WO2014192841A1

WO2014192841A1 - Method for producing optically active isoxazoline compound

Info

Publication number: WO2014192841A1
Application number: PCT/JP2014/064204
Authority: WO
Inventors: 維奇王; 宮本　隆史; 崇三木; 池本　哲哉
Original assignee: 住友化学株式会社
Priority date: 2013-05-27
Filing date: 2014-05-22
Publication date: 2014-12-04
Also published as: JP2015007029A

Abstract

An optically active isoxazoline compound represented by formula (2) can be produced by reacting a compound represented by formula (1) with hydroxyamine in the presence of both at least one compound selected from compounds mentioned in Group 1 and enantiomeric compounds thereof and a carbonate salt. (In the formulae, Ar represents a phenyl group which may have a substituent or the like; Ar¹ and Ar² independently represent a phenyl group which may have a substituent; R¹ and R² are the same as or different from each other and independently represent a phenyl group which may have a substituent or the like; R³ and R⁴ are the same as or different from each other and independently represent a C1-C3 alkyl group which may have a phenyl group or the like; R⁵ and R⁶ are the same as or different from each other and independently represent a C1-C3 alkyl group which may have a phenyl group; and Ar³ represents a quinolyl group which may have a substituent.) AA Group 1

Description

Method for producing optically active isoxazoline compound

The present invention relates to a method for producing an optically active isoxazoline compound.

The compound represented by the formula (2) (wherein each symbol is as described below)

For example, as shown in WO2010 / 090344, it is known to be useful as an active ingredient of a pest control agent and an intermediate for the production thereof.
In WO2009 / 063910 and Angewante Chemie, International Edition (2010), 49 (33), 5762-5766, a compound represented by the formula (1) and a hydroxyamine are mixed between a chiral phase in a solvent in the presence of a base and water. It has been shown that an optically active compound represented by the formula (2) can be produced by adding a transfer catalyst and reacting it.

The present invention provides a novel method for producing an optically active compound represented by the formula (2).
According to the present invention, the compound represented by the formula (1) and hydroxyamine are reacted with any one selected from the compounds described in group 1 described later and enantiomers thereof and carbonate. By reacting, an optically active compound represented by the formula (2) can be produced.
[Group 1]

(In the formula, Ar has a phenyl group which may have a substituent, a naphthyl group which may have a substituent, an indanyl group which may have a substituent, or a substituent. Represents an indolizinyl group, Ar ¹ and Ar ² represent a phenyl group which may have a substituent, and R ¹ and R ² are the same or different and represent a phenyl group which may have a substituent. Or R ¹ and R ² together represent — (CH ₂ ) _u —, u represents an integer of 2 to 6, and R ³ and R ⁴ are the same or different, Represents a C1-C3 alkyl group which may have a group, or R ³ and R ⁴ together represent — (CH ₂ ) _v —, and v is an integer of any one of 2 to 6 R ⁵ and R ⁶ are the same or different and may have a phenyl group. Ar ³ represents an optionally substituted quinolyl group, and the hydrogen atom bonded to the carbon atom of the compound described in Group 1 may be substituted).
Or an enantiomeric compound thereof.

Hereinafter, the present invention will be described in detail.
In the present specification, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
In the present specification, examples of the C1-C12 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a neopentyl group. Group, 1-ethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, heptyl group, octyl group, nonyl Group, a decyl group, an undecyl group, and a dodecyl group are mentioned, A C1-C6 alkyl group is preferable and a C1-C4 alkyl group is more preferable.
In the present specification, examples of the C1-C6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, and a neopentyl group. Group, 1-ethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group and 2-ethylbutyl group, C1-C4 alkyl Group is preferable, and a methyl group and an ethyl group are more preferable.
In the present specification, examples of the C1-C4 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
In the present specification, examples of the C1-C3 alkyl group optionally having a phenyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a 3-phenylpropyl group, and a 3-phenylpropyl group. Is preferred.
In the present specification, examples of the C3-C8 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, and a C3-C6 cycloalkyl group is preferable.
In the present specification, examples of the C3-C6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
In the present specification, examples of the C2-C12 alkoxycarbonyl group include a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert- Examples thereof include a butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, and a hexyloxycarbonyl group, and a C2-C6 alkoxycarbonyl group is preferable.
In the present specification, examples of the C2-C6 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert- Examples include butoxycarbonyl group and pentyloxycarbonyl group.
In the present specification, examples of the C2-C12 alkylcarbonyl group include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, lauroyl group and the like, and C2-C6 alkylcarbonyl group Is preferred.
In the present specification, examples of the C2-C6 alkylcarbonyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an invaleryl group, and a pivaloyl group.
In the present specification, examples of the C6-C14 aryl group include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, an acenaphthylenyl group, and a biphenylyl group, and a C6-C10 aryl group is preferable.
In the present specification, examples of the C6-C10 aryl group include a phenyl group and a naphthyl group.
In the present specification, examples of the benzyl group optionally having a substituent on the benzene ring include a benzyl group and a 4-methoxybenzyl group, and a benzyl group is preferable.
In the present specification, examples of the phenyl group optionally having one or more halogen atoms include a phenyl group, a 3,5-dichlorophenyl group, and a 3,5-dichloro-4-fluorophenyl group. A 3,5-dichlorophenyl group is preferred.
In the present specification, examples of the substituent in the phenyl group, naphthyl group, indanyl group or indolizinyl group which may have a substituent include the following substituent B. Moreover, the following substituent B is mentioned also as a substituent of the phenyl group which may have a substituent, and the quinolyl group which may have a substituent. Furthermore, Y represents any one group in group 1 (provided that the hydrogen atom bonded to the carbon atom of the group in group 1 may be substituted), and the substituent B is as follows: Is mentioned.
[Substituent B]
C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, C3-C8 cycloalkenyl group, C4-C8 cycloalkadienyl group, C6-C14 aryl group, C7-C16 An aralkyl group, a heterocyclic group;
Hydroxy group, C1-C6 alkoxy group, C2-C6 alkenyloxy group, C2-C6 alkynyloxy group, C3-C8 cycloalkyloxy group, C3-C8 cycloalkenyloxy group, C4-C8 cycloalkadienyloxy group, C6 -C14 aryloxy group, C7-C16 aralkyloxy group, heterocyclic oxy group;
Formyl group, C1-C6 alkylcarbonyl group, C2-C6 alkenylcarbonyl group, C2-C6 alkynylcarbonyl group, C3-C8 cycloalkylcarbonyl group, C3-C8 cycloalkenylcarbonyl group, C4-C8 cycloalkadienylcarbonyl group, A C6-C14 arylcarbonyl group, a C7-C16 aralkylcarbonyl group, a heterocyclic carbonyl group;
Carboxy group, C1-C6 alkoxy C1-C6 alkoxycarbonyl group, C2-C6 alkenyloxycarbonyl group, C2-C6 alkynyloxycarbonyl group, C3-C8 cycloalkoxycarbonyl group, C3-C8 cycloalkenyloxycarbonyl group, C4-C8 A cycloalkadienyloxycarbonyl group, a C6-C14 aryloxycarbonyl group, a C7-C16 aralkyloxycarbonyl group, a heterocyclic oxycarbonyl group;
C1-C6 alkylcarbonyloxy group, C2-C6 alkenylcarbonyloxy group, C2-C6 alkynylcarbonyloxy group, C3-C8 cycloalkylcarbonyloxy group, C3-C8 cycloalkenylcarbonyloxy group, C4-C8 cycloalkadienylcarbonyl An oxy group, a C6-C14 arylcarbonyloxy group, a C7-C16 aralkylcarbonyloxy group, a heterocyclic carbonyloxy group;
Sulfanyl group, C1-C6 alkylsulfanyl group, C2-C6 alkenylsulfanyl group, C2-C6 alkynylsulfanyl group, C3-C8 cycloalkylsulfanyl group, C3-C8 cycloalkenylsulfanyl group, C4-C8 cycloalkadienylsulfanyl group, A C6-C14 arylsulfanyl group, a C7-C16 aralkylsulfanyl group, a heterocyclic sulfanyl group;
Sulfinyl group, C1-C6 alkylsulfinyl group, C2-C6 alkenylsulfinyl group, C2-C6 alkynylsulfinyl group, C3-C8 cycloalkylsulfinyl group, C3-C8 cycloalkenylsulfinyl group, C4-C8 cycloalkadienylsulfinyl group, A C6-C14 arylsulfinyl group, a C7-C16 aralkylsulfinyl group, a heterocyclic sulfinyl group;
Sulfo group, C1-C6 alkylsulfonyl group, C2-C6 alkenylsulfonyl group, C2-C6 alkynylsulfonyl group, C3-C8 cycloalkylsulfonyl group, C3-C8 cycloalkenylsulfonyl group, C4-C8 cycloalkadienylsulfonyl group, A C6-C14 arylsulfonyl group, a C7-C16 aralkylsulfonyl group, a heterocyclic sulfonyl group;
C1-C6 alkylsulfonyloxy group, C2-C6 alkenylsulfonyloxy group, C2-C6 alkynylsulfonyloxy group, C3-C8 cycloalkylsulfonyloxy group, C3-C8 cycloalkenylsulfonyloxy group, C4-C8 cycloalkadienylsulfonyl An oxy group, a C6-C14 arylsulfonyloxy group, a C7-C16 aralkylsulfonyloxy group, a heterocyclic sulfonyloxy group;
Amino group, mono- or di-C1-C6 alkylamino group, mono- or di-C2-C6 alkenylamino group, mono- or di-C2-C6 alkynylamino group, mono- or di-C3-C8 cycloalkylamino group, mono- or Di-C3-C8 cycloalkenylamino group, mono- or di-C4-C8 cycloalkadienylamino group, mono- or di-C6-C14 arylamino group, mono- or di-C7-C16 aralkylamino group, mono- or di- A heterocyclic amino group;
Carbamoyl group, mono- or di-C1-C6 alkylcarbamoyl group, mono- or di-C2-C6 alkenylcarbamoyl group, mono- or di-C2-C6 alkynylcarbamoyl group, mono- or di-C3-C8 cycloalkylcarbamoyl group, mono- or Di-C3-C8 cycloalkenylcarbamoyl group, mono- or di-C4-C8 cycloalkadienylcarbamoyl group, mono- or di-C6-C14 arylcarbamoyl group, mono- or di-C7-C16 aralkylcarbamoyl group, mono- or di- A heterocyclic carbamoyl group;
Thiocarbamoyl group, mono- or di-C1-C6 alkylthiocarbamoyl group, mono- or di-C2-C6 alkenylthiocarbamoyl group, mono- or di-C2-C6 alkynylthiocarbamoyl group, mono- or di-C3-C8 cycloalkylthiocarbamoyl group Mono- or di-C3-C8 cycloalkenylthiocarbamoyl group, mono- or di-C4-C8 cycloalkadienylthiocarbamoyl group, mono- or di-C6-C14 arylthiocarbamoyl group, mono- or di-C7-C16 aralkylthio A carbamoyl group, a mono- or di-heterocyclic thiocarbamoyl group;
A halogen atom;
A cyano group;
A nitro group;
An oxo group; and a thioxo group.
The number of substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each substituent may be the same or different. The above substituent may further have a substituent A.
Ar is preferably a phenyl group which may have one or more selected from the group consisting of a halogen atom and the following group.

(Wherein R ⁷ represents a C _3-8 cycloalkyl group, and R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a formyl group, a C1-C12 alkyl group, a C2-C12 alkoxycarbonyl group, a C2- Represents a C12 alkylcarbonyl group or a C6-C14 aryl group, and X ¹ and X ² are the same or different and each represents a hydrogen atom, a formyl group, a C2-C12 alkylcarbonyl group, a C2-C12 alkoxycarbonyl group, an allyloxycarbonyl group, A benzyloxycarbonyl group or a benzyl group optionally having a substituent on the benzene ring, and * represents a binding site).
As a more preferred specific example of Ar, R ⁷ is a C3-C8 cycloalkyl group, R ⁸ and R ⁹ are a hydrogen atom, a C1-C12 alkyl group or a C2-C12 alkoxycarbonyl group, and X ¹ and X ² In which is a hydrogen atom.
Particularly preferred examples of Ar are 4-chlorophenyl group and 3- (2-cyclopropanecarbohydrazino) -4-chlorophenyl group.
Ar ¹ is preferably a phenyl group which may have one or more selected from the group consisting of a halogen atom and a trifluoromethyl group, and particularly preferably 3,5-dichlorophenyl group, 3-chloro-5-triphenyl. A fluoromethylphenyl group or a 3,5-dichloro-4-fluorophenyl group;
Ar ² is preferably a phenyl group which may have one or more selected from the group consisting of a nitro group and a trifluoromethyl group.
Ar ² is more preferably a phenyl group optionally having one or more trifluoromethyl groups, and particularly preferably a 3,5-ditrifluoromethylphenyl group.
In the production method of the present invention, a compound represented by the formula (1) and a hydroxyamine are combined with any one selected from the compounds described in Group 1 and enantiomers thereof and a carbonate. By reacting, an optically active compound represented by the formula (2) is synthesized (isoxazoline ring formation reaction).
In this specification, the optical activity means that a compound having an asymmetric carbon contains one enantiomer in excess relative to the other enantiomer, or only one enantiomer is included. Represents the state of being.
Specific examples of the compounds described in Group 1 and their enantiomeric compounds include the following compounds.

Among these, the following compounds are preferable because a product having high optical purity can be obtained.

The compounds described in Group 1 and their enantiomeric compounds may be commercially available products, or may be produced according to known methods. For example, it can manufacture according to the method as described in USP7632970 or OrganicLetters 14 (2012) 3296-3299.
In the isoxazoline ring formation reaction, the amount of the compound described in Group 1 and its enantiomeric compound is usually 0.1% with respect to the compound represented by formula (1) from the viewpoint of yield and economy. It is ˜50 mol%, preferably 0.5 to 20 mol%.
The compound represented by the formula (1) used as a raw material may be a commercially available product, or may be produced according to a known method. For example, it can be produced according to the method described in EP2716628.
Examples of the hydroxylamine used in the isoxazoline ring formation reaction include hydroxylamine and its salt with a mineral acid such as hydrochloric acid. Hydroxylamine may be used as it is or in the form of an aqueous solution. The amount of hydroxylamine to be used is usually 1 to 20 moles, preferably 1 to 10 moles, relative to the compound represented by the formula (1) from the viewpoint of yield and economy.
Examples of the carbonate used in the isoxazoline ring formation reaction include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate, and alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate, and barium carbonate. Can be mentioned. Of these, alkali metal carbonates are preferable, and cesium carbonate is particularly preferable.
The amount of the carbonate used is usually 1 to 10 mol times, preferably 1 to 5 mol times based on the compound represented by the formula (1).
The isoxazoline ring formation reaction may be performed by adding an inorganic oxide. Examples of the inorganic oxide include aluminum oxide (alumina), magnesium oxide, calcium oxide, and the like. Aluminum oxide and magnesium oxide are preferable, and aluminum oxide is particularly preferable.
The amount of the inorganic oxide used is usually 0.1 to 10 times by weight, preferably 0.1 to 2 times by weight, relative to the compound represented by the formula (1).
The isoxazoline ring formation reaction is usually performed in a solvent. Examples of the solvent include aliphatic hydrocarbon solvents such as hexane, cyclohexane and heptane; aromatic hydrocarbon solvents such as toluene, xylene and mesitylene; aliphatic halogenated hydrocarbon solvents such as chloroform, dichloromethane and butane chloride; chlorobenzene, Aromatic halogenated hydrocarbon solvents such as dichlorobenzene, fluorobenzene and trifluoromethylbenzene; ether solvents such as tert-butyl methyl ether, tetrahydrofuran and cyclopentyl methyl ether; nitrile solvents such as acetonitrile; N, N-dimethylformamide and the like Amide solvents and mixed solvents thereof are preferable, and from the viewpoint of reactivity and selectivity, aliphatic halogenated hydrocarbon solvents, aromatic halogenated hydrocarbon solvents, and aromatic hydrocarbon solvents are preferable, and chloroform, chlorobenze are particularly preferable. , Toluene is preferred.
The amount of the solvent used is usually 1 to 100 times by weight, preferably 1 to 30 times by weight with respect to the compound represented by the formula (1).
The isoxazoline ring formation reaction is preferably performed within a range of −30 to 60 ° C., more preferably within a range of −10 to 30 ° C., and the reaction time is preferably 0.5 to 100 hours, more preferably 1 to 48 hours.
The progress of the isoxazoline ring formation reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
The post-treatment of the isoxazolinization reaction can be performed by subjecting the reaction mixture to conventional methods (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.). Further, the purification is performed by subjecting the optically active compound represented by the formula (2) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica gel, alumina and the like, and chromatography treatment such as silica gel column chromatography. It can be carried out.

Hereinafter, the present invention will be described in more detail with reference to examples.
Examples 1-4
Compound 2a Synthesis of 3- (4-chlorophenyl) -5- (3,5-dichlorophenyl) -4,5-dihydro-5-trifluoromethylisoxazoline

Compound 1a (1- (4-chlorophenyl) -3- (3,5-dichlorophenyl) -4,4,4-trifluoro-2-buten-1-one) (99 mg, 0.25 mmol), compound (S, S) -C- 1 (21 mg, 0.05 mmol), cesium carbonate (163 mg, 0.50 mmol) and the solvent described in Table 1 (1 mL) were mixed, and the temperature of the mixture was adjusted to −10 ° C., and then 50% Hydroxyamine aqueous solution (50 mg, 0.75 mmol) was added dropwise. After stirring at the same temperature for 22 hours, the yield and optical purity of compound 2a were determined by HPLC analysis. The results are shown in Table 1.
The HPLC analysis of Examples 1 to 4 was performed under the following conditions.
Yield analysis conditions:
Column L-column-2 ODS (250 mm * 4.6 mm, 5 μm)
Column temperature 40 ° C
Mobile phase Acetonitrile: Ion exchange water 70:30 (v / v)
Flow rate 1.5mL / min
Detection wavelength 220nm
Retention time Compound 1a 15.4 min, Compound 2a 19.0 min
The yield was calculated as the area percentage of Compound 2a / (area percent area percent + compound 2a compound 1a).
Optical purity analysis conditions:
Column CHIRAPAK OJ-H (250 mm * 4.6 mm, 5 μm)
Column temperature 30 ° C
Moving bed hexane: 2-propanol 98: 2 (v / v),
Flow rate 1.2mL / min
Detection wavelength 254nm
Retention time Compound 2a Enantiomer 1 9.7 min, Enantiomer 2 14.6 min

Example 5
Compound 2b Synthesis of 2- {2-chloro-5- [3- (3,5-dichlorophenyl) 4,5-dihydro-5- (trifluoromethyl) -3-isoxazoyl] phenyl} cyclopropanecarbohydrazide

Compound 1b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} cyclopropanecarbohydrazide ) (49 mg, 0.1 mmol), compound (S) -C- 5 (8 mg, 0.02 mmol), cesium carbonate (98 mg, 0.3 mmol) and chlorobenzene (2 mL) are mixed, and the temperature of the mixture is brought to 20 ° C. After the adjustment, 50% aqueous hydroxyamine solution (27 mg, 0.4 mmol) was added dropwise. After stirring at the same temperature for 30 hours, the yield and optical purity of compound 2b were determined by HPLC analysis. The yield was 38.8%, and the optical purity was 59% ee (R form).
The HPLC analysis of Example 5 was performed under the following conditions.
Yield analysis conditions:
The measurement was performed according to the HPLC conditions described in Examples 1 to 4.
Retention time Compound 1b 6.7 min, Compound 2b 7.1 min
The yield was calculated as the area of the compound 2b percentage / (area percent area percent + Compound 2b of compound 1b).
Optical purity analysis conditions:
Column CHIRALCELL AD-H (250 mm * 4.6 mm, 5 μm)
Column temperature 30 ° C
Moving bed hexane: 2-propanol 85:15 (v / v),
Flow rate 1.0mL / min
Detection wavelength 254nm
Retention time Compound 2b (S) enantiomer 3 13.2 min, (R) enantiomer 4 16.9 min
Example 6
Synthesis of Compound 2b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) 4,5-dihydro-5- (trifluoromethyl) -3-isoxazoyl] phenyl} cyclopropanecarbohydrazide)

Compound 1b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} cyclopropanecarbohydrazide ) (24 mg, 0.05 mmol), compound (S) -C- 5 (4 mg, 0.01 mmol), cesium carbonate (49 mg, 0.15 mmol) and chlorobenzene (1 mL), and the temperature of the mixture is brought to 25 ° C. After the adjustment, 50% aqueous hydroxyamine solution (20 mg, 0.3 mmol) was added dropwise. After stirring at the same temperature for 20 hours, the yield and optical purity of compound 2b were determined according to the HPLC analysis conditions described in Example 5. The yield was 52.3% and the optical purity was 57% ee (R form).
Examples 7 and 8
Synthesis of Compound 2b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) 4,5-dihydro-5- (trifluoromethyl) -3-isoxazoyl] phenyl} cyclopropanecarbohydrazide)

Compound 1b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} cyclopropanecarbohydrazide ) (24 mg, 0.05 mmol), Compound (S) -C- 5 (7 mg, 0.018 mmol), Cesium carbonate (49 mg, 0.15 mmol), Additives listed in Table 2 (25 mg) and chlorobenzene (1 mL) After adjusting the temperature of the mixture to 20 ° C., 50% aqueous hydroxyamine solution (20 mg, 0.3 mmol) was added dropwise. After stirring at the same temperature for the time described in Table 2, the yield and optical purity of Compound 2b were determined according to the HPLC analysis conditions described in Example 5. The results are shown in Table 2.

Example 9
Synthesis of Compound 2b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) 4,5-dihydro-5- (trifluoromethyl) -3-isoxazoyl] phenyl} cyclopropanecarbohydrazide)

Compound 1b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} cyclopropanecarbohydrazide ) (48 mg, 0.1 mmol), compound (S) -C- 5 (8 mg, 0.02 mmol), cesium carbonate (98 mg, 0.3 mmol), and chlorobenzene (2 mL) are mixed, and the temperature of the mixture is adjusted to 20 ° C. After adjustment, 50% aqueous hydroxyamine solution (27 mg, 0.4 mmol) was added dropwise. After stirring at the same temperature for 29 hours, the yield and optical purity of compound 2b were analyzed according to the HPLC analysis conditions described in Example 5. The yield was 51.4% and the optical purity was 58% ee (R form).
Example 10
Synthesis of Compound 2b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) 4,5-dihydro-5- (trifluoromethyl) -3-isoxazoyl] phenyl} cyclopropanecarbohydrazide)

Compound 1b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} cyclopropanecarbohydrazide ) (49 mg, 0.1 mmol), compound (S) -C- 5 (8 mg, 0.02 mmol), cesium carbonate (98 mg, 0.3 mmol) and chlorobenzene (2 mL) are mixed, and the temperature of the mixture is brought to 20 ° C. After the adjustment, a 50% hydroxyamine aqueous solution (40 mg, 0.6 mmol) was added dropwise. After stirring at the same temperature for 67 hours, the yield and optical purity of compound 2b were analyzed according to the HPLC analysis conditions described in Example 5. The yield was 95.2%, and the optical purity was 50% ee (R form).
Example 11
Synthesis of Compound 2b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) 4,5-dihydro-5- (trifluoromethyl) -3-isoxazoyl] phenyl} cyclopropanecarbohydrazide)

Compound 1b (2- {2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} cyclopropanecarbohydrazide ) (2.87 g, 6.0 mmol), Compound (S) -C- 5 (0.46 g, 0.12 mmol), Alumina (Merck, for chromatography, 2.0 g) and chlorobenzene (86 mL) were mixed. After adjusting the temperature of the mixture to 13 to 15 ° C., 50% aqueous hydroxyamine solution (2.38 g, 36 mmol) and cesium carbonate (5.86 g, 18 mmol) were added. After stirring at the same temperature for 78 hours, anhydrous magnesium sulfate (about 10 g) was added and dried. The mixture was filtered, and the residue obtained by concentrating the filtrate was purified by silica gel chromatography to obtain Compound 2b (2.71 g) as a yellow foam-like solid. In addition, the optical purity of Compound 2b was analyzed according to the HPLC analysis conditions described in Example 5. The optical purity was 54% ee (R form).
Example 12
Compound A Synthesis of ethyl 2-({2-chloro-5- [5- (3,5-dichlorophenyl) -4,5-dihydro-5-trifluoromethyl-3-isoxazolyl] phenyl} hydrazono) propionate

Compound a 2-({2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} hydrazono) propionic acid Mix ethyl (50 mg, 0.10 mmol), (9R) -CINN-TC (11 mg, 0.02 mmol), cesium carbonate (96 mg, 0.30 mmol) and chlorobenzene (1 mL) and adjust the temperature of the mixture to 0 ° C. Later, 50% aqueous hydroxyamine (39 mg, 0.59 mmol) was added. After stirring at the same temperature for 20 hours, the yield and optical purity of Compound A were determined by HPLC analysis. The yield was 97.7%, and the optical purity was 75% ee (S form).
Example 13
Compound B Synthesis of diethyl 2-({2-chloro-5- [5- (3,5-dichlorophenyl) -4,5-dihydro-5-trifluoromethyl-3-isoxazolyl] phenyl} hydrazono) malonate

Compound b 2-({2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} hydrazono) malonic acid Mix diethyl (51 mg, 0.091 mmol), (9R) -CINN-TC (10 mg, 0.017 mmol), cesium carbonate (91 mg, 0.28 mmol) and chlorobenzene (1 mL) and adjust the temperature of the mixture to 0 ° C. Later, 50% aqueous hydroxyamine (36 mg, 0.54 mmol) was added. After stirring at the same temperature for 29 hours, the yield and optical purity of Compound B were determined by HPLC analysis. The yield was 92.6%, and the optical purity was 74% ee (S form).
Example 14
Compound C 2-({2-chloro-5- [5- (3,5-dichlorophenyl) -4,5-dihydro-5-trifluoromethyl-3-isoxazolyl] phenyl} hydrazono) -3-phenylpropionate Synthesis of

Compound c 2-({2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} hydrazono) -3 -Ethyl phenylpropionate (48 mg, 0.083 mmol), (9R) -CINN-TC (9 mg, 0.016 mmol), cesium carbonate (84 mg, 0.26 mmol) and chlorobenzene (1 mL) were mixed and the temperature of the mixture was After adjusting to 0 ° C., 50% aqueous hydroxyamine solution (34 mg, 0.51 mmol) was added. After stirring at the same temperature for 48.5 hours, the yield and optical purity of Compound C were determined by HPLC analysis. The yield was 98.5%, and the optical purity was 70% ee (S form).
The HPLC analysis of Examples 12 to 14 was performed under the following conditions.
Column CHIRALCEL OZ-RH (4.6 * 250 mm, 10 μm)
Column temperature 30 ° C
Mobile phase A: Water, B: Acetonitrile 0 min A / B = 50/50, 20 min A / B = 30/70, 35 min A / B = 30/70
Flow rate 1mL / min
Detection wavelength 254nm
Retention time Compound a , 20.8 min, Compound A , 22.1 min, 22.9 min
Compound b , 24.5 min, Compound B , 26.2 min, 27.1 min
Compound c , 26.5 min, Compound C , 28.4 min, 29.7 min
Yield, respectively, (the area percentage of the area percentage + compound a compound A) area percent / compounds A, the area percentage of Compound B / (area percent area percent + compound b Compound B), the area of the compound C It was calculated as percentage / (area percentage of compound C + area percentage of compound c ).
Example 15
Compound D 2-({2-chloro-5- [5- (3,4,5-trichlorophenyl) -4,5-dihydro-5-trifluoromethyl-3-isoxazolyl] phenyl} hydrazono) ethyl propionate Composition

Compound d 2-({2-chloro-5- [3- (3,4,5-trichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} hydrazono ) Ethyl propionate (137 mg, 0.25 mmol), (9R) -CINN-TC (29 mg, 0.05 mmol), cesium carbonate (163 mg, 0.50 mmol) and chlorobenzene (1.76 g) were mixed and the temperature of the mixture Was adjusted to 20-25 ° C., and 50% aqueous hydroxyamine solution (50 mg, 0.75 mmol) was added. After stirring at the same temperature for 4 hours, the yield and optical purity of Compound D were determined by HPLC analysis. The yield was 99.9%, and the optical purity was 62% ee (enantiomer 2).
Example 16
Synthesis of compound D

(9R) -CINN-TC (0.54 g, 0.96 mmol), toluene (27.7 g), cesium carbonate (6.01 g, 18.4 mmol), 50% hydroxyamine aqueous solution (1.7 mL, 28 mmol) were mixed. The temperature of the mixture was adjusted to 20-25 ° C. Here, 2-({2-chloro-5- [3- (3,4,5-trichlorophenyl) -4,4,4-trifluoro-1-oxo-2-) dissolved in toluene (103.5 g). Buten-1-yl] phenyl} hydrazono) ethyl propionate (5.00 g, 9.2 mmol) was added dropwise at 20-25 ° C. over 2.5 hours. After stirring at the same temperature for 2.5 hours, the yield and optical purity of Compound D were determined by HPLC analysis. The yield was 99.3%, and the optical purity was 62% ee (enantiomer 2).
The HPLC analysis of Examples 15 to 16 was performed under the following conditions.
Yield analysis conditions:
Column Sumipax ODS Z-CLUE (4.6 * 150 mm, 5 μm)
Column temperature 40 ° C
Mobile phase A: 0.1% phosphoric acid aqueous solution, B: acetonitrile 0 min A / B = 70/30, 15 min A / B = 10/90, 30 min A / B = 10/90
Flow rate 1mL / min
Detection wavelength 254nm
Retention time Compound d 21.0 min, Compound D 21.4 min
The yield was calculated as the compound D of the area percent / (area percent area percent + compound d Compound D).
Optical purity analysis conditions:
Column CHIRALCEL OZ-RH (4.6 * 150 mm, 5 μm)
Column temperature 40 ° C
Mobile phase A: 0.1% phosphoric acid aqueous solution, B: acetonitrile 0 min A / B = 50/50, 20 min A / B = 30/70, 35 min A / B = 30/70
Flow rate 0.8mL / min
Detection wavelength 254nm
Retention time Compound D 24.7 min, 25.5 min
Example 17
Compound E 2-({2-chloro-5- [5- (3,4,5-trichlorophenyl) -4,5-dihydro-5-trifluoromethyl-3-isoxazolyl] phenyl} hydrazono) of diethyl malonate Composition

Compound e 2-({2-chloro-5- [3- (3,4,5-trichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} hydrazono ) Diethyl malonate (151 mg, 0.25 mmol), (9R) -CINN-TC (14 mg, 0.025 mmol), cesium carbonate (187 mg, 0.57 mmol) and chlorobenzene (1.80 g) were mixed and the temperature of the mixture Was adjusted to 20-25 ° C., and 50% aqueous hydroxyamine solution (50 mg, 0.75 mmol) was added. After stirring at the same temperature for 4 hours, the yield of Compound E was determined by HPLC analysis. The yield was 99.7%.
Example 18
Compound F 2-({2-chloro-5- [5- (3,5-dichloro-4-fluorophenyl) -4,5-dihydro-5-trifluoromethyl-3-isoxazolyl] phenyl} hydrazono) propionic acid Synthesis of ethyl

Compound f 2-({2-chloro-5- [3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl } Hydrazono) ethyl propionate (131 mg, 0.25 mmol), (9R) -CINN-TC (14 mg, 0.025 mmol), cesium carbonate (168 mg, 0.52 mmol) and toluene (1.65 g) were mixed and the mixture After adjusting the temperature to 20 to 25 ° C., a 50% aqueous hydroxyamine solution (50 mg, 0.75 mmol) was added. After stirring at the same temperature for 6 hours, the yield of Compound F was analyzed by HPLC analysis. The yield was 100%.
The HPLC analysis of Examples 17 to 18 was performed under the following conditions.
Column Sumipax ODS Z-CLUE (4.6 * 150 mm, 5 μm)
Column temperature 40 ° C
Mobile phase A: 0.1% phosphoric acid aqueous solution, B: acetonitrile 0 min A / B = 70/30, 15 min A / B = 10/90, 30 min A / B = 10/90
Flow rate 1mL / min
Detection wavelength 254nm
Retention time Compound e 22.4 min, Compound E 23.4 min
Compound f 20.0 min, Compound F 20.4 min
Yield, respectively, the area of the compound E percentage / (area percent area percent + of compound e Compound E), was calculated as the compound F area percent / (area percent area percent + compound f of the compound F).
Examples 19-20
Compound G (3-{-4-chloro-3- [2- (prop-2-ylidene) hydrazinyl] phenyl} -5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5- Of dihydro-1,2-oxazole)

Compound g ((2Z) -1- {4-chloro-3-[(2Z) -1- {4-chloro-3- [2- (propane-2-ylidene) hydrazinyl] phenyl} -3- (3 , 5-dichlorophenyl) -4,4,4-trifluorobut-2-en-1-one) (45 mg, 0.1 mmol), catalyst compounds listed in Table 3, alumina (Merck, for chromatography, 45 mg), cesium carbonate (98 mg, 0.3 mmol) and chlorobenzene (1 mL) were mixed, the temperature of the mixture was adjusted to 10 ° C., and 50% aqueous hydroxyamine solution (40 mg, 0.6 mmol) was added. After stirring at the same temperature for the time described in Table 3, the yield and optical purity of Compound G were determined by HPLC analysis. HPLC analysis was performed under the following conditions.
Yield analysis conditions:
Column L-column ODS (150 mm * 4.6 mm, 5 μm)
Column temperature 40 ° C
Mobile phase Acetonitrile-0.1 w% phosphoric acid water Acetonitrile concentration: 15% → 90% / 0 min → 15 min; 90% / 10 min (retention)
Flow rate 1.5mL / min
Detection wavelength 230nm
Retention time Compound g 17.3 min, Compound G 17.6 min
The yield was calculated as the area of Compound G a percentage / (area percent area percent + compound g of compound G).
Optical purity analysis conditions:
Column CHIRALCELL OZ-RH (150 mm * 4.6 mm, 5 μm)
Column temperature 30 ° C
Moving bed Acetonitrile-ion exchange water Acetonitrile concentration: 50% → 70% / 0 min → 20 min; 70% / 5 min (retention)
Flow rate 1.0mL / min
Detection wavelength 254nm
Retention time Product 6b Enantiomer 1 20.1 min, Enantiomer 2 20.8 min

Examples 21-23

Compound a 2-({2-chloro-5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-1-oxo-2-buten-1-yl] phenyl} hydrazono) propionic acid Ethyl (51 mg, 0.1 mmol), the catalyst compound listed in Table 4, alumina (Merck, for chromatography, 45 mg), cesium carbonate (98 mg, 0.3 mmol) and chlorobenzene (1 mL) were mixed together. After adjusting the temperature to 10 ° C., 50% aqueous hydroxyamine solution (40 mg, 0.6 mmol) was added. After stirring for the time indicated in Table 4 at the same temperature, the yield and optical purity of Compound A were determined by HPLC analysis.

Reference production example 1
Synthesis of (S) -C-5 1-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -3- [3,5-bis (trifluoromethyl) phenyl] thiourea

(S)-(−)-3-Aminoquinuclidine dihydrochloride (1.0 g, 5.0 mmol), triethylamine (4.0 g, 39 mmol), and tetrahydrofuran (5 mL) were mixed, and the temperature of the mixture was adjusted to 20. After adjusting to ~ 30 ° C, 3,5-ditrifluoromethylphenylisothiocyanic acid (1.34 g, 5 mmol) was added dropwise and stirred at the same temperature for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography to obtain an off-white solid compound (S) -C- 5 (1.52 g).
¹ H NMR (400 MHz, DMSO-d6) δ ppm: 1.40 (1H, br.s), 1.57-1.63 (2H, br.s), 1.63-1.70 (1H, br. s), 1.98 (1H, dd, J = 6, 3 Hz), 2.58 (1H, m), 2.60-2.80 (4H, m), 3.17-3.30 (1H, m), 4.23 (1H, br.s), 7.72 (1H, s), 8.26 (2H, s), 8.41 (1H, br, s), 9.91 (1H, br) , S)

An optically active isoxazoline compound can be produced by the method of the present invention.

Claims

The compound represented by the formula (1) is reacted with hydroxyamine in the presence of a carbonate and any one selected from the compounds described in Group 1 and its enantiomeric compounds. , A process for producing an optically active compound represented by formula (2)

(In the formula, Ar has a phenyl group which may have a substituent, a naphthyl group which may have a substituent, an indanyl group which may have a substituent, or a substituent. Represents an indolizinyl group, Ar 1 and Ar 2 represent a phenyl group which may have a substituent, and R 1 and R 2 are the same or different and represent a phenyl group which may have a substituent. Or R 1 and R 2 together represent — (CH 2 ) u —, u represents an integer of 2 to 6, and R 3 and R 4 are the same or different, Represents a C1-C3 alkyl group which may have a group, or R 3 and R 4 together represent — (CH 2 ) v —, and v is an integer of any one of 2 to 6 R 5 and R 6 are the same or different and may have a phenyl group. Ar 3 represents an optionally substituted quinolyl group, and the hydrogen atom bonded to the carbon atom of the compound described in Group 1 may be substituted).
The production method according to claim 1, wherein the compounds described in Group 1 are the following compounds.
The production method according to claim 1, wherein the compounds described in Group 1 are the following compounds.
The production method according to claim 1, wherein Ar is a phenyl group which may have one or more selected from the group consisting of a halogen atom and a group shown below.

(Wherein R 7 represents a C3-C8 cycloalkyl group, and R 8 and R 9 are the same or different and each represents a hydrogen atom, a formyl group, a C1-C12 alkyl group, a C2-C12 alkoxycarbonyl group, a C2-C12). It represents an alkylcarbonyl group or a C6-C14 aryl group, X 1 and X 2 are different each same or different, a hydrogen atom, a formyl group, C2-C12 alkylcarbonyl group, C2-C12 alkoxycarbonyl group, allyloxycarbonyl group, benzyl Represents an oxycarbonyl group or a benzyl group optionally having a substituent on the benzene ring, and * represents a binding site).
5. R 7 is a C3-C8 cycloalkyl group, R 8 and R 9 are hydrogen atoms, C1-C12 alkyl groups or C2-C12 alkoxycarbonyl groups, and X 1 and X 2 are hydrogen atoms. The manufacturing method as described.
6. The production method according to claim 1, wherein Ar 1 is a phenyl group optionally having one or more atoms or groups selected from a halogen atom and a trifluoromethyl group.