
• one or more substituents independently selected from the substituent group (a) are independently selected from the substituent group (b). And 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 an isomer includes all isomers and an arbitrary mixture thereof in an arbitrary ratio.
• 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.
• the method according to the present invention includes the following scheme (wherein R 1 and R 2 are as described in [1] above).
• the process according to the invention comprises reacting a compound of formula (1) ( ⁇ -disubstituted- ⁇ , ⁇ -unsaturated aldehyde) with hydroxylamine (NH 2 OH) in the presence of a catalyst, ) Compound (5,5-disubstituted-4,5-dihydroisoxazole).
• the method according to the present invention uses a compound of formula (1).
• the compound of the formula (1) is a known compound, or can be produced from a known compound according to a known method.
• compounds of formula (1) include, but are not limited to: 3-methyl-2-butene-1-al (3- Methyl-2-buten-1-al is also referred to as 3-methyl-2-butenal, 3-methylbut-2-enal or prenal), 3-methyl-2-pentene -1-R, 3-ethyl-2-penten-1-al, 3,4-dimethyl-2-penten-1-al, 3,4,4-trimethyl-2-penten-1-al, 4-chloro -3-Methyl-2-buten-1-al, 4,4,4-trifluoro-3-methyl-2-buten-1-al, 3-cyclopropyl-2-buten-1-al, 2-cyclo Butylideneacetaldehyde, 2-cyclopentylideneacetaldehyde, 2-cyclohexylideneacetaldehyde, 3-methyl-2-hepten-1-al, 3,7-dimethyl-2,6-octadien-1-
• the product of the present invention is 5,5-disubstituted-4,5-dihydroisoxazole corresponding to the compound of formula (1) used as a raw material.
• Specific examples of compounds of formula (3) include, but are not limited to: 5,5-dimethyl-4,5-dihydroisoxazole, 5-ethyl-5-methyl-4,5-dihydro Isoxazole, 5,5-diethyl-4,5-dihydroisoxazole, 5-isopropyl-5-methyl-4,5-dihydroisoxazole, 5- (tert-butyl) -5-methyl-4,5-dihydro Isoxazole, 5- (chloromethyl) -5-methyl-4,5-dihydroisoxazole, 5-methyl-5- (trifluoromethyl) -4,5-dihydroisoxazole, 5-cyclopropyl-5-methyl -4,5-dihydroisoxazole, 5-oxa-6
• hydroxylamine used in the present invention is not particularly limited as long as the reaction proceeds and safety is ensured.
• examples of hydroxylamine include, but are not limited to, hydroxylamine (free) and its salts.
• examples of hydroxylamine (free) include, but are not limited to, 50% aqueous hydroxylamine, 60% aqueous hydroxylamine, 70% aqueous hydroxylamine, 80% aqueous hydroxylamine, 90% aqueous hydroxylamine, and the like.
• “50% hydroxylamine aqueous solution” is also referred to as “Hydroxylamine (50% solution in water)”.
• hydroxylamine salts include hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate (eg, 50% aqueous solution), hydroxylamine carbonate, hydroxylamine phosphate, hydroxylamine acetate, hydroxylamine oxalate, and the like. It is not limited.
• the hydroxylamine used in the present invention may be used alone or in combination of two or more in any ratio.
• the form of hydroxylamine used in the present invention 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 the form include solids and liquids, aqueous solutions of any concentration, solutions of solvents other than water (for example, organic solvents), and the like.
• the form of hydroxylamine may be any form as long as the reaction proceeds and safety is ensured.
• preferred examples of the hydroxylamine (free) form include an aqueous solution having a concentration of 10% to less than 70%, preferably an aqueous solution having a concentration of 45% to 55%.
• hydroxylamine include free hydroxylamine aqueous solution and hydroxylamine salt, more preferably free hydroxylamine aqueous solution, hydroxylamine hydrochloride, hydroxyl group sulfate.
• An amine more preferably 45% to 55% aqueous hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, more preferably 45% to 50% aqueous hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate.
• the amount of hydroxylamine used in the present invention is as follows.
• the hydroxylamine (NH 2 OH) is 0.9 to 2.0 mol, preferably 0.9 to 1.5 mol, more preferably 0, relative to 1 mol of the compound of the formula (1).
• a range of 0.9 to 1.1 mol, and more preferably 0.9 to 1.1 mol can be exemplified.
• a range of 0.0 to 1.2 mol, more preferably 1.0 to 1.1 mol can also be exemplified.
• the hydroxylamine (NH 2 OH) is 0.90 mol or more and less than 1.00 mol, preferably 0.90 mol or more and 0.99 mol or less, relative to 1 mol of the compound of the formula (1). More preferably, a range of 0.90 mol to 0.98 mol, more preferably 0.93 mol to 0.97 mol, can also be exemplified.
• the reaction of the present invention is preferably carried out using a neutralizing agent.
• the neutralizing agent is a base for neutralizing the hydroxylamine salt to release free hydroxylamine.
• neutralizing agents include alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (for example, magnesium hydroxide, calcium hydroxide, water) Barium oxide etc.), alkali metal carbonates (eg lithium carbonate, sodium carbonate, potassium carbonate etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate, barium carbonate etc.), alkali metal bicarbonates (eg Lithium carbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carboxylates (eg, lithium acetate, sodium acetate, potassium acetate, etc.), amines (eg, triethylamine, tributylamine, diisopropylethylamine, 1,8 -Diazabicyclo [5.4.0] -7-unde -7-ene (DBU), pyridine, etc.), ammonia (e.g., 25-30% ammonia water,
• the neutralizing agent include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like, ammonia, more preferably sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, ammonia, More preferably, it contains sodium hydroxide.
• sodium hydroxide include sodium hydroxide beads, 48% aqueous sodium hydroxide, 25% aqueous sodium hydroxide, 10% aqueous sodium hydroxide, preferably 48% aqueous sodium hydroxide, 25% aqueous sodium hydroxide, and more.
• it includes 48% aqueous sodium hydroxide solution, but is not limited thereto.
• the form of the neutralizing agent may be any form as long as the reaction proceeds. Examples of forms include solids with only neutralizers, liquids and gases, aqueous solutions of any concentration, solutions of 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 neutralizing agent used may be any amount as long as the reaction proceeds.
• examples of the amount of the neutralizing agent include an amount that can neutralize the hydroxylamine salt to liberate free hydroxylamine. From the viewpoint of yield, by-product suppression, economic efficiency, etc., 0.9 to 1.1 equivalents, preferably 0.9 to 1.0 equivalents can be exemplified with respect to 1 equivalent of hydroxylamine salt. However, the amount used can be appropriately adjusted by those skilled in the art.
• the reaction of the present invention is preferably carried out in the presence of a solvent.
• the solvent may be any solvent as long as the reaction of the present invention proceeds and safety is ensured.
• the solvent include water, alcohols (eg, methanol, ethanol, 2-propanol, butanol, tert-butanol (tert-butanol is also referred to as tert-butyl alcohol)), ethers (eg, 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), diglyme, triglyme ), Nitriles (eg acetonitrile), amides (eg N, N-dimethyl)
• preferred examples of the solvent include water, alcohols, nitriles, ethers, aromatic hydrocarbon derivatives, halogenated aliphatic carbonization. Hydrogens and any combination thereof in any proportion, more preferably water, nitriles, aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons and any combination thereof in any proportion, more preferably water , Aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons and any combination thereof in any proportion, particularly preferably any combination of water and halogenated aliphatic hydrocarbons in any proportion.
• solvents are water, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, tetrahydrofuran (THF), toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion.
• More preferably water, acetonitrile, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion more preferably water, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any proportion thereof Including any combination of water and dichloromethane.
• the presence of water is preferable. In either case, as long as the reaction proceeds, the solvent may be separated into a single layer or two layers.
• preferable examples of the solvent include water, alcohols, nitriles, ethers, aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, and an arbitrary ratio thereof. Any combination, more preferably water, alcohols, nitriles, halogenated aliphatic hydrocarbons and any combination thereof in any proportion, more preferably water, nitriles, halogenated aliphatic hydrocarbons and any Any combination thereof, particularly preferably any combination of water and halogenated aliphatic hydrocarbons.
• solvents are water, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, tetrahydrofuran (THF), toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane and any combination thereof in any proportion. More preferably water, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, dichloromethane and any combination thereof in an arbitrary ratio, more preferably water, acetonitrile, dichloromethane and any combination thereof in an arbitrary ratio Particularly preferably, it contains any combination of water and dichloromethane in any proportion. However, in any case, the presence of water is preferable. In either case, as long as the reaction proceeds, the solvent may be separated into a single layer or two layers.
• Water derived from an aqueous hydroxylamine solution can be understood as a solvent.
• a neutralizing agent eg, hydroxylamine hydrochloride, hydroxylamine sulfate, etc.
• water derived from an aqueous solution of the neutralizing agent eg, 48% aqueous sodium hydroxide
• Water produced by neutralization can also be understood as a solvent.
• the amount of the solvent used 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., more than 0 (zero) and not more than 10 L (liter), preferably 0.001 to 5 L, 0.001 with respect to 1 mol of the compound of formula (1) To 0.5 L, 0.001 to 0.2 L, preferably 0.01 to 5 L, 0.01 to 0.5 L, 0.01 to 0.2 L, more preferably 0.02 to 0.5 L, more preferably Can exemplify a range of 0.02 to 0.2 L. When a combination of two or more solvents is used, the ratio of the two or more solvents may be any ratio as long as the reaction proceeds.
• the reaction of the present invention is preferably performed in the presence of water.
• the amount of water is as follows.
• the amount of water is, for example, 50 mol% or more, preferably 100 mol% or more, more preferably 150 mol% or more, and still more preferably 180 mol% or more with respect to 1 mol of the compound of formula (1).
• 50 mol% to 6000 mol% preferably 50 mol% to 3000 mol%, more preferably 50 mol% to 1500 mol%, more preferably 50 mol% to 1000 mol%, still more preferably 50 mol% to 800 mol%, still more preferably 50 mol%.
• 150 mol% to 6000 mol% preferably 150 mol% to 3000 mol%, more preferably 150 mol% to 1500 mol%, more preferably 150 mol% to 1000 mol%, still more preferably 150 mol% to 800 mol%, still more preferably. It is 150 mol% to 500 mol%, more preferably 150 mol% to 400 mol%, more preferably 150 mol% to 350 mol%.
• reaction temperature is not particularly limited. From the viewpoints of yield, by-product suppression, economic efficiency, etc., -30 ° C (minus 30 ° C) to 160 ° C, preferably 0 ° C to 80 ° C, more preferably 20 ° C to 80 ° C, still more preferably 20 ° C to A range of 60 ° C., more preferably 30 ° C. to 50 ° C. can be exemplified.
• the reaction proceeds satisfactorily in an industrially preferable temperature range (for example, 40 to 60 ° C.) as understood from the Examples.
• an industrially preferable temperature range for example, 40 to 60 ° C.
• the reaction proceeds satisfactorily even at a relatively low temperature (for example, 20 to 40 ° C.).
• the reaction temperature of the present invention is not limited to these temperature ranges.
• reaction time is not particularly limited. From the viewpoint of yield, by-product suppression, economic efficiency, etc., the range is 0.5 hours to 96 hours, preferably 1 hour to 50 hours, more preferably 6 hours to 50 hours, still more preferably 6 hours to 24 hours. Can be illustrated.
• the reaction of the present invention is performed in the presence of a catalyst.
• the catalyst used in the present invention is preferably an acid catalyst or an acid-base catalyst.
• the compound of formula (3) is prepared in the presence of an acid catalyst.
• the acid catalyst may be any acid catalyst as long as the reaction proceeds. In addition, as long as the reaction proceeds, any of the following forms may be used and are included in the scope of the present invention.
• a free acid can be used as the acid catalyst.
• the acid catalyst may be used in the form of a partial salt. When the acid catalyst is a partial salt, the acid catalyst may be a single salt or a double salt.
• the acid catalyst may be used in the form of an anhydride.
• the acid catalyst may be used in the form of a hydrate.
• the acid catalyst may be used in the form of a dimer, trimer or higher order multimer.
• acid catalysts include, but are not limited to:
• Mineral acids can be used as the acid catalyst.
• Specific examples of mineral acids include, but are not limited to, hydrochloric acid, sulfuric acid, and nitric acid.
• Carboxylic acids can be used as the acid catalyst. As long as the reaction proceeds, the carboxylic acid may be used as the free acid or as its anhydride.
• examples of carboxylic acids include saturated or unsaturated aliphatic (C1-C8) monocarboxylic acids, dicarboxylic acids and tricarboxylic acids, and halogen atoms, optionally substituted by one or more halogen atoms,
• C1 Includes aromatic (C7-C11) monocarboxylic acids, dicarboxylic acids and tricarboxylic acids optionally substituted by one or more substituents independently selected from -C4) alkyl and (C1-C4) haloalkyl.
• polycarboxylic acids such as dicarboxylic acids and tricarboxylic acids may be partially salted with a plurality of carboxy groups.
• Examples of preferred carboxylic acids include saturated or unsaturated aliphatic (C1-C8) carboxylic acids that may be substituted with one or more halogen atoms.
• Examples of carboxylic anhydrides are those anhydrides.
• examples of carboxylic acids include saturated or unsaturated aliphatic (C1-C8) carboxylic acids that may be substituted with one or more halogen atoms, and halogen atoms, (C1-C4) alkyl and (C1 -C4) including benzoic acid optionally substituted by one or more substituents independently selected from haloalkyl.
• Examples of preferred carboxylic acids include saturated or unsaturated aliphatic (C1-C8) carboxylic acids that may be substituted with one or more halogen atoms.
• Examples of carboxylic anhydrides are those anhydrides.
• carboxylic acid examples include acetic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid, citric acid, benzoic acid and phthalic acid.
• carboxylic acid anhydride examples include trifluoroacetic anhydride, maleic anhydride, and phthalic anhydride.
• the maleic acid may be maleic anhydride.
• sulfonic acid can be used as the acid catalyst. So long as the reaction proceeds, the sulfonic acid may be used as the free acid or as its anhydride.
• sulfonic acids include methane sulfonic acid, trifluoromethane sulfonic acid (TfOH), benzene sulfonic acid, p-toluene sulfonic acid (TsOH) and 10-camphor sulfonic acid (CSA).
• p-toluenesulfonic acid (TsOH) includes “p-toluenesulfonic acid monohydrate (TsOH ⁇ H 2 O)”.
• Specific examples of sulfonic acid anhydrides include methanesulfonic anhydride and trifluoromethanesulfonic anhydride.
• Phosphoric acids and derivatives thereof can be used as the acid catalyst.
• phosphoric acids and derivatives thereof are not particularly limited. Examples of phosphoric acids and derivatives thereof include, but are not limited to:
• phosphoric acid may be used as a free acid, or one or more OH groups in the molecule may partially form a salt.
• phosphoric acid may be an anhydride thereof.
• Specific examples of phosphoric acids include phosphoric acid (orthophosphoric acid; H 3 PO 4 ), ammonium dihydrogen phosphate, polyphosphoric acid, pyrophosphoric acid (diphosphoric acid) and diphosphorus pentoxide.
• Phosphoric acid monoesters As long as the reaction proceeds, the phosphoric acid monoester may be used as a free acid, or one or more OH groups in the molecule partially form a salt. It may be. Phosphoric acid monoester may be used as its anhydride as long as it is chemically acceptable. Specific examples of phosphate monoesters include ethyl phosphate (ie, ethyl dihydrogen phosphate; (C 2 H 5 O) P ( ⁇ O) (OH) 2 ) and phenyl phosphate (ie, phosphoric acid). Dihydrogen phenyl; (C 6 H 5 O) P ( ⁇ O) (OH) 2 ).
• Phosphoric acid diesters As long as the reaction proceeds, the phosphoric acid diester may be used as the free acid or as its anhydride as long as it is chemically acceptable. Good. Specific examples of phosphate diesters include diethyl phosphate (ie, diethyl hydrogen phosphate; (C 2 H 5 O) 2 P ( ⁇ O) OH) and diphenyl phosphate (ie, diphenyl hydrogen phosphate; ( C 6 H 5 O) 2 P ( ⁇ O) OH).
• diethyl phosphate ie, diethyl hydrogen phosphate; (C 2 H 5 O) 2 P ( ⁇ O) OH
• diphenyl phosphate ie, diphenyl hydrogen phosphate; ( C 6 H 5 O) 2 P ( ⁇ O) OH.
• Solid acids can be used as the acid catalyst.
• solid acids include, but are not limited to, cation exchange resins, heteropoly acids, zeolites, montmorillonite, alumina and the like.
• the term “cation exchange resin” is not particularly limited, and means a known cation exchange resin having strong or weak acidity.
• Specific examples of the cation exchange resin include Diaion (registered trademark) series (for example, Diaion SK1B, SK110, SK116, P206, WK40, etc.) manufactured by Mitsubishi Chemical Corporation, and Amberlite (registered by Rohm and Haas). Trademark) series (for example, Amberlite IR-120B, IR-200CT, IRC50, IR-124, etc.), Dowex (registered trademark) series (for example, 50W-X8, etc.) manufactured by The Dow Chemical Company, etc. Including, but not limited to.
• heteropolyacids include 12-molybdo (VI) phosphoric acid n-hydrate (H 3 [PMo 12 O 40 ] .nH 2 O (n ⁇ 30)). 12 tungsto (VI) phosphoric acid n-hydrate (H 3 [PW 12 O 40 ] ⁇ nH 2 O (n ⁇ 30)), 12 tungsto (VI) Examples include, but are not limited to, acid n hydrate (12-tungsto (VI) silicic acid n-hydrate; H 4 [SiW 12 O 40 ] ⁇ nH 2 O (eg, n ⁇ 26)). 12 molybdo (VI) phosphate n-hydrate is also referred to as phosphomolybdic acid n-hydrate.
• 12 tungsto (VI) phosphate n-hydrate is also referred to as phosphotungstic acid n-hydrate.
• 12 tungsto (VI) silicic acid n-hydrate is also referred to as silicotungstic acid n-hydrate.
• a salt of a heteropolyacid can also be used. Specific examples of the salt of the heteropolyacid include sodium 12-molybdo (VI) phosphate n-hydrate; Na 3 [PMo 12 O 40 ] ⁇ nH 2 O (n ⁇ 30)) etc., but is not limited to this.
• 12 molybdo (VI) sodium phosphate n-hydrate is also referred to as sodium phsophomolybdate n-hydrate.
• zeolite examples include, but are not limited to, ZSM-5 type, mordenite type, L type, Y type, X type and beta type, etc.
• preferred examples of the acid catalyst are as follows, but are not limited thereto.
• One or more acids preferably 1 to 3, more preferably 1 or 2, more preferably 1) selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids and phosphoric acids are preferred.
• preferred specific examples of the acid catalyst are as follows, but are not limited thereto.
• Hydrochloric acid sulfuric acid, nitric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid, maleic anhydride, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, phosphoric acid 1 or more (preferably 1 to 3, more preferably 1 or 2 and even more preferably 1) acids selected from the group consisting of ethyl phosphate, phenyl phosphate, diethyl phosphate and diphenyl phosphate preferable.
• Nitric acid trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid, maleic anhydride, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and diphenyl phosphate
• One or more (preferably 1 to 3, more preferably 1 or 2, and still more preferably 1) acids are more preferable.
• One or more selected from the group consisting of nitric acid, trifluoroacetic acid, trichloroacetic acid, maleic acid, maleic anhydride, benzenesulfonic acid and p-toluenesulfonic acid (preferably 1 to 3, more preferably 1 or 2; More preferred is 1) acid.
• One or more selected from the group consisting of nitric acid, trifluoroacetic acid, trichloroacetic acid, maleic acid, maleic anhydride, and p-toluenesulfonic acid preferably 1 to 3, more preferably 1 or 2, more preferably 1 Are more preferred.
• 1 or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid, maleic anhydride and p-toluenesulfonic acid Acid is more preferred.
• One or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) acids selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and p-toluenesulfonic acid are more preferred.
• One or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) acids selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and maleic anhydride are also more preferred.
• One to three (preferably one or two, more preferably one) acids selected from the group consisting of trifluoroacetic acid, maleic acid and maleic anhydride are more preferred. More preferred are 1 or 2 (preferably 1) acids selected from the group consisting of trifluoroacetic acid and maleic acid. More preferred is trifluoroacetic acid.
• the acid catalyst may be used alone or in combination of two or more in any ratio.
• the form of the acid catalyst may be any form as long as the reaction proceeds. Examples of the form include a solid containing only an acid catalyst, a liquid or a gas, an aqueous solution of any concentration, or a solution of a solvent other than water (for example, an organic solvent).
• the form can be appropriately selected by those skilled in the art.
• the amount of the acid catalyst used may be any amount as long as the reaction proceeds. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., 0.01 to 1.0 mol, preferably 0.01 to 0.30 mol, more preferably, relative to 1 mol of the compound of formula (1). Examples thereof include 0.02 to 0.30 mol, 0.02 to 0.20 mol, and 0.02 to 0.10 mol.
• the amount of hydroxylamine used is 0.5-2 mol, preferably 0.9-1.5 mol, more preferably 0, relative to 1 mol of the compound of formula (1).
• examples include 9.9 to 1.2 mol, 1.0 to 1.2 mol, more preferably 0.9 to 1.1 mol, and 1.0 to 1.1 mol.
• the compound of formula (3) is prepared in the presence of an acid-base catalyst.
• An acid-base catalyst is a mixture of an acid and a base.
• the acid-base catalyst may be any acid-base catalyst as long as the reaction proceeds. In addition, any form may be used as long as the reaction proceeds, and it is included in the scope of the present invention.
• the acid-base catalyst is a salt
• the acid-base catalyst may be a single salt or a double salt.
• the acid-base catalyst may be used in the form of an anhydride.
• the acid-base catalyst may be used in the form of a hydrate.
• the acid and / or base of the acid-base catalyst may be used in the form of a dimer or the like.
• the acid-base catalyst may be used alone or in combination of two or more in any ratio.
• the form of the acid-base catalyst may be any form as long as the reaction proceeds. Examples of the form include a solid or liquid containing only an acid-base catalyst, an aqueous solution of any concentration, or a solution of a solvent other than water (for example, an organic solvent).
• the form can be appropriately selected by those skilled in the art.
• the acids exemplified as the acid catalyst can be used.
• preferred examples of the acid of the acid-base catalyst are as follows, but are not limited thereto.
• One or more acids preferably 1 to 3, more preferably 1 or 2, more preferably 1) selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids and phosphoric acids are preferred.
• One or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) acids selected from the group consisting of mineral acids, carboxylic acids and sulfonic acids are preferred.
• One or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) acids selected from the group consisting of mineral acids and carboxylic acids are more preferred.
• preferred specific examples of the acid-base catalyst acid are as follows, but are not limited thereto.
• Hydrochloric acid sulfuric acid, nitric acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid, maleic anhydride, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, phosphoric acid 1 or more (preferably 1 to 3, more preferably 1 or 2 and even more preferably 1) acids selected from the group consisting of ethyl phosphate, phenyl phosphate, diethyl phosphate and diphenyl phosphate preferable.
• Nitric acid trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, maleic acid, maleic anhydride, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and diphenyl phosphate
• One or more (preferably 1 to 3, more preferably 1 or 2, and still more preferably 1) acids are more preferable.
• One or more selected from the group consisting of nitric acid, trifluoroacetic acid, trichloroacetic acid, maleic acid, maleic anhydride, benzenesulfonic acid and p-toluenesulfonic acid (preferably 1 to 3, more preferably 1 or 2; More preferred is 1) acid.
• One or more selected from the group consisting of nitric acid, trifluoroacetic acid, trichloroacetic acid, maleic acid, maleic anhydride, and p-toluenesulfonic acid preferably 1 to 3, more preferably 1 or 2, more preferably 1 Are more preferred.
• 1 or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid, maleic anhydride and p-toluenesulfonic acid Acid is more preferred.
• One or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) acids selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and p-toluenesulfonic acid are more preferred.
• One or more (preferably 1 to 3, more preferably 1 or 2, more preferably 1) acids selected from the group consisting of nitric acid, trifluoroacetic acid, maleic acid and maleic anhydride are also more preferred.
• One to three acids selected from the group consisting of nitric acid, trifluoroacetic acid and maleic acid are more preferred. Also preferred are 1 to 3 (preferably 1 or 2, more preferably 1) acids selected from the group consisting of trifluoroacetic acid, maleic acid and maleic anhydride. More preferred are 1 or 2 (preferably 1) acids selected from the group consisting of trifluoroacetic acid and maleic acid. More preferred is trifluoroacetic acid.
• amines are preferable.
• R 3 , R 4 and R 5 are each independently hydrogen, optionally substituted (C1-C6) alkyl; optionally substituted (C3-C6) cycloalkyl; Optionally substituted (C2-C6) alkenyl; optionally substituted (C2-C6) alkynyl; or optionally substituted aryl; or any two of R 3 , R 4 and R 5 are Together with the nitrogen atom to which is attached forms a 4- to 12-membered heterocycle, in which the ring formed may be substituted, wherein R 3 , R 4 and R 5 At least one is not hydrogen) 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, but are not limited to, diethylamine, dipropylamine, diisopropylamine, N-methylaniline (PhNHMe), N-ethylaniline, piperidine, 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 amine examples include pyridine, 4- (dimethylamino) -pyridine, 4-pyrrolidinopyridine, 2,6-lutidine, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0].
• pyridine 4- (dimethylamino) -pyridine
• 4-pyrrolidinopyridine 2,6-lutidine
• quinoline isoquinoline
• DBU -7-undec-7-ene
• DBN 1,5-diazabicyclo [4.3.0] non-5-ene
• Nona-5-ene also belongs to a tertiary amine.
• 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 a secondary amine.
• Preferred specific examples of acid-base catalyzed bases include N-methylaniline, morpholine and pyrrolidine, more preferably N-methylaniline.
• the amount of the acid-base catalyst used may be any amount as long as the reaction proceeds.
• the acid to base ratio of the acid-base catalyst may be 1: 1 or not 1: 1.
• the amount of acid used in the acid-base catalyst is from 0.001 to 1.00 mol, preferably from 0.001 mol to 1 mol of the compound of formula (1), from the viewpoints of yield, suppression of by-products, economic efficiency and the like. Examples include 005 to 0.30 mol, 0.005 to 0.10 mol, more preferably 0.01 to 0.10 mol, and 0.01 to 0.05 mol.
• the amount of base used in the acid-base catalyst is 0.001 to 1.00 mol, preferably 0.001 mol per 1 mol of the compound of formula (1) from the viewpoints of yield, by-product suppression, economic efficiency, and the like.
• Examples include 005 to 0.30 mol, 0.005 to 0.10 mol, more preferably 0.01 to 0.10 mol, and 0.01 to 0.05 mol.
• the amount of hydroxylamine used is 0.5-2 mol, 0.9-1.5 mol, 0.9-1 with respect to 1 mol of the compound of the formula (1).
• a range of 2 moles can be exemplified.
• the amount of hydroxylamine used is preferably less than the compound of formula (1). In one embodiment, the amount of hydroxylamine used is less than 1.00 mol, preferably 0.99 mol or less, more preferably 0.98 mol or less, per 1 mol of the compound of the formula (1).
• it is 0.90 mol or more and 1.00 mol or less, preferably 0.90 mol or more and less than 1.00 mol, more preferably 0.90 mol or more and 0 mol per 1 mol of the compound of formula (1).
• An example is a range of .99 mol or less, more preferably 0.90 mol to 0.98 mol.
• Examples 2 to 11 As shown in the table below, the amount of hydroxylamine (NH 2 OH), the type and amount of acid, and the stirring conditions (aging conditions) were changed as in Example 1, except that 5,5- Dimethyl-4,5-dihydroisoxazole was prepared.
• the components other than the solvent and the like in the reaction mixture include (1-a; raw material) and (3-a; target product), and (2-a; intermediate) ), (9-1-a; aldehyde derivative of dimer intermediate) and (9-2-a; oxime derivative of dimer intermediate) were detected.
• GC by analysis such as GC-MS and 1 H NMR, (1-a ; raw material), (3-a; target product), (2-a; Intermediate) (9- 1-a; aldehyde derivative of dimer intermediate) and (9-2-a; oxime derivative of dimer intermediate) were identified.
• Example 12 Production of 5,5-dimethyl-4,5-dihydroisoxazole (3-a) using an acid catalyst in a solvent containing an organic solvent.
• Prenal (478 ⁇ l, specific gravity: 0.879 20 ° C.), 421 mg, purity: 98% (GC area%), 4.9 mmol, 100 mol%) was added by a microsyringe.
• Dichloromethane (0.5 ml, 0.1 L / mol) and trifluoroacetic acid (38 ⁇ l, specific gravity: 1.49 (20 ° C.), 58 mg, 0.5 mmol, 10 mol%) were added thereto.
• Hydroxylamine aqueous solution (282 ⁇ l, specific gravity: 1.122 (20 ° C.), 316 mg, purity: 52% (titration with 1.0 M hydrochloric acid), 4.98 mmol, 102 mol%) was performed so as not to exceed 30 ° C. under ice cooling. In addition, the mixture was stirred at 50 ° C. for 20 hours (aging). The reaction mixture was analyzed by GC (area percentage).
• Examples 13-15 As shown in the following table, the same as Example 12 except that the type and amount of the solvent, the amount of hydroxylamine (NH 2 OH), the type and amount of the acid catalyst, and the stirring conditions (aging conditions) were changed. Thus, 5,5-dimethyl-4,5-dihydroisoxazole was produced.
• Example 16 Preparation of 5,5-dimethyl-4,5-dihydroisoxazole (3-a) using an acid-base catalyst
• Prenal (478 ⁇ l, specific gravity: 0.879 (20 ° C.), 421 mg, purity: 98% (GC area%), 4.9 mmol, 100 mol%) was added with a microsyringe.
• Trifluoroacetic acid (19 ⁇ l, specific gravity: 1.49 (20 ° C.), 29 mg, 0.25 mmol, 5 mol%) was added thereto.
• Examples 17-31 As shown in the table below, the procedure was the same as in Example 16 except that the amount of hydroxylamine (NH 2 OH), the type and amount of acid, the type and amount of base, and the stirring conditions (aging conditions) were changed. Thus, 5,5-dimethyl-4,5-dihydroisoxazole was produced.
• Comparative Example 1 As shown in the table below, the amount of hydroxylamine (NH 2 OH), the type and amount of base, and the stirring conditions (aging conditions) were changed and the same as in Example 16 except that no acid was added. An attempt was made to produce 5,5-dimethyl-4,5-dihydroisoxazole.
• Examples 1 to 6 are examples using an acid catalyst. When an acid catalyst was used, good yields were obtained with both prenal excess (Examples 2, 4, 6) and hydroxylamine excess (Examples 1, 3, 5). When an acid catalyst was used, an effect was obtained in which the yield was not affected by the amount ratio (molar ratio) of prenal and hydroxylamine.
• the results of Examples 7 to 11 show that various acids can be used as the acid catalyst of the present invention.
• Examples 12 to 15 are examples using an acid catalyst in a solvent containing an organic solvent. Good yields were obtained in the presence of various organic solvents.
• Examples 16 to 25 are examples using an acid-base catalyst. Good yields were also obtained in Example 17 using the same amount (equimolar) of prenal and hydroxylamine.
• Examples 16 and 18 to 23 which were reacted under the condition of excess plenal obtained further excellent yields.
• the results of Examples 26 to 31 show that various acids and bases can be used as the acid-base catalyst of the present invention.
• Comparative Example 1 is an example in which the reaction was attempted without an acid catalyst. The reaction hardly proceeded without the acid catalyst.
• Trifluoroacetic acid (3.8 ⁇ l, specific gravity: 1.49 (20 ° C.), 5.7 mg, 0.050 mmol, 1 mol%) and N-methylaniline (5.4 ⁇ l, specific gravity: 0.99 (20 ° C.), 5 .4 mg, 0.050 mmol, 1 mol%) was taken in the same gas tight syringe and mixed in the syringe. This mixture was added to the previous test tube in several portions so that the internal temperature did not exceed 20 ° C., and the mixture was stirred at 30 ° C. for 20 hours (aging).
• an aqueous hydroxylamine solution (7.55 g, purity: 52% (titrated with 1.0 M hydrochloric acid), 118.8 mmol, 102 mol%) was added thereto so as not to exceed 30 ° C., and the mixture was stirred at 45 ° C. for 20 hours. (Aging).
• the components other than the solvent in the reaction mixture were as follows; 5,5-dimethyl-4,5-dihydroisoxazole (3-a; target product) ): 96%.
• a saturated aqueous sodium hydrogen carbonate 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 (3-a, colorless oil, 9.3 g, 93.8 mmol, yield: 81%, Boiling point: 75-77 ° C./50 Torr) was obtained.
• 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 (3-a, colorless oil, 10.1 g, 101.9 mmol, yield: 87%, Boiling point: 75-77 ° C./50 Torr) was obtained.
• Examples 34 and 35 As in Examples 32 and 33 except that the type and amount of the solvent, the type of catalyst, and the stirring conditions (aging conditions) were changed as shown in the table below, 5,5-dimethyl-4, 5-Dihydroisoxazole was prepared. The results are shown in the table below.
• Example 37 Preparation of 5,5-dimethyl-4,5-dihydroisoxazole (3-a) Prenal (10.0 g, purity: 98% (GC area%), 116.5 mmol, 100 mol%) was added to a 50 ml eggplant flask. Thereafter, trifluoroacetic acid (178 ⁇ l, specific gravity: 1.49 (20 ° C.)), 266 mg, 2.33 mmol, 2 mol%) was added under ice cooling.
• Examples 36, 38 and 39 As shown in the table below, 5,5-dimethyl-4,5-dihydroisoxazole was prepared in the same manner as in Example 37 except that the type and amount of the catalyst and the stirring conditions (aging conditions) were changed. Manufactured.
• Example 40 Preparation of 5,5-dimethyl-4,5-dihydroisoxazole (3-a) using hydroxylamine hydrochloride and acid catalyst
• prenal (10.0 g, purity: 98% (GC area%), 116.5 mmol, 100 mol%) was dissolved in dichloromethane (11.7 ml, 0.1 L / mol), and then trifluoroacetic acid (0.89 ml, specific gravity: 1.49 (20 ° C.)), 1. 33 g, 11.7 mmol, 10 mol%) and hydroxylamine hydrochloride (8.26 g, 118.8 mmol, 102 mol%) were added.
• Example 41 Preparation of 5,5-dimethyl-4,5-dihydroisoxazole (3-a) using hydroxylamine hydrochloride and acid-base catalyst Plenal (10.0 g, purity: 98% (GC area%) in a 100 ml eggplant flask , 116.5 mmol, 100 mol%) in dichloromethane (11.7 ml, 0.1 L / mol), trifluoroacetic acid (178 ⁇ l, specific gravity: 1.49 (20 ° C.)), 266 mg, 2 .33 mmol, 2 mol%) and hydroxylamine hydrochloride (7.91 g, 113.9 mmol, 98 mol%) were added.
• Example 42 Preparation of 5,5-dimethyl-4,5-dihydroisoxazole (3-a) using hydroxylamine sulfate and acid catalyst
• prenal (10.0 g, purity: 98% (GC area%), 116.5 mmol, 100 mol%) was dissolved in dichloromethane (11.7 ml, 0.1 L / mol), and then hydroxylamine sulfate (9.75 g, 59.4 mmol, 51 mol%, 102 mol% as hydroxylamine (NH 2 OH)).
• hydroxylamine sulfate 9.75 g, 59.4 mmol, 51 mol%, 102 mol% as hydroxylamine (NH 2 OH)
• the 5,5-disubstituted-4,5-dihydroisoxazole of the formula (3) produced by the method of the present invention is useful as an intermediate for producing pharmaceuticals, agricultural chemicals and the like, especially the herbicide pyroxasulfone.
• generation of by-products and / or waste can be suppressed, and atomic efficiency can be improved.
• the target compound can be produced efficiently by a safe and simple operation. Therefore, the method of the present invention is safe, industrially favorable, economical, environmentally friendly and has high industrial utility value. In short, the present invention has high industrial applicability.

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