JP5653442B2 - Fused ring compounds - Google Patents

Description

The present invention relates to a condensed ring compound that can be an intermediate for producing an isoxazoline derivative disclosed in Patent Document 1 and the like.
The present application was filed in Japan in Japanese Patent Application No. 2010-186680 filed on August 23, 2010, Japanese Patent Application No. 2011-025367 filed on February 8, 2011, and February 25, 2011. Claiming priority based on Japanese Patent Application No. 2011-040966, Japanese Patent Application No. 2011-080164 filed on March 31, 2011, and Japanese Patent Application No. 2011-110665 filed on May 17, 2011, The contents are incorporated here.

  Many pesticides, acaricides, and other pesticides are used in the fields of agriculture, horticulture, livestock, etc., but their use is insufficient or due to drug resistance problems. It may be restricted, or it may cause phytotoxicity or contamination of the plant body, or it may be highly toxic to livestock fish. Therefore, an isoxazoline derivative represented by the formula (A) (hereinafter referred to as isoxazoline derivative A) is disclosed in Patent Document 1, Patent Document 2 or Patent Document 3 as a drug that can be safely used with few such drawbacks. Yes.

(In Formula (A), Z represents an unsubstituted or substituted aryl group (halogen atom, haloalkyl group, etc.), etc. R ₀ represents a halogen atom, haloalkyl group, etc. Y represents a nitro group, etc. P represents an integer of 0 to _3. R ₁ and R ₂ each independently represents a hydrogen atom, a nitro group, a hydroxyl group, a mercapto group, an unsubstituted or substituted amino group, or an organic group. Show.)

WO2009 / 022746 Pamphlet WO2009 / 112275 Pamphlet WO2010 / 027051 pamphlet

Tetrahedron Lett. 1976, 51, 4691-4694 J. Org. Chem. 2002, 67, 4615-4618 J. Org. Chem. 1999, 64, 2873-2876

The isooxalin derivative A has a broad insecticidal and acaricidal spectrum, is excellent in low concentration activity, and is expected to be developed as a compound that overcomes the above-mentioned drawbacks.
However, since the isoxazoline derivative A has a characteristic 1-substituted indane skeleton, it is difficult to produce it industrially stably and efficiently.
Accordingly, an object of the present invention is to provide a condensed ring compound that can be a production intermediate useful for industrially and efficiently producing isoxazoline derivative A and the like useful as a pest control agent. To do.

  The inventors of the present invention have made extensive studies in order to solve the above problems. As a result, a condensed ring compound represented by the formula (I) or the formula (II) was found. It was found that isoxazoline derivative A and the like can be efficiently produced by using this condensed ring compound. The present invention has been completed based on these findings.

That is, this invention includes the following forms.
[1] A condensed ring compound represented by formula (I), formula (II), formula (VII) or formula (VIII).
[2] An intermediate for producing an isoxazoline derivative comprising a condensed ring compound represented by formula (I), formula (II), formula (VII) or formula (VIII).
[3] A method for producing an isoxazoline derivative comprising using a condensed ring compound represented by formula (I), formula (II), formula (VII) or formula (VIII) as a production intermediate.

In the formula (I), X ″ has a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted group. A C2-6 alkynyl group, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group is shown.
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
X ′ is a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, a hydroxyl group , An unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group.
m represents the number of substitutions of X ′ and is an integer of 0 to 7. When m is 2 or more, X ′ may be the same as or different from each other.
R ¹ represents a hydrogen atom, a halogen atom, or an unsubstituted or substituted C 1-6 alkyl group.
R ² is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group , An azide group, a succinimide group, a phthalimide group, a formamide group, or an acetylamide group.
R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C 1-6 alkoxy group, an unsubstituted or substituted C 1-6 alkylcarbonyloxy group, or a tri C 1-6 alkyl substituted silyloxy group. , An azide group, a succinimide group, a phthalimide group, a formamide group, or an acetylamide group.
q represents the number of carbon atoms and is 1 or 2.
p represents the number of substitutions of R ³ and is 0 or 1.
The bond between carbon atom 1 and carbon atom 2 indicates a single bond when p is 1 and a double bond when p is 0.
R ² and R ³ together may form an oxo group or an unsubstituted or substituted hydroxyimino group.

X ′ in the formula (II) has a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted group. A C2-6 alkynyl group, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group is shown.
m represents the number of substitutions of X ′ and is an integer of 0 to 7. When m is 2 or more, X ′ may be the same as or different from each other.
When two X ′ are substituted on the same carbon atom, they may be taken together to form an oxo group.
R ⁴ is a halogen atom, a formyl group, a hydroxyiminomethyl group, an N-hydroxy-chlorocarbonimidoyl group, a 1,1-di (C1-6 alkoxy) methyl group [C1-6 alkoxy are bonded together to form a ring May be formed. 1-C1-6 alkoxyvinyl group, 1-C3-6 cycloalkoxyvinyl group, acetyl group, 2- (C1-6 alkoxy) carbonylacetyl group, 3- (C1-6 alkoxy) carbonyl-3-oxo- A propionyl group or a cyano group is shown.
R ²¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group. , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
R ³¹ is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
q represents the number of carbon atoms and is 1 or 2.
p ′ represents the number of substitutions of R ³¹ and is 0 or 1.
The bond between carbon atom 1 and carbon atom 2 indicates a single bond when p ′ is 1 and a double bond when p ′ is 0.
R ²¹ and R ³¹ may be combined to form an oxo group, or an unsubstituted or substituted hydroxyimino group.

In the formula (VII), X ″ has a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted group. A C2-6 alkynyl group, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group is shown.
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
X ′ is a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, a hydroxyl group , An unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group.
m represents the number of substitutions of X ′ and is an integer of 0 to 7. When m is 2 or more, X ′ may be the same as or different from each other.
When two X ′ are substituted on the same carbon atom, they may be taken together to form an oxo group.
R ¹ represents a hydrogen atom, a halogen atom, or an unsubstituted or substituted C 1-6 alkyl group.
R ²¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group. , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
R ³¹ is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
q represents the number of carbon atoms and is 1 or 2.
p ′ represents the number of substitutions of R ³¹ and is 0 or 1.
The bond between carbon atom 1 and carbon atom 2 indicates a single bond when p ′ is 1 and a double bond when p ′ is 0.
R ²¹ and R ³¹ may be combined to form an oxo group, or an unsubstituted or substituted hydroxyimino group.
The bond represented by the wavy line indicates a trans conformation or cis conformation with respect to R ¹ .
Z represents an oxygen atom or a hydroxyimino group.

In the formula (VIII), X ″ has a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted group. A C2-6 alkynyl group, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group is shown.
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
X ′ is a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, a hydroxyl group , An unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group.
m represents the number of substitutions of X ′ and is an integer of 0 to 7. When m is 2 or more, X ′ may be the same as or different from each other.
When two X ′ are substituted on the same carbon atom, they may be taken together to form an oxo group.
R ¹ represents a hydrogen atom, a halogen atom, or an unsubstituted or substituted C 1-6 alkyl group.
R ²¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group. , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
R ³¹ is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
q represents the number of carbon atoms and is 1 or 2.
p ′ represents the number of substitutions of R ³¹ and is 0 or 1.
The bond between carbon atom 1 and carbon atom 2 indicates a single bond when p ′ is 1 and a double bond when p ′ is 0.
R ²¹ and R ³¹ together may form an oxo group, an unsubstituted or substituted hydroxyimino group.

Furthermore, this invention includes the following forms.
[4] Aromatic carbonization having an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, or an unsubstituted or substituted C1-6 alkylcarbonyloxy group at the allylic position By reacting a condensed ring compound of a hydrogen ring and an aliphatic hydrocarbon ring with an unsubstituted or substituted C1-6 alkyl cyanide compound in the presence of a protonic acid or a Lewis acid, the allylic position is unsubstituted. Alternatively, a method for producing a condensed ring compound of an aromatic hydrocarbon ring having a C1-6 alkylcarbonylamino group having a substituent and an aliphatic hydrocarbon ring.
[5] The method according to [4], wherein the condensed ring compound is an indane derivative or a tetrahydronaphthalene derivative.

[6] A condensed ring compound represented by the following formula (X) is reacted with an unsubstituted or substituted C1-6 alkyl cyanide compound in the presence of a protonic acid or a Lewis acid, and the following formula (XI) The method according to [5] above, wherein a condensed ring compound represented by the formula:

In the formula (X), X ″ has a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted group. A C2-6 alkynyl group, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group is shown.
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
X ′ is a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, a hydroxyl group , An unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group.
m represents the number of substitutions of X ′ and is an integer of 0 to 7. When m is 2 or more, X ′ may be the same as or different from each other.
R ¹ represents a hydrogen atom, a halogen atom, or an unsubstituted or substituted C 1-6 alkyl group.
R ²² represents an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, or an unsubstituted or substituted C1-6 alkylcarbonyloxy group.
q represents the number of carbon atoms and is 1 or 2.

In the formula (XI), X ″, n, X ′, m, R ¹ and q have the same meaning as described above.
R ²³ represents an unsubstituted or substituted C 1-6 alkyl group.

[7] A condensed ring compound represented by the following formula (XII) is reacted with an unsubstituted or substituted C1-6 alkyl cyanide compound in the presence of a protonic acid or a Lewis acid to form the following formula (XIII The method according to [5] above, wherein a condensed ring compound represented by the formula:

In the formula (XII), X ″ has a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted group. A C2-6 alkynyl group, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group is shown.
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
X ′ is a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2-6 alkynyl group, a hydroxyl group , An unsubstituted or substituted C1-6 alkoxy group, a nitro group, or a cyano group.
m represents the number of substitutions of X ′ and is an integer of 0 to 7. When m is 2 or more, X ′ may be the same as or different from each other.
R ¹ represents a hydrogen atom, a halogen atom, or an unsubstituted or substituted C 1-6 alkyl group.
R ²² represents an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, or an unsubstituted or substituted C1-6 alkylcarbonyloxy group.
q represents the number of carbon atoms and is 1 or 2.
The bond represented by the wavy line indicates a trans conformation or cis conformation with respect to R ¹ .
Z represents an oxygen atom or a hydroxyimino group.

In the formula (XIII), X ″, n, X ′, m, R ¹ , q, Z and the bond represented by a broken line have the same meaning as described above.
R ²³ represents an unsubstituted or substituted C 1-6 alkyl group.

  The condensed ring compound according to the present invention is a substance that can be a production intermediate useful for industrially and efficiently producing isoxazoline derivative A and the like useful as a pest control agent.

  The condensed ring compound according to the first embodiment of the present invention is a compound represented by the formula (I) (hereinafter sometimes referred to as the compound (I)). Compound (I) is a substance that can be a production intermediate such as isoxazoline derivative A.

The meanings of symbols and terms used in formula (I) are as follows.
First, the term “unsubstituted” means that the group is only a parent nucleus. When there is no description of “having a substituent” and only the name of the group serving as a mother nucleus is used, it means “unsubstituted” unless otherwise specified.
On the other hand, the term “having a substituent” means that any hydrogen atom of a group serving as a mother nucleus is substituted with a group having the same or different structure from the mother nucleus. Accordingly, the “substituent” is another group bonded to a group serving as a mother nucleus. The number of substituents may be one, or two or more. Two or more substituents may be the same or different.
Terms such as “C1-6” indicate that the number of carbon atoms of the group serving as the mother nucleus is 1-6. This number of carbon atoms does not include the number of carbon atoms present in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group.

The “substituent” is not particularly limited as long as it is chemically acceptable and has the effects of the present invention.
Examples of the group that can be a “substituent” include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom; methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl C1-6 alkyl group such as a group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group; C3-8 such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group A cycloalkyl group; a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 1-methyl-2-propenyl group, a 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hetenyl group C2-6 alkenyl groups such as a senyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group; 2-cyclopropenyl group, 2-cyclopentenyl group, 3-cyclohexenyl group, 4- C3-8 cycloalkenyl groups such as cyclooctenyl group; ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2- Methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, A C2-6 alkynyl group such as a 1,1-dimethyl-2-butynyl group;

  C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group; vinyloxy group, allyloxy group, propenyl C2-6 alkenyloxy groups such as oxy group and butenyloxy group; C2-6 alkynyloxy groups such as ethynyloxy group and propargyloxy group; C6-10 aryl groups such as phenyl group and naphthyl group; phenoxy group and 1-naphthoxy group A C7-11 aralkyl group such as a benzyl group or a phenethyl group; a C7-11 aralkyloxy group such as a benzyloxy group or a phenethyloxy group; a formyl group; an acetyl group, a propionyl group, a benzoyl group; C1- such as a cyclohexylcarbonyl group 6 alkylcarbonyl group; formyloxy group; C1-6 alkylcarbonyloxy group such as acetyloxy group, propionyloxy group; methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl A C1-6 alkoxycarbonyl group such as a group or t-butoxycarbonyl group; a carboxyl group;

  Hydroxyl group; oxo group; C1-6 haloalkyl such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group, perfluoro-n-pentyl group Group; C2-6 haloalkenyl group such as 2-chloro-1-propenyl group and 2-fluoro-1-butenyl group; 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group, 5- C2-6 haloalkynyl group such as bromo-2-pentynyl group; C1-6 haloalkoxy group such as 2-chloro-n-propoxy group and 2,3-dichlorobutoxy group; 2-chloropropenyloxy group, 3-bromo C2-6 haloalkenyloxy groups such as butenyloxy group; 4-chlorophenyl group, 4-fluorophenyl group, 2,4-dichlorophen A C6-10 haloaryl group such as a chloro group; a C6-10 haloaryloxy group such as a 4-fluorophenyloxy group or a 4-chloro-1-naphthoxy group; a halogen such as a chloroacetyl group, a trifluoroacetyl group or a trichloroacetyl group A substituted C1-6 alkylcarbonyl group;

  Cyano group; isocyano group; nitro group; isocyanato group; cyanato group; amino group; C1-6 alkylamino group such as methylamino group, dimethylamino group and diethylamino group; C6-10 arylamino group such as anilino group and naphthylamino group Group: C7-11 aralkylamino group such as benzylamino group, phenylethylamino group; formylamino group; C1-6 alkylcarbonylamino group such as acetylamino group, propanoylamino group, butyrylamino group, i-propylcarbonylamino group A C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, or an i-propoxycarbonylamino group; an aminocarbonyl group, a dimethylaminocarbonyl group, a fluorine; An unsubstituted or substituted aminocarbonyl group such as nylaminocarbonyl group, N-phenyl-N-methylaminocarbonyl group; iminomethyl group, (1-imino) ethyl group, (1-imino) -n-propyl group A C1-6 alkyl group substituted with an imino group such as: methoxyiminomethyl group, (1-methoxyimino) ethyl group; hydroxyiminomethyl group, (1-hydroxyimino) ethyl group, (1-hydroxyimino) propyl group A C1-6 alkyl group substituted with a hydroxyimino group such as;

  Mercapto group; isothiocyanato group; thiocyanato group; C1-6 alkylthio such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group C2-6 alkenylthio groups such as vinylthio groups and allylthio groups; C2-6 alkynylthio groups such as ethynylthio groups and propargylthio groups; C6-10 arylthio groups such as phenylthio groups and naphthylthio groups; thiazolylthio groups and pyridylthio groups A heteroarylthio group of C7-11 aralkylthio group such as benzylthio group and phenethylthio group; (methylthio) carbonyl group, (ethylthio) carbonyl group, (n-propylthio) carbonyl group, (i-propylthio) carbonyl group, ( - butylthio) carbonyl group, (i-butylthio) carbonyl group, (s-butylthio) carbonyl group, (t-butylthio) (Cl to 6 alkylthio, such as carbonyl groups) carbonyl group;

  C1-6 alkylsulfinyl groups such as methylsulfinyl group, ethylsulfinyl group, t-butylsulfinyl group; C2-6 alkenylsulfinyl groups such as allylsulfinyl group; C2-6 alkynylsulfinyl groups such as propargylsulfinyl group; phenylsulfinyl group and the like A heteroarylsulfinyl group such as thiazolylsulfinyl group and pyridylsulfinyl group; a C7-11 aralkylsulfinyl group such as benzylsulfinyl group and phenethylsulfinyl group; a methylsulfonyl group, an ethylsulfonyl group, t- C1-6 alkylsulfonyl group such as butylsulfonyl group; C2-6 alkenylsulfonyl group such as allylsulfonyl group; C2 such as propargylsulfonyl group A C6-10 arylsulfonyl group such as a phenylsulfonyl group; a heteroarylsulfonyl group such as a thiazolylsulfonyl group or a pyridylsulfonyl group; a C7-11 aralkylsulfonyl group such as a benzylsulfonyl group or a phenethylsulfonyl group;

  5-membered heteroaryl groups such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl; pyridyl, pyrazinyl Groups, 6-membered heteroaryl groups such as pyrimidinyl groups, pyridinidyl groups, triazinyl groups; saturated heterocyclyl groups such as aziridinyl groups, epoxy groups, pyrrolidinyl groups, tetrahydrofuranyl groups, piperidyl groups, piperazinyl groups, morpholinyl groups; trimethylsilyl groups, triethylsilyl groups A tri-C1-6 alkyl-substituted silyl group such as a t-butyldimethylsilyl group; a triphenylsilyl group;

  These “substituents” may be those in which any hydrogen atom in the group is further substituted with another “substituent”.

(X ")
X ″ in formula (I) is a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2 -6 alkynyl group, hydroxyl group, unsubstituted or substituted C1-6 alkoxy group, nitro group, or cyano group.
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.

  Examples of the “halogen atom” in X ″ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

  The “C 1-6 alkyl group” in X ″ may be linear or branched. As the alkyl group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, i-propyl group, i-butyl group, s-butyl group, t-butyl group I-pentyl group, neopentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, i-hexyl group and the like.

  Examples of the “C1-6 alkyl group having a substituent” in X ″ include C3-8 such as cyclopropylmethyl group, 2-cyclopropylethyl group, cyclopentylmethyl group, 2-cyclohexylethyl group, 2-cyclooctylethyl group and the like. Cycloalkyl C1-6 alkyl group; fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, trifluoromethyl group, trichloromethyl group, tribromomethyl group, 2,2,2 -Trifluoroethyl group, 2,2,2-trichloroethyl group, pentafluoroethyl group, 4-fluorobutyl group, 4-chlorobutyl group, 3,3,3-trifluoropropyl group, 2,2,2-tri Fluoro-1-trifluoromethylethyl group, perfluorohexyl group, perchloro A C1-6 haloalkyl group such as a hexyl group or a 2,4,6-trichlorohexyl group;

  Hydroxy C1-6 alkyl groups such as hydroxymethyl group and 2-hydroxyethyl group; methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, methoxy-n-propyl group, n-propoxymethyl group, i-propoxy group C1-6 alkoxy C1-6 alkyl groups such as ethyl group, s-butoxymethyl group, t-butoxyethyl group; methoxymethoxymethyl group, 1-methoxyethoxymethyl group, 2-methoxyethoxymethyl group, 2- (1- C1-6 alkoxy C1-6 alkoxy C1-6 alkyl groups such as methoxyethoxy) ethyl group, 2- (2-methoxyethoxy) ethyl group; dimethoxymethyl group, diethoxymethyl group, 2,2-dimethoxyethyl group, 1 , 2-dimethoxyethyl group, 3,3-dimethoxy n-propyl group, Di-C1-6 alkoxy C1-6 alkyl group such as 2-diethoxyethyl group; formyloxy C1-6 alkyl group such as formyloxymethyl group; acetoxymethyl group, 2-acetoxyethyl group, propionyloxymethyl group, propionyl C1-6 carbonyloxy C1-6 alkyl group such as oxyethyl group; C1-6 alkyl group substituted with imino group such as iminomethyl group, (1-imino) ethyl group, (1-imino) propyl group; hydroxyimino C1-6 alkyl substituted with a hydroxyimino group such as methyl, (1-hydroxyimino) ethyl, (1-hydroxyimino) -n-propyl, methoxyiminomethyl, (1-methoxyimino) ethyl Group; unsubstituted or substituted benzyl group, unsubstituted or C7~11 aralkyl group having unsubstituted or substituted group such as a phenethyl group having a substituent; and the like.

As the “C2-6 alkenyl group” in X ″, a vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl Group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group and the like.
Examples of the “C2-6 alkenyl group having a substituent” in X ″ include C2-6 haloalkenyl groups such as 2-chloro-1-propenyl group and 2-fluoro-1-butenyl group;

Examples of the “C2-6 alkynyl group” in X ″ include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl And a 1,1-dimethyl-2-butynyl group.
Examples of the “substituent C2-6 alkynyl group” in X ″ include C2-6 such as 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group, 5-bromo-2-pentynyl group and the like. A haloalkynyl group; and the like.

As the “C1-6 alkoxy group” in X ″, a methoxy group, an ethoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, an n-pentyloxy group, An i-pentyloxy group, n-hexyloxy group, etc. can be mentioned.
Examples of the “C1-6 alkoxy group having a substituent” in X ″ include a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, Tribromomethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, pentafluoroethoxy group, 4-fluorobutoxy group, 3,3,3-trifluoropropoxy group, 2, C1-6 haloalkoxy groups such as 2,2-trifluoro-1-trifluoromethylethoxy group and perfluorohexyloxy group; methoxymethoxy group, 1-methoxyethoxy group, 2-methoxyethoxy group, ethoxymethoxy group, 1 -Ethoxyethoxy group, 2-ethoxyethoxy group, 1-methyl A C1-6 alkoxy C1-6 alkoxy group such as a toxi-n-propoxy group, 2-methoxy-n-propoxy group, 3-methoxy-n-propoxy group; cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, C3-8 cycloalkyl C1-6 alkoxy groups such as cyclohexylmethoxy group, 2-methylcyclopropylmethoxy group, 2,3-dimethylcyclopropylmethoxy group, 2-cyclopropylethoxy group; benzyloxy group, phenethyloxy group, etc. C7-11 aralkyloxy group; and the like.

  Of these, X ″ is preferably a halogen atom or a C 1-6 haloalkyl group.

(X ')
X ′ in formula (I) is a halogen atom, an unsubstituted or substituted C1-6 alkyl group, an unsubstituted or substituted C2-6 alkenyl group, an unsubstituted or substituted C2 -6 alkynyl group, hydroxyl group, unsubstituted or substituted C1-6 alkoxy group, nitro group, or cyano group.
m represents the number of substitutions of X ′ and is an integer of 0 to 7. When m is 2 or more, X ′ may be the same as or different from each other.

As the “halogen atom”, “C1-6 alkyl group”, “C2-6 alkenyl group”, “C2-6 alkynyl group”, and “C1-6 alkoxy group” in X ′, those mentioned in the above X ″ The same thing can be mentioned.
Of these, X ′ is preferably a hydrogen atom.

(R ¹ )
R ¹ in formula (I) represents a hydrogen atom, a halogen atom, or an unsubstituted or substituted C 1-6 alkyl group.

As the “halogen atom” and “C1-6 alkyl group” in R ¹ , the same groups as those described above for X ″ can be used.
Of these, R ¹ is preferably a C 1-6 haloalkyl group.

(R ² )
R ² in formula (I) is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C 1-6 alkoxy group, a tri C 1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C 1 -6 represents an alkylcarbonyloxy group, an azide group, a succinimide group, a phthalimide group, a formamide group, or an acetylamide group.

As the “halogen atom” and “C1-6 alkoxy group” for R ² , the same groups as those described above for X ″ can be used.
Examples of the “tri C 1-6 alkyl-substituted silyloxy group” in R ² include a trimethylsilyloxy group, a triethylsilyloxy group, a t-butyldimethylsilyloxy group, and the like.

Examples of the “C1-6 alkylcarbonyloxy group” for R ² include C1-6 alkylcarbonyloxy groups such as acetyloxy group and propionyloxy group.
Among these, R ² is preferably an unsubstituted or substituted C 1-6 alkoxy group or a tri C 1-6 alkyl-substituted silyloxy group.

(R ³ )
R ³ in the formula (I) is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group, or tri-C1. -6 represents an alkyl-substituted silyloxy group, an azide group, a succinimide group, a phthalimide group, a formamide group, or an acetylamide group.

As the “halogen atom” and “C1-6 alkoxy group” for R ³ , the same groups as those described above for X ″ can be used.
Examples of the “tri-C 1-6 alkyl-substituted silyloxy group” in R ³ include the same as those mentioned for R ² above.
As the “C 1-6 alkylcarbonyloxy group” for R ³ , the same groups as those described above for R ² can be mentioned.
Of these, R ³ is preferably a hydrogen atom.

(Q)
Q in the formula (I) represents the number of carbon atoms and represents 1 or 2. When q is 1, the fused ring compound of the present invention represents an indane derivative. When q is 2, the fused ring compound of the present invention represents a tetrahydronaphthalene derivative.

p represents the number of substitutions of R ³ and represents 0 or 1.
When p is 1, the bond between carbon atom 1 and carbon atom 2 is a single bond, and when p is 0, the bond between carbon atom 1 and carbon atom 2 is a double bond.
That is, when p is 1, an indane ring or tetrahydronaphthalene ring is formed, and when p is 0, an indene ring or 1,2-dihydronaphthalene ring is formed.

R ² and R ³ together may form an oxo group or an unsubstituted or substituted hydroxyimino group.
Examples of the “hydroxyimino group having a substituent” formed by R ² and R ³ together include C 1-6 alkoxyimino groups such as a methoxyimino group and an ethoxyimino group.

  The condensed ring compound according to the second embodiment of the present invention is a compound represented by the formula (II) (hereinafter sometimes referred to as compound (II)). Compound (II) is a production intermediate of the aforementioned compound (I); or a condensed ring compound represented by formula (VII), a condensed ring compound represented by formula (VIII), or an isoxazoline derivative A It can be a production intermediate of

The meanings of symbols, terms, etc. used in the formula (II) are as follows.
The terms “unsubstituted” and “having a substituent” have the same meaning as in formula (I). X ′, m and q in the formula (II) have the same meaning as X ′, m and q in the formula (I).
When two X ′ are substituted on the same carbon atom, they may be taken together to form an oxo group.

(R ⁴ )
R ⁴ is a halogen atom, a formyl group, a hydroxyiminomethyl group, an N-hydroxy-chlorocarbonimidoyl group, a 1,1-di (C1-6 alkoxy) methyl group [C1-6 alkoxy are bonded together to form a ring 1-C1-6 alkoxyvinyl group, 1-C3-6 cycloalkoxyvinyl group, acetyl group, 2- (C1-6 alkoxy) carbonylacetyl group, 3- (C1-6 alkoxy) A carbonyl-3-oxo-propionyl group or a cyano group is shown.
As the “halogen atom” in R ⁴ , the same ones as mentioned for X ″ can be mentioned.
As the “1,1-di (C1-6 alkoxy) methyl group” in R ⁴ , a 1,1-dimethoxymethyl group, a 1,1-diethoxymethyl group, a [1.3] dioxolan-2-yl group, [1.3] Dioxane-2-yl group and the like can be mentioned.

Examples of the “1-C1-6 alkoxyvinyl group” in R ⁴ include 1-methoxyvinyl group, 1-ethoxyvinyl group, 1-n-propoxyvinyl group, 1-n-butoxyvinyl group and the like.
Examples of the “1-C3-6 cycloalkoxyvinyl group” in R ⁴ include 1-cyclopropoxyvinyl group, 1-cyclobutoxyvinyl group, 1-cyclopentyloxyvinyl group, 1-cyclohexyloxyvinyl group and the like. .

Examples of the “2- (C1-6 alkoxy) carbonylacetyl group” for R ⁴ include a 2-methoxycarbonylacetyl group, a 2-ethoxycarbonylacetyl group, a 2-n-propoxycarbonylacetyl group, and the like.
As the “3- (C 1-6 alkoxy) carbonyl-3-oxo-propionyl group” in R ⁴ , 3-methoxycarbonyl-3-oxo-propionyl group, 3-ethoxycarbonyl-3-oxo-propionyl group, 3- An n-propoxycarbonyl-3-oxo-propionyl group and the like can be mentioned.

(R ²¹ )
R ²¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group. , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
As the “halogen atom” and “C1-6 alkoxy group” for R ²¹ , the same groups as those described above for X ″ can be mentioned.
As the “tri C 1-6 alkyl-substituted silyloxy group” for R ²¹ , the same groups as those described above for R ² can be mentioned.
As the “C 1-6 alkylcarbonyloxy group” for R ²¹ , the same groups as those described above for R ² can be mentioned.

Examples of the “C 1-6 alkylcarbonylamino group” for R ²¹ include acetylamino group, propionylamino group, n-propylcarbonylamino group, i-propylcarbonylamino group and the like.
Examples of the “substituted C1-6 alkylcarbonylamino group” in R ²¹ include a cyclopropylmethylcarbonylamino group, a cyclobutylmethylcarbonylamino group, a cyclopentylmethylcarbonylamino group, a cyclohexylmethylcarbonylamino group, and 2-cyclopropylethyl. C3-8 cycloalkyl C1-6 alkylcarbonylamino group such as carbonylamino group; difluoroacetylcarbonylamino group, dichloroacetylcarbonylamino group, trifluoroacetylamino group, trichloroacetylamino group, 2,2,2-trifluoroethyl A C1-6 haloalkylcarbonylamino group such as a carbonylamino group, 2,2,2-trichloroethylcarbonylamino group, pentafluoroethylcarbonylamino group; A C1-6 alkoxy C1-6 alkylcarbonylamino group such as a cetylamino group, a 2-methoxyethylcarbonylamino group, a 2-methoxy-n-propylcarbonylamino group;
Among these, R ²¹ is preferably an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonylamino group.

(R ³¹ )
R ³¹ is a hydrogen atom, a halogen atom, a hydroxyl group, an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, an unsubstituted or substituted C1-6 alkylcarbonyloxy group , An azido group, an amino group, a succinimide group, a phthalimide group, a formamide group, or an unsubstituted or substituted C1-6 alkylcarbonylamino group.
As the “halogen atom” and “C1-6 alkoxy group” for R ³¹ , the same groups as those described above for X ″ can be mentioned.
Examples of the “tri-C 1-6 alkyl-substituted silyloxy group” for R ³¹ include the same as those described for R ² above.
As the “C 1-6 alkylcarbonyloxy group” for R ³¹ , the same groups as those described above for R ² can be mentioned.
As the “C 1-6 alkylcarbonylamino group” for R ³¹ , the same groups as those described above for R ²¹ can be mentioned.
Of these, R ³¹ is preferably a hydrogen atom.

p ′ represents the number of substitutions of R ³¹ and represents 0 or 1.
When p ′ is 1, the bond between carbon atom 1 and carbon atom 2 is a single bond, and when p ′ is 0, the bond between carbon atom 1 and carbon atom 2 is a double bond. .

R ²¹ and R ³¹ may be combined to form an oxo group, or an unsubstituted or substituted hydroxyimino group. Examples of the “hydroxyimino group having a substituent” formed by R ²¹ and R ³¹ together include the same groups as those described above for R ² and R ³ .

  The fused ring compound according to the third embodiment of the present invention is a compound represented by the formula (VII) (hereinafter sometimes referred to as compound (VII)). Compound (VII) is a substance that can be a production intermediate of the aforementioned compound (I) or a production intermediate such as isoxazoline derivative A.

The meanings of symbols and terms used in formula (VII) are as follows.
The terms “unsubstituted” and “having a substituent” have the same meaning as in formula (I). Also, m in the formula (VII), X ", n , q and ^{R 1,} m, X of formula (I)" is a, n, same as q and ^{R 1} meaning. Formula (VII) in the ^{X ', R 21, R 31} , and p' are ^{X ', R 21, R 31} , and p' the same meanings of formula (II).
The bond represented by the wavy line in the formula (VII) indicates a trans conformation or a cis conformation with respect to R ¹ .

(Z)
Z represents an oxygen atom or a hydroxyimino group.

  The condensed ring compound according to the fourth embodiment of the present invention is a compound represented by the formula (VIII) (hereinafter sometimes referred to as the compound (VIII)). Compound (VIII) is a substance that can be a production intermediate of the production intermediate of the aforementioned compound (VII).

The meanings of symbols, terms, etc. used in formula (VIII) are as follows.
The terms “unsubstituted” and “having a substituent” have the same meaning as in formula (I). Also, m in the formula (VIII), X ", n , q, and ^{R 1,} m, X of formula (I)" is, n, q, and ^{R 1} means the same. Formula (VIII) in the ^{X ', R 21, R 31} , and p' are ^{X ', R 21, R 31} , and p' the same meanings of formula (II).

[Use as production intermediate]
The condensed ring compound represented by the formula (I) or the formula (II) of the present invention is a useful substance that can be a production intermediate of the isoxazoline derivative represented by the formula (III).

X ″, n, R ¹ , X ′, m, and q in the formula (III) have the same meaning as in formula (I) or (II).
R ^X and R ^y can each independently represent a hydrogen atom or an unsubstituted or substituted C 1-6 alkylcarbonyl group.

  As an embodiment of the present invention, an example of a production flow from a condensed ring compound represented by formula (1), formula (2), formula (3), formula (9), etc. to an isoxazoline derivative (A ′) Indicates.

In the following production flows, Ph in the formula represents an unsubstituted or substituted phenyl group.
R ¹ in the expression of each of the following production flow represent the same as those of R ¹ in the formula (I).
Q in the formulas in the following production flows represents the number of carbon atoms and represents 1 or 2.
^{R a} in the expression of each of the following production flow indicates Cl to 6 alkyl, Cl to 6 alkoxy Cl to 6 alkyl group, a protecting group such as tri-substituted silyl group.
R in the formulas in the following production flows represents a C1-6 alkyl group which may be unsubstituted or may have a substituent.
R ^b in the following formula (2) represents a hydrogen atom, a C1-6 alkyl group, or the like.
X in the following formula (6) represents a halogen atom.
R < ^c > in following formula (7) shows a hydrogen atom, a C1-6 alkyl group, and a C6-10 aryl group each independently. Here, R ^c together may form an ethylene group or a phenylene group.
The term “unsubstituted” and the term “having a substituent” are the same as in the formula (I).

  In the first production route, a compound represented by formula (9) and a compound represented by formula (10) are converted into a 2 + 3 cyclization reaction (reaction) described in Patent Document 1 (for example, see page 28, paragraph 0085). m) to be condensed into an isoxazoline derivative (A ′). Here, the 2 + 3 cyclization reaction means a cycloaddition reaction (1,3-dipole addition reaction) between a 1,3-dipole and a double bond. As the nitrile oxide derived from the compound (9) becomes a 1,3-dipole, the addition reaction proceeds with respect to the double bond of the compound (10), and an isoxazoline ring can be constructed.

  In the second production route, the compound represented by the formula (3) is represented by the formula (6) by the halogenation method (reaction e) described in Patent Document 3 (for example, see page 48, paragraph 0074). A general halogen atom amination method described in Patent Document 3 (see, for example, page 46, paragraph 0068 and page 47, paragraph 0069) of the compound represented by formula (6) by derivatization into a compound (see, for example, The compound represented by formula (8) is derived by reaction h), and finally the compound represented by formula (8) is derived into isoxazoline derivative (A ′) by general acylation (reaction k). To do.

Induction to the compound represented by the formula (8), which is an intermediate of the second production route, can also be performed by another method.
The compound represented by formula (6), which is an intermediate, is derived into a compound represented by formula (7) by phthalimidation (reaction i), and then the compound represented by formula (7) is patented. The compound can be derived into the compound represented by the formula (8) by the deprotection method (reaction j) described in Reference 2 (for example, see page 126, Step 6).

The compound represented by formula (6), which is a production intermediate of the compound represented by formula (8), can also be derived from the compound represented by formula (1) or the compound represented by formula (2).
The compound represented by the formula (1) is deprotected (reaction a) by a conventional method to be derived into the compound represented by the formula (4), and the compound represented by the formula (4) is converted into a general halogen of a hydroxyl group. The compound represented by formula (6) can be derived by the chemical method (reaction f).
Moreover, the compound represented by Formula (2) is induced | guided | derived to the compound represented by Formula (5) on acidic conditions (reaction b), and the compound represented by Formula (5) is patent document 2 (for example, The compound is represented by the general reduction method (reaction d) described in page 126, step 5) to the compound represented by formula (4) and represented by formula (6) by the same method (reaction f) as described above. Can be derived into the resulting compound.

The compound represented by the formula (8) can be derived from the compound represented by the formula (1) or the compound represented by the formula (2) through other production routes.
The compound represented by the formula (1) is deprotected (reaction a) by a conventional method to induce the compound represented by the formula (4), and the compound represented by the formula (4) is converted into a general oxidation method ( The compound represented by formula (5) is derived by reaction c), and the compound represented by formula (5) is represented by formula (8) by reductive amination of the carbonyl group or the like (reaction g). Can be derived into a compound.
In addition, the compound represented by formula (2) is induced to the compound represented by formula (5) under acidic conditions (reaction b), and the compound represented by formula (5) is converted into the same method (reaction as described above). The compound represented by formula (8) can be derived by g).

  The third production route is that the compound represented by the formula (1) or the compound represented by the formula (4) is subjected to the formula: RC≡N (wherein R is unsubstituted or A C1-6 alkyl group which may have a substituent.) Is reacted with an alkyl cyanide compound represented by formula (A ′) to induce a compound represented by the formula (A ′). A so-called liter reaction (reaction p) can be used.

The compound represented by the formula (1) includes a compound represented by the formula (11) and a compound represented by the formula (10) in the 2 + 3 ring described in Patent Document 1 (for example, see page 28, paragraph 0085). It can be induced by condensation by a crystallization reaction (reaction m ′).
In addition, the compound represented by the formula (1) is prepared by adding a hydroxyamine to the compound represented by the formula (14) in the presence of a base in Patent Document 3 (for example, refer to page 70, paragraph 0091). It can be induced by condensation by reaction o).
The compound represented by formula (14) is obtained by converting the compound represented by formula (12) and the compound represented by formula (13) into a method described in Patent Document 3 (for example, see page 70, paragraph 0091) ( It can be induced by condensation by reaction n).

  The fourth production route is that the compound represented by the formula (14) is subjected to the formula: RC≡N (wherein R is unsubstituted or may have a substituent) under acidic conditions. And an alkyl cyanide compound represented by formula (15) to induce a compound represented by formula (15). Further, hydroxyamine can be condensed in the presence of a base by a method (reaction r) described in Patent Document 3 (for example, see page 70, paragraph 0091) to obtain a compound represented by the formula (A ′). it can. In addition, in the formula (14) and the formula (15), the bond represented by the wavy line indicates a trans conformation or a cis conformation with respect to Ph.

In the formula, ^{R e} represents a C1~6 alkyl group.
R ^d represents OR ^a or NHCOR.
The bond represented by the wavy line indicates a trans or cis conformation with respect to Ph.

The compound represented by Formula (14) or the compound represented by Formula (15) (the compound represented by Formula (18)) is the compound represented by Formula (17) or Formula (19). It can be derived from the compound represented.
Specifically, the compound represented by the formula (18) is dehydrated from the compound represented by the formula (17) using acetic anhydride, thionyl chloride or the like in the presence of a base such as pyridine or DMAP. (Reaction t). In addition, the compound represented by Formula (17) includes a compound represented by Formula (16) and a compound represented by Formula (13) described in Non-Patent Document 2 (for example, page 4161) in a weak alkaline aqueous solution. , See scheme 2) and can be induced by condensation by the method (reaction s).
In addition, the compound represented by the formula (18) includes the compound represented by the formula (19) and the compound represented by the formula (13) described in Non-Patent Document 1 (for example, see page 4692, scheme). It can also be induced by condensation by the method (reaction u).

Of the compounds represented by the formula (13), compounds represented by the following formula (22) (in the formula (22), X ″ and n have the same meaning as in the formula (I). ) Can be induced by the method described in Non-Patent Document 3 (for example, see page 2874, scheme 2).
Specifically, in the presence of a catalyst such as tetra-n-butylammonium fluoride or cesium fluoride, a compound represented by the following formula (20) (in the formula (20), X ″ and n are R ^a1 represents a C1-6 alkyl group) and trifluoromethyltrimethylsilane, and the compound represented by the following formula (21) (in formula (21), X ″ , N and R ^a1 have the same meaning as above. Next, the resulting silyl ether can be cleaved by a hydrolysis reaction to be derived into a compound represented by the formula (22).

  In addition, as a compound represented by Formula (21), the following compounds can be illustrated.

Among the condensed ring compounds represented by formula (II), in the indane derivative, the indane ring itself can be constructed by the following method.
The amino group of the β-phenyl-β-alanine derivative represented by the following formula (IV) is protected with a protecting group to obtain a compound represented by the following formula (V), and this compound is Friedel-Crafts acylated By doing, the compound represented by the following formula (VI) can be obtained. Furthermore, the compound represented by the following formula (VI) can remove an oxo group by a known method.

(In formula (IV), Y ′ has the same meaning as R ^{4 in} formula (II), preferably a halogen atom.)

(In formula (V), A represents an R ⁵ CO— group. R ⁵ represents a hydrogen atom or an alkyl group (preferably a C1-6 alkyl group), etc. Y ′ has the same meaning as described above.)

(In formula (VI), A and Y ′ have the same meaning as described above.)

[Litter reaction]
The manufacturing method according to the fifth embodiment of the present invention uses a liter reaction as a key reaction.
That is, an aromatic hydrocarbon having an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, or an unsubstituted or substituted C1-6 alkylcarbonyloxy group at the allylic position A condensed ring compound of a ring and an aliphatic hydrocarbon ring and an unsubstituted or substituted C1-6 alkyl cyanide compound are reacted in the presence of a protonic acid or a Lewis acid, and the allylic position is substituted or This is a method for producing a condensed ring compound of an aromatic hydrocarbon ring having a C1-6 alkylcarbonylamino group having a substituent and an aliphatic hydrocarbon ring.

(Fused ring compound)
The compound used as a starting material for this reaction is “a C1-6 alkoxy group which is unsubstituted or substituted at the allylic position, a triC1-6 alkyl-substituted silyloxy group, or a C1-6 alkylcarbonyl which is unsubstituted or has a substituent. “A condensed ring compound of an aromatic hydrocarbon ring having an oxy group and an aliphatic hydrocarbon ring”.
Examples of the “C1-6 alkoxy group” include the same groups as those described above for X ″.
Examples of the “tri-C1-6 alkyl-substituted silyloxy group” and “C1-6 alkylcarbonyloxy group” include the same as those mentioned for R ² above.
Of these, C1-6 alkoxy groups are preferred.

"A condensed ring compound of an aromatic hydrocarbon ring and an aliphatic hydrocarbon ring" includes an aromatic hydrocarbon ring such as a benzene ring and a naphthalene ring, and an aliphatic carbon ring such as a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring. A condensed ring compound with a hydrogen ring can be raised.
Of these, an indane ring or a tetrahydronaphthalene ring is preferred.

That is, the condensed ring compound used as a raw material for this reaction includes “a C1-6 alkoxy group that is unsubstituted or substituted at the allylic position, a tri C1-6 alkyl-substituted silyloxy group, or an unsubstituted or substituted group. “Indane derivatives or tetrahydronaphthalene derivatives having a C1-6 alkylcarbonyloxy group” are preferred.
Examples of the “C1-6 alkoxy group” include the same groups as those described above for X ″.
Examples of the “tri-C1-6 alkyl-substituted silyloxy group” and “C1-6 alkylcarbonyloxy group” include the same as those mentioned for R ² above.
Of these, indane derivatives or tetrahydronaphthalene derivatives having a C1-6 alkoxy group at the allylic position are particularly preferred.

The target compound of this reaction is “a condensed ring compound of an aromatic hydrocarbon ring having an unsubstituted or substituted C1-6 alkylcarbonylamino group at the allylic position and an aliphatic hydrocarbon ring”. And “an indane derivative or a tetrahydronaphthalene derivative having a C1-6 alkylcarbonylamino group which is unsubstituted or has a substituent at the allylic position”.
As the “C 1-6 alkylcarbonylamino group”, the same groups as those described above for R ²¹ can be mentioned.
Examples of the “substituted C1-6 alkylcarbonylamino group” include a cyclopropylmethylcarbonylamino group, a cyclobutylmethylcarbonylamino group, a cyclopentylmethylcarbonylamino group, a cyclohexylmethylcarbonylamino group, and a 2-cyclopropylethylcarbonylamino group. C3-8 cycloalkyl C1-6 alkylcarbonylamino group such as: difluoroacetylcarbonylamino group, dichloroacetylcarbonylamino group, trifluoroacetylamino group, trichloroacetylamino group, 2,2,2-trifluoroethylcarbonylamino group , 2,2,2-trichloroethylcarbonylamino group, C1-6 haloalkylcarbonylamino group such as pentafluoroethylcarbonylamino group; methoxyacetylamino group 2-methoxyethyl carbonyl amino group, Cl to 6 alkoxy Cl to 6 alkyl carbonyl amino group such as 2-methoxy -n- propyl carbonyl amino group; and the like.

(Alkyl cyanide compounds)
As the “C 1-6 alkyl group”, the same groups as those described above for X ″ can be mentioned.
Examples of the “substituted C1-6 alkyl group” include a C3-8 cycloalkyl C1-6 alkyl group such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a 2-cyclopropylethyl group. A C1-6 haloalkyl group such as a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a pentafluoroethyl group; A C1-6 alkoxy C1-6 alkyl group such as a methoxymethyl group, 2-methoxyethyl group, 2-methoxy-n-propyl group;

(Protic acid or Lewis acid)
Examples of the protonic acid include sulfuric acid, fuming sulfuric acid, sulfan, benzoic acid, acetic acid, formic acid, phosphoric acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic acid, cation exchange resin, and the like. be able to.

Protic acids may be used alone or in combination of two or more. These may be used in catalytic amounts or in stoichiometric amounts. In the case of a solution-like proton acid, the amount of solvent may be used.
The catalyst amount means that the amount of reagent used is small relative to the raw material for the reaction, and in terms of a numerical value, it means 1/10 to 1/100 equivalent. On the other hand, the stoichiometric amount means a case where the necessary amount of the reagent is speculatively equivalent or more than the reaction raw material.

As Lewis acid,
Metal trifluoromethanesulfonates such as mercury triflate, mercury sulfate, silver triflate, copper triflate, iron triflate, zinc triflate, indium triflate, scandium triflate;
Metal tetrafluoroborate salts such as silver tetrafluoroborate;
Metal perchlorates such as silver perchlorate;
Metal SbF ₆ salts such as silver hexafluoroantimonate;
Metal nitrates such as silver nitrate;
Metal sulfates such as silver sulfate; and the like.

A Lewis acid may be used independently or may be used in mixture of 2 or more types. These may be used in catalytic amounts or in stoichiometric amounts.
When a Lewis acid is used, a reaction accelerator may be added. Examples of the reaction accelerator include the above protonic acids.

In the production, a solvent can be used or no solvent can be used. The cyanide compound may be used as a solvent.
The solvent that can be used for production is not particularly limited as long as the reaction is not inhibited.
Halogenated hydrocarbons such as methylene chloride, chloroform, chlorobenzene;
Ketones such as acetone and MIBK;
Esters such as ethyl acetate;
Ether solvents such as tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether (CPME), t-butyl methyl ether (MTBE);
Hydrocarbon solvents such as toluene, heptane, hexane, cyclohexane;
Aprotic solvents such as DMF, DMSO, HMPA, NMP, DMI;
Alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol, ethylene glycol monomethyl ether;
Ionic liquids such as 1-ethyl-3-methylimidazolium tetrafluoroborate;
Water; and the like.
These solvents can be used alone or in combination of two or more. The amount of the solvent (L) is preferably 1.0 to 100 times, more preferably 3 to 3 times the volume (L) / weight (kg) with respect to the condensed ring compound (kg) used as the raw material for the liter reaction. 30 times.

  The reaction is carried out by stirring and is carried out at an appropriate temperature from the melting point to the boiling point of the solvent, preferably -20 ° C to 180 ° C. Preferably it is -20 degreeC-140 degreeC. Although reaction time can be set suitably according to reaction rate, Preferably it is 3 to 50 hours, More preferably, it is 6 to 24 hours.

A suitable reaction system can be selected as appropriate.
All the reagents to be used can be mixed and reacted at one time. Moreover, it can also be made to react by dripping a protonic acid, a Lewis acid, etc. (It may dilute to a suitable solvent) in the reaction system containing another reagent. In addition, the condensed ring compound as a raw material for the liter reaction and a protonic acid, a Lewis acid or the like (which may be diluted in an appropriate solvent) may be simultaneously dropped into the reaction system.
The reaction system can be under a nitrogen atmosphere. Moreover, it can carry out also on recirculation | reflux conditions and pressurization conditions.
When the reaction is performed under anhydrous conditions, degassing under reduced pressure and the use of a dehydrating solvent can be performed.

  The production method according to the sixth embodiment of the present invention is a method for producing a condensed ring compound represented by the formula (XI) using the liter reaction.

In the formula (XI), X ″, n, X ′, m, R ¹ and q have the same meaning as in the formula (I).
R ²³ represents an unsubstituted or substituted C 1-6 alkyl group.
In R ²³ , examples of the “C 1-6 alkyl group” include the same groups as those described above for X ″.
Examples of the “substituted C1-6 alkyl group” include a C3-8 cycloalkyl C1-6 alkyl group such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a 2-cyclopropylethyl group. A C1-6 haloalkyl group such as a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a pentafluoroethyl group; A C1-6 alkoxy C1-6 alkyl group such as a methoxymethyl group, 2-methoxyethyl group, 2-methoxy-n-propyl group;

  The raw material used in the production method of the present invention is a condensed ring compound represented by the following formula (X).

In formula (X), X ″, n, X ′, m, R ¹ , and q have the same meaning as in formula (XI).
R ²² represents an unsubstituted or substituted C1-6 alkoxy group, a tri-C1-6 alkyl-substituted silyloxy group, or an unsubstituted or substituted C1-6 alkylcarbonyloxy group.

Examples of the “C1-6 alkoxy group” include the same groups as those described above for X ″.
Examples of the “tri-C1-6 alkyl-substituted silyloxy group” and “C1-6 alkylcarbonyloxy group” include the same as those mentioned for R ² above.
Of these, C1-6 alkoxy groups are preferred.

  The production method according to the seventh embodiment of the present invention is a method for producing a condensed ring compound represented by the formula (XIII) using the liter reaction.

In formula (XIII), X ″, n, X ′, m, R ¹ , q, and R ²³ have the same meaning as in formula (XI).
Z represents an oxygen atom or a hydroxyimino group.
The bond represented by the wavy line indicates a trans conformation or cis conformation with respect to R ¹ .

  The raw material used in the production method of the present invention is a condensed ring compound represented by the formula (XII).

In formula (XII), X ″, n, X ′, m, R ¹ , q, and R ²² have the same meanings as in formula (X).
Z and the bond represented by the wavy line have the same meaning as in the formula (XIII).

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the examples.
First, Table 1 shows production examples of the condensed ring compound represented by the formula (I).

  Further, Table 2 shows production examples of the condensed ring compound represented by the formula (II) which is a raw material of the condensed ring compound represented by the formula (I).

  Furthermore, Table 3 shows production examples of the condensed ring compound represented by the formula (VII).

  Further, Table 4 shows production examples of the condensed ring compound represented by the formula (VIII).

Next, production examples of some of the above compounds will be shown and described in more detail.
Production Example (Example 1)
Synthesis of 1- (methoxymethoxy) -2,3-dihydro-1H-indene-5-carbaldehyde oxime [1- (methoxymethoxy) -2,3-dihydro-1H-indene-5-carbaldehyde oxime] 7.24 g (35.1 mmol) of (methoxy) -2,3-dihydro-1H-indene-5-carbaldehyde [1- (methoxymethoxy) -2,3-dihydro-1H-indene-5-carbaldehyde] in 130 ml of dioxane and Dissolved in 20 ml of water. To this, 2.68 g (38.6 mmol) of hydroxylammonium chloride and 2.08 g (19.7 mmol) of sodium carbonate were added and reacted at room temperature for 2 hours. After completion of the reaction, dioxane was distilled off, water was added, and then extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off. 7.65 g (34.8 mmol, 99% yield) of 1- (methoxymethoxy) -2,3-dihydro-1H-indene-5-carbaldehyde oxime was obtained. Used in the reaction of Example 2 without further purification.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.13 (s, 1H), 7.58 (br, 1H), 7.39-7.49 (m, 3H), 5.13 (dd, 1H), 4.80 (s, 2H), 3.45 (s, 3H), 3.03-3.13 (m, 1H), 2.78-2.88 (m, 1H), 2.38-2.49 (m, 1H), 2.06-2.17 (m, 1H).

Moreover, the NMR analysis result of 1- (methoxymethoxy) -2,3-dihydro-1H-indene-5-carbaldehyde as a raw material was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.0 (s, 1H), 7.77-7.74 (m, 2H), 7.54 (d, 1H), 5.16 (t, 1H), 4.81 (s, 2H), 3.47 (s, 3H), 3.17-3.07 (m, 1H), 2.93-2.83 (m, 1H), 2.55-2.44 (m, 1H), 2.19-2.07 (m, 1H).

(Example 2)
3- (1- (methoxymethoxy) -2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5- Dihydroisoxazole (3- (1- (methoxymethoxy) -2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole ]

1- (methoxymethoxy) -2,3-dihydro-1H-indene-5-carbaldehyde oxime [1- (methoxymethoxy) -2,3-dihydro-1H-indene-
5-carbaldehyde oxime] 3.80 g (17.2 mmol) was dissolved in 60 ml of N, N-dimethylformamide. To this, 2.29 g (17.2 mmol) of N-chlorosuccinimide was added and reacted at 40 ° C. for 1 hour. Subsequently, the reaction solution was cooled to 5 ° C., and 1- (trifluoromethyl) -3- (3,3,3-trifluoroprop-1-en-2-yl) benzene [1- (trifluoromethyl) -3- 5.23 g (20.6 mmol) of (3,3,3-trifluoroprop-1-en-2-yl) benzene] and 2.08 g (20.6 mmol) of triethylamine were added and reacted at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography. 3- (1- (methoxymethoxy) -2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5- 7.26 g (15.8 mmol, 92% yield) of dihydroisoxazole was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.87-7.81 (m, 2H), 7.69 (d, 1H), 7.52-7.61 (m, 3H), 7.49 (d, 1H), 5.13 (t, 1H ), 4.78 (s, 2H), 4.13 (d, 1H), 3.75 (d, 1H), 3.44 (s, 3H), 3.03-3.08 (m, 1H), 2.81-2.86 (m, 1H), 2.41- 2.49 (m, 1H), 2.04 -2.16 (m, 1H).

Example 3
5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-ol Synthesis of [5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-ol]

  3- (1- (methoxymethoxy) -2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5- Dihydroisoxazole 3.00 g (6.53 mmol) was dissolved in 20 ml of dioxane. To this, 14.5 ml of 2% hydrochloric acid was added and reacted at 40 ° C. for 7 hours and then at 60 ° C. for 51 hours. After completion of the reaction, dioxane was distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography. 5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-ol 2.24 g (5.39 mmol, 83% yield) was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.81-7.87 (m, 2H), 7.69 (d, 1H), 7.53 -7.61 (m, 3H), 7.49 (d, 1H), 5.26 (t, 1H ), 4.14 (d, 1H), 3.75 (d, 1H), 3.02-3.07 (m, 1H), 2.81-2.89 (m, 1H), 2.49 -2.60 (m, 1H), 1.91-2.01 (m, 1H ).

Example 4
3- (1-Bromo-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole Synthesis of [3- (1-bromo-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole]

  5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-ol 0.21 g (0.51 mmol) was dissolved in 1.5 ml of methylene chloride and cooled to 5 ° C. To this, 0.51 g (0.76 mmol) of phosphorus tribromide was added and reacted at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water and extracted with methylene chloride. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off. 3- (1-Bromo-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole 0.21 g (0.44 mmol, yield 87%) was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.81-7.87 (m, 2H), 7.70 (d, 1H), 7.53-7.61 (m, 3H), 7.47 (d, 1H), 5.54 (dd, 1H ), 4.14 (d, 1H), 3.74 (d, 1H), 3.16-3.26 (m, 1H), 2.88-2.95 (m, 1H), 2.49-2.69 (m, 2H).

(Example 5)
3- (1-Chloro-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole Synthesis of [3- (1-cholro-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole]

  5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-ol 0.30 g (0.72 mmol) was dissolved in 1.4 ml of methylene chloride and cooled to 5 ° C. To this, 0.094 g (0.79 mmol) of thionyl chloride was added and reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with methylene chloride. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off. 3- (1-Chloro-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole 0.27 g (0.62 mmol, 86% yield) was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.81-7.87 (m, 2H), 7.70 (d, 1H), 7.54-7.61 (m, 3H), 7.48 (d, 1H), 5.40 (dd, 1H ), 4.19 (d, 1H), 3.74 (d, 1H), 3.16-3.26 (m, 1H), 2.88-2.98 (m, 1H), 2.70-2.58 (m, 1H), 2.46-2.36 (m, 1H ).

(Example 6)
2- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-indene- 1-yl) isoindoline-1,3-dione [2- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3 -dihydro-1H-inden-1-yl) isoindoline-1,3-dione]

  3- (1-Chloro-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole 0.42 g (0.97 mmol) was dissolved in 2 ml of N, N-dimethylformamide. To this, 0.31 g (1.65 mmol) of potassium phthalimide was added and reacted at 80 ° C. for 1.5 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography. 2- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-indene- 0.37 g (0.69 mmol, 71% yield) of 1-yl) isoindoline-1,3-dione was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.41-7.86 (m, 11H), 5.87 (dd, 1H), 4.11 (d, 1H), 3.72 (d, 1H), 3.30-3.41 (m, 1H ), 2.92-3.07 (m, 1H), 2.42-2.63 (m, 2H).

The following compounds were synthesized by the same method as described above.
1- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-indene- 1-yl) pyrrolidine-2,5-dione [1- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3- dihydro-1H-inden-1-yl) pyrrolidine-2,5-dione)
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.85 (s, 1H), 7.40 -7.85 (m, 5H), 7.06 (d, 1H), 5.71 (dd, 1H), 4.08-4.18 (m, 1H ), 3.68-3.75 (m, 1H), 3.22-3.38 (m, 1H), 2.85-3.00 (m, 1H), 2.60-2.80 (m, 4H), 2.28-2.52 (m, 2H),

(Example 7)
Synthesis of 1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde oxime [1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde oxime]

  7.02 g (40 mmol) of 1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde [1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde] in 120 ml of dioxane and 25 ml of water Dissolved. To this, 3.34 g (48 mmol) of hydroxylammonium chloride and 2.54 g (24 mmol) of sodium carbonate were added and reacted at room temperature for 2 hours. After completion of the reaction, dioxane was distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off. 7.84 g (34.8 mmol, 100% yield) of 1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde oxime was obtained. Used in the reaction of Example 8 without further purification.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.13 (s, 1H), 7.79 (br, 1H), 7.39-7.48 (m, 3H), 4.82 (dd, 1H), 3.42 (s, 3H), 3.03-3.13 (m, 1H), 2.77-2.87 (m, 1H), 2.31-2.43 (m, 1H), 2.06-2.15 (m, 1H).

The NMR analysis results of the raw material 1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde [1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde] are as follows. Met.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.0 (s, 1H), 7.76-7.73 (m, 2H), 7.54 (d, 1H), 4.84 (dd, 1H), 3.45 (s, 3H), 3.17-3.07 (m, 1H), 2.93-2.82 (m, 1H), 2.48-2.37 (m, 1H), 2.17-2.06 (m, 1H).

(Example 8)
3- (1-Methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole Synthesis of [3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole]

  1.91 g (10 mmol) of 1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde oxime was dissolved in 36 ml of N, N-dimethylformamide. To this, 1.34 g (10 mmol) of N-chlorosuccinimide was added and reacted at 40 ° C. for 1 hour. Subsequently, the reaction solution was cooled to 5 ° C., 2.88 g (12 mmol) of 1- (trifluoromethyl) -3- (3,3,3-trifluoroprop-1-en-2-yl) benzene and triethylamine 1 .21 g (12 mmol) was added and reacted at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography. 3- (1-Methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole 3.75 g (8.7 mmol, 87% yield) was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.81-7.87 (m, 2H), 7.69 (d, 1H), 7.50-7.61 (m, 3H), 7.44 (d, 1H), 4.82 (dd, 1H ), 4.14 (d, 1H), 3.74 (d, 1H), 3.42 (s, 3H), 3.03-3.30 (m, 1H), 2.60-2.88 (m, 1H), 2.33-2.45 (m, 1H), 2.05-2.14 (m, 1H).

  Further, N-hydroxy-1-methoxy-2,3-dihydro-1H-indene-5-carbimidoyl chloride produced in the reaction system [N-hydroxy-1-methoxy-2,3-dihydro-1H-indene -5-carbimidoyl chloride] can be synthesized by the following method.

  382 mg (2.0 mmol) of 1- (methoxyimino) -2,3-dihydro-1H-indene-5-carbaldehyde oxime [1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde oxime] , N-dimethylformamide was dissolved in 7.2 ml. 267 mg (2.0 mmol) of N-chlorosuccinimide was added to the solution and stirred at 40 ° C. for 1 hour. Subsequently, the reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The extract was washed 3 times with water and then with saturated brine. Then, it was made to dry with magnesium sulfate, the solvent was distilled off, and 450 mg (2.0 mmol, yield 100%) of N-hydroxy-1-methoxy-2,3-dihydro-1H-indene-5-carbimidoyl chloride was obtained. Obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.28 (s, 1H), 7.71-7.69 (m, 2H), 7.43-7.41 (d, 1H), 4.85 (dd, 1H), 3.43 (S, 3H ), 3.10-3.07 (m, 1H), 2.88-2.83 (m, 1H), 2.41-2.34 (m, 1H), 2.16-2.10 (m, 1H).

In the same manner as described above, 3- [1- (t-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl] -5-trifluoromethyl-5- (3-trifluoromethyl -Phenyl) -4,5-dihydroisoxazole [3- [1-((tert-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl] -5-trifluoromethyl-5- (3-trifluoromethyl- phenyl) -4,5-dihydroisoxazole] was synthesized.
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.89 (1H, s, Ar-H), 7.82 (1H, d, Ar-H), 7.68 (1H, d, Ar-H), 7.51-7.60 ( 3H, m, Ar-H), 7.34 (1H, d, Ar-H), 5.25 (1H, t, O-CH), 4.15 (1H, dd, N = C-CH2), 3.75 (1H, dd, N = C-CH2), 2.72-3.06 (2H, m, Ar-CH2), 2.40-2.51 (1H, m, O-CH-CH2), 1.90-2.00 (1H, m, O-CH-CH2), 0.95 (9H, s, tBu), 0.17 (6H, d, SiCH3).

The starting material 1- (tert-butyldimethylsilyloxy) -2,3-dihydro-1H-indene-5-carbaldehyde oxime [1- (tert-butyldimethylsilyloxy) -2,3-dihydro-1H-indene- The NMR analysis results of 5-carbaldehyde oxime] were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.98 (s, 1H), 8.15 (s, 1H), 7.30-7.45 (m, 3H), 5.25 (t, 1H), 2.93-3.03 (m, 1H ), 2.72-2.83 (m, 1H), 2.40-2.49 (m, 1H), 1.88-2.00 (m, 1H), 0.96 (s, 9H), 0.17 (d, 6H).

Example 9
5- (3,5-dichlorophenyl) -3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -4,5-dihydroisoxazole [5- Synthesis of (3,5-dichlorophenyl) -3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -4,5-dihydroisoxazole]

The flask was charged with 5 ml of methylene chloride, 14.89 g (10 mmol) of 5% sodium hypochlorite, and 1,3-dichloro-5- (3,3,3-trifluoroprop-1-en-2-yl) benzene [ 1,3-dichloro-5- (3,3,3-trifluoroprop-1-en-2-yl) benzene] 2.89 g (12 mmol) was charged, and the internal temperature was adjusted to 15 ° C. A solution prepared by dissolving 1.91 g (10 mmol) of 1-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde oxime in 10 ml of methylene chloride over 15 hours was adjusted to an internal temperature of 15 to The solution was added dropwise while maintaining 20 ° C. After completion of dropping, the mixture was further stirred for 2 hours at an internal temperature of 20 ° C. After completion of the reaction, the lower layer of methylene chloride was separated, the product was further extracted from the aqueous layer with methylene chloride, and the organic layers were combined. The organic layer was washed with water, 5% sodium thiosulfate, water and saturated brine, dried over magnesium sulfate, and then the solvent was distilled off to purify the resulting crude product by silica gel column chromatography. .59 g (8.3 mmol, 83% yield) of 5- (3,5-dichlorophenyl) -3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoro Methyl) -4,5-dihydroisoxazole was obtained.
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.57 (d, 1H), 7.52-7.49 (m, 3H), 7.45 (s, 1H), 7.43-7.41 (m, 2H), 4.83 (dd, 1H ), 4.09 (d, 1H), 3.70 (d, 1H), 3.42 (s, 3H), 3.10-3.04 (m, 1H), 2.82-2.81 (m, 1H), 2.43-2.34 (m, 1H), 2.13-2.05 (m, 1H).

(Example 10)
5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one O-methyl oxime [5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one O -methyl oxime] (Step 1) 1- (methoxyimino) -2,3-dihydro-1H-indene-5-carbaldehyde oxime [1- (methoxyimino) -2,3-dihydro-1H-indene-5 -carbaldehyde oxime)

  1- (methoxyimino) -2,3-dihydro-1H-indene-5-carbaldehyde [1- (methoxyimino) -2,3-dihydro-1H-indene-5-carbaldehyde] 74.03 g (393 mmol) was added to dioxane. Dissolved in 590 ml and 275 ml of water. To this, 32.77 g (472 mmol) of hydroxylammonium chloride and 24.99 g (236 mmol) of sodium carbonate were added and reacted at room temperature for 2 hours. After completion of the reaction, dioxane was distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off. 80.30 g (393 mmol, 100% yield) of 1- (methoxyimino) -2,3-dihydro-1H-indene-5-carbaldehyde oxime was obtained. Used in the reaction of Example 10 without further purification.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35-8.13 (m, 4H), 4.01 (s, 3H), 2.96-3.09 (m, 2H), 2.86-2.93 (m, 2H).

(Step 2) 5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-indene -1-one O-methyl oxime [5- (5-
Synthesis of (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one O-methyl oxime]

  1- (Methoxyimino) -2,3-dihydro-1H-indene-5-carbaldehyde 2.72 g (13.3 mmol) of oxime was dissolved in 48 ml of N, N-dimethylformamide and cooled to 5 ° C. To this, 1.78 g (13.3 mmol) of N-chlorosuccinimide was added and reacted at room temperature for 1.5 hours. Subsequently, the reaction solution was cooled to 5 ° C., 4.21 g (17.6 mmol) of 1- (trifluoromethyl) -3- (3,3,3-trifluoroprop-1-en-2-yl) benzene and 1.61 g (16.0 mmol) of triethylamine was added and reacted at 5 ° C. for 4 hours and then at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography. 5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one 5.12 g (11.6 mmol, yield 87%) of O-methyloxime was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.54-7.87 (m, 7H), 4.10 (d, 1H), 4.01 (s, 3H), 3.76 (d, 1H), 3.02-3.14 (m, 2H ), 2.87-2.96 (m, 2H).

(Example 11)
5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one Synthesis of [5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one]

  5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one 1.77 g (4.0 mmol) of O-methyloxime was dissolved in 6 ml of dioxane and 6 ml of acetone. To this, 6 ml of 6N hydrochloric acid was added and refluxed for 3 hours. After completion of the reaction, dioxane and acetone were distilled off, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography. 5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-one 1.50 g (3.64 mmol, 91% yield) was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.58-7.87 (m, 7H), 4.18 (d, 1H), 3.79 (d, 1H), 3.17-3.21 (m, 2H), 2.73-2.77 (m , 2H).

(Example 12)
N-hydroxy-1- (3-methoxypropanamide) -2,3-dihydro-1H-indene-5-carboimidoyl chloride [N-hydroxy-1- (3-
Synthesis of (methoxypropanamido) -2,3-dihydro-1H-indene-5-carbimidoyl chloride)

  N- (5-((hydroxyimino) methyl) -2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide [N- (5-((hydroxyimino) methyl) -2,3- dihydro-1H-inden-1-yl) -3-methoxypropanamide] 0.30 g (1.14 mmol) was dissolved in 4.1 ml of N, N-dimethylformamide. N-chlorosuccinimide 0.15g (1.14mmol) was added to this, and it was made to react at 45 degreeC for 1.5 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography. 0.16 g (0.54 mmol, 47% yield) of N-hydroxy-1- (3-methoxypropanamide) -2,3-dihydro-1H-indene-5-carboimidoyl chloride was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.70 (m, 1H), 7.26-7.38 (m, 3H), 6.62 (br, 1H), 5.51 (m, 1H), 3.68 (t, 2H), 3.36 (s, 3H), 2.82-3.03 (m, 2H), 2.59-2.68 (m, 1H), 2.49-2.54 (m, 2H), 1.76-1.89 (m, 1H).

Further, N- (5-((hydroxyimino) methyl) -2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide [N- (5-((hydroxyimino) methyl)] which is a raw material NMR analysis results of -2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.51 (br, 1H), 8.09 (s, 1H), 7.43 (s, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 6.62 ( br, 1H), 5.48 (dd, 1H), 3.69 (t, 2H), 3.36 (s, 3H), 3.01-2.79 (m, 2H), 2.66-2.49 (m, 3H), 1.87-1.74 (m, 1H).

(Example 13)
In the same manner as in Example 10, N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl ) -2,3-Dihydro-1H-inden-1-yl) -acetamide [N- {5- [5-trifluoromethyl-5- (3-trifluoromethyl-phenyl) -4,5-dihydroisoxazol-3-yl]- 2,3-dihydro-1H-inden-1-yl} -acetamide] was synthesized.
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.87 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 7.46 -7.62 (m, 3H), 7.34 (d, 1H), 5.66 (d, 1H), 5.51 (dd, 1H), 4.14 (dd, 1H), 3.74 (dd, 1H), 2.84-3.04 (m, 2H), 2.59-2.68 (m, 1H), 2.06 (s, 3H), 1.50-1.90 (m, 1H).

N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-indene- 1-yl) -formamide [N- {5- [5-trifluoromethyl-5- (3-trifluoromethyl-phenyl) -4,5-dihydroisoxazol-3-yl] -2,3-dihydro-1H-inden-1- yl} -formamide]
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.30 (s, 1H), 7.87 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 7.47-7.64 (m, 3H), 7.35 (d, 1H), 5.80 (d, 1H), 5.60 (dd, 1H), 4.14 (dd, 1H), 3.75 (dd, 1H), 2.81-3.10 (m, 2H), 2.60-2.70 (m, 1H), 1.81-1.95 (m, 1H).

3- (2,3-dihydro-1H-inden-5-yl) -5-trifluoromethyl-5- (3-trifluoromethyl-phenyl) -4,5-dihydroisoxazole [3- (2,3 -dihydro-1H-inden-5-yl) -5-trifluoromethyl-5- (3-trifluoromethyl-phenyl) -4,5-dihydroisoxazole)
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.87 (s, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.11-7.60 (m, 4H), 4.13 (d, 1H), 3.73 (d, 1H), 2.92 (t, 4H), 2.08-2.17 (m, 2H)

3- (1H-inden-6-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole [3- (1H-inden-6- yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole)
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.89-7.83 (m, 3H), 7.69 (d, 1H), 7.61-7.54 (m, 2H), 7.43 (d, 1H), 6.90 (m, 1H ), 6.70 (m, 1H), 4.19 (d, 1H), 3.78 (d, 1H), 3.45 (s, 2H).

(Example 14)
Synthesis of 5-bromo-1- (methoxymethoxy) -2,3-dihydro-1H-indene [5-bromo-1- (methoxymethoxy) -2,3-dihydro-1H-indene] using known methods did.
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.40 (s, 1H), 7.36-7.24 (m, 2H), 5.06 (dd, 1H), 4.78 (s, 2H), 3.42 (s, 3H), 3.11-3.01 (m, 1H), 2.85-2.75 (m, 1H), 2.46-2.34 (m, 1H), 2.15-2.04 (m, 1H).

5-bromo-1-methoxy-2,3-dihydro-1H-indene [5-bromo-1-methoxy-2,3-dihydro-1H-indene]
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.39 (s, 1H), 7.35-7.24 (m, 2H), 4.75 (dd, 1H), 3.40 (s, 3H), 3.11-3.00 (m, 1H ), 2.84-2.75 (m, 1H), 2.39-2.28 (m, 1H), 2.13-2.02 (m, 1H).

5-iodo-2,3-dihydro-1H-inden-1-one O-methyl oxime [5-iodo-2,3-dihydro-1H-inden-1-one O-methyl oxime]
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.68 (s, 1H), 7.57 (d, 1H), 7.41 (d, 1H), 3.97 (s, 3H), 3.03-2.96 (m, 2H), 2.89-2.80 (m, 2H).

N- (5-bromo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide [N- (5-bromo-2,3-dihydro-1H-inden-1-yl)- 3-
methoxypropanamide)
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37 (s, 1H), 7.33 (d, 1H), 7.14 (d, 1H), 6.37 (br, 1H), 5.43 (dd, 1H), 3.66 ( t, 2H), 3.35 (s, 3H), 2.95-2.78 (m, 2H), 2.65-2.48 (m, 3H), 1.85-1.72 (m, 1H).

N- (5-iodo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide [N- (5-iodo-2,3-dihydro-1H-inden-1-yl)- 3-
methoxypropanamide)
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.59 (s, 1H), 7.53 (d, 1H), 7.02 (d, 1H), 6.37 (br, 1H), 5.44 (dd, 1H), 3.66 ( t, 2H), 3.49 (s, 3H), 2.99-2.78 (m, 2H), 2.63-2.48 (m, 3H), 1.83-1.70 (m, 1H).

N- (5-cyano-2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide [N- (5-cyano-2,3-dihydro-1H-inden-1-yl)- 3-
methoxypropanamide)
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.52 (s, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 6.45 (br, 1H), 5.55 (dd, 1H), 3.67 ( t, 2H), 3.36 (s, 3H), 3.05-2.84 (m, 2H), 2.70-2.60 (m, 1H), 2.53 (t, 2H), 1.89-1.76 (m, 1H).

(Example 15)
(E) -5-Dimethoxymethyl-2,3-dihydro-1H-inden-1-one O-methyl-oxime [(E) -5-Dimethoxymethyl-2,3-dihydro-1H-inden-1-one O -Methyl-oxime] (E) -5-formyl-2,3-dihydro-1H-inden-1-one O-methyl-oxime obtained by a known method [(E) -5-formyl-2, 3-dihydro-1H-inden-1-one O-methyl-oxime] 1.24 g (6.56 mmol), trimethyl orthoformate 2.37 g (13.78 mmol), and p-toluenesulfonic acid (TsOH) 20 mg (0 0.1 mmol) was added to a 50 mL flask and heated to reflux for 3.5 hours for reaction. After completion of the reaction, 10 mL of saturated aqueous sodium hydrogen carbonate solution was added thereto, and the organic phase was extracted twice with 20 mL of ethyl acetate.
The organic phase obtained by each extraction operation was put together. It was washed with 10 mL of brine and separated. Then, it dried with magnesium sulfate and concentrated. The target product (E) -5-dimethoxymethyl-2,3-dihydro-1H-inden-1-one O-methyl-oxime (1.57 g) was obtained. Used in Example 16 without further purification.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 7.68 (2H, d), 7.41 (1H, s), 7.33 (1H, d), 5.39 (1H, s), 3.99 (3H, s), 3.32 (6H, s ), 3.06-3.02 (2H, m), 2.91-2.88 (2H, m)
¹³ C-NMR (CDCl ₃ ) δ: 162.1, 148.1, 140.1, 136.2, 125.5, 123.6, 102.9, 62.0, 52.8, 28.6, 26.6

(Example 16)
Synthesis of (E) -5-dimethoxymethyl-2,3-dihydro-1H-inden-1-amine [(E) -5-Dimethoxymethyl-2,3-dihydro-1H-inden-1-amine] 100 mL of 4 In a cervical flask, 800 mg (3.4 mmol) of (E) -5-dimethoxymethyl-2,3-dihydro-1H-inden-1-one O-methyl-oxime obtained in Example 15 and methanol in a nitrogen atmosphere. 7 mL was charged, and then 180 mg (10 wt%) of Pd-C was added under ice cooling. Then, it was made to react at 25 degreeC by a suitable quantity hydrogen atmosphere for 5 hours using the balloon. After completion of the reaction, the Pd—C debris was filtered through Celite (registered trademark), and the filtrate was concentrated to dryness. As a result, 0.64 g (yield 92.6%, 2step) of (E) -5-dimethoxymethyl-2,3-dihydro-1H-indene-1-amine was obtained. Used in Example 17 without further purification.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.28 (3H, m), 5.36 (1H, s), 4.37 (1H, t), 3.36 (6H, s), 2.98-2.95 (1H, m), 2.80 -2.78 (1H, m), 2.52-2.35 (1H, m), 1.75-1.70 (1H, m)

(Example 17)
N- (5- (Dimethoxymethyl) -2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide [N- (5- (Dimethoxymethyl) -2,3-dihydro-1H-inden- 1-yl) -3-methoxypropanamide] In a 100 mL 4-neck flask, 640 mg of (E) -5-dimethoxymethyl-2,3-dihydro-1H-indene-1-amine obtained in Example 16 (3 0.09 mmol) and 7 mL of dichloromethane were added, followed by addition of 890 mg (3.40 mmol) of 3-methoxypropionic acid under ice cooling. To this was added 350 mg (4.63 mmol) of ethyl [(3-dimethylamino) propyl] carbodiimide hydrochloride (EDCI-HCl). Then, it heated up to room temperature and made it react for 1 hour. After completion of the reaction, 10 mL of water was added and the organic phase was separated. Extracted twice with 10 mL of dichloromethane. The organic phases obtained by each extraction operation were combined into one, washed sequentially with a saturated aqueous NaHCO3 solution and 10 mL of brine, and then separated. It was then dried over magnesium sulfate and then concentrated. As a result, 780 mg (yield: 86.1%) of N- (5- (dimethoxymethyl) -2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 7.33 (1H, s), 7.30-7.25 (2H, m), 6.38 (2H, d), 5.50 (1H, q), 5.35 (1H, s), 5.36 (1H , s), 3.67 (2H, t), 3.38 (9H, s), 3.05-2.80 (2H, m), 2.70-2.55 (2H, m), 2.51 (2H, t), 1.85-1.75 (2H, m )

The obtained N- (5- (dimethoxymethyl) -2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide was converted to a formyl form by deprotection. The obtained N- (5-formyl-2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide [N- (5-formyl-2,3-dihydro-1H-inden-1- yl) -3-methoxypropanamide] NMR analysis results were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.99 (s, 1H), 7.75 (s, 1H), 7.73 (d, 1H), 7.42 (d, 1H), 6.51 (br, 1H), 5.56 ( dd, 1H), 3.68 (t, 2H), 3.36 (s, 3H), 3.06-2.90 (m, 2H), 2.72-2.62 (m, 1H), 2.53 (t, 2H), 1.91-1.78 (m, 1H).

  Thereafter, N- (5-((hydroxyimino) methyl) -2,3-dihydro-1H-inden-1-yl) -3-methoxypropanamide is derived in the same manner as described in Example 1. be able to.

(Example 18)
N- (5-Bromo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropionamide [N- (5-Bromo-2,3-dihydro-1H-inden-1-yl)- 3-
Synthesis of methoxypropionamide] (Step 1) Synthesis of 3- (4-Bromophenyl) -3- (3-methoxypropionylamino) propionic acid [3- (4-Bromophenyl) -3- (3-methoxypropionylamino) propionic acid] In vessel A, 3.13 g (30.1 mmol) of 3-methoxypropionic acid was dissolved in 30 mL of tetrahydrofuran. This was cooled to 0 ° C., and 4.81 g (29.7 mmol) of carbonyldiimidazole was added and reacted for 11.5 hours.
In reactor B, 3.87 g (20.0 mmol) of 3-amino-3- (4-bromophenyl) propionic acid obtained by a known method [3-amino-3- (4-bromophenyl) propionic acid], Triethylamine 6.07g (60.0mmol), acetone 30mL and water 10mL were dissolved. It was then cooled to 0 ° C.
The total amount of the solution prepared in the reactor A was added to the reactor B while keeping the temperature at 4 ° C. or lower. The mixture was then stirred for 1 hour. It was then left overnight at room temperature. To the resulting solution, 6.46 g (45.2 mmol) of 28% aqueous sodium hydroxide solution was added and reacted for 7 hours. The reaction was stopped by adding 35% hydrochloric acid and extracted with methylene chloride. The extract was washed with water and dried over magnesium sulfate. Thereafter, the solvent was distilled off. The obtained crude product was washed with hot hexane and dried under reduced pressure. The target product, 3- (4-bromophenyl) -3- (3-methoxypropionylamino) propionic acid, was obtained as white crystals, 1.57 g (4.76 mmol, 24% yield).

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 2.50 (t, 2H), 2.88 (ddd, 2H), 3.36 (s, 3H), 3.60-3.69 (m, 2H), 5.37-5.42 (m, 1H), 7.18 (d, 2H), 7.45 (d, 2H).
¹³ C-NMR (CDCl ₃ ) δ: 36.9, 39.7, 48.8, 58.8, 68.6, 121.4, 127.9, 131.6, 139.3, 171.1, 174.0.

(Step 2) Synthesis of 3- (4-Bromophenyl) -3- (3-methoxypropionylamino) propionic acid chloride [3- (4-Bromophenyl) -3- (3-methoxypropionylamino) propionyl chloride] 3- (4 -Bromophenyl) -3- (3-methoxypropionylamino) propionic acid 1.57 g (4.76 mmol) was dissolved in 19.3 g of methylene chloride. To this, 1.05 g (8.83 mmol) of thionyl chloride was added and allowed to react at room temperature for 2.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Methylene chloride was added to the resulting residue, and the solvent was distilled off again under reduced pressure. The desired product 3- (4-bromophenyl) -3- (3-methoxypropionylamino) propionic acid chloride was obtained. Used in Example 20 without further purification.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 2.60 (bs, 2H), 3.37 (s, 3H), 3.37-3.59 (ddd, 2H), 3.65 (bs, 2H), 5.39 (q, 1H), 7.19 (d , 2H), 7.50 (d, 2H).
¹³ C-NMR (CDCl ₃ ) δ: 36.2, 49.8, 51.9, 58.9, 68.3, 122.2, 128.0, 132.0, 137.4, 171.0, 172.3.

(Step 3) N- (5-Bromo-3-oxo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropionamide [N- (5-Bromo-3-oxo-2,3 -dihydro-1H-inden-1-yl) -3-methoxypropionamide] 3- (4-bromophenyl) -3- (3-methoxypropionylamino) propionic acid chloride with 10.4 g of methylene chloride and aluminum chloride 81 g (13.6 mmol) was added and reacted by refluxing for 4 hours. The reaction solution was poured into ice water, neutralized with 28% aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was washed with water and dried over magnesium sulfate. Thereafter, the solvent was distilled off. 1.15 g (3.68 mmol, yield) of N- (5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropionamide as a target product as light brown crystals 77%, 2 steps). Used in Example 21 without further purification.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 2.48-2.54 (m, 3H), 3.24 (dd, 1H), 3.35 (s, 3H), 3.66 (t, 2H), 5.64 (td, 1H), 6.67 (d , 1H), 7.50 (d, 1H), 7.76 (dd, 1H), 7.88 (s, 1H).
¹³ C-NMR (CDCl ₃ ) δ: 37.0, 45.0, 47.0, 58.9, 68.5, 123.5, 126.2, 127.4, 138.0, 138.2, 152.4, 171.5, 201.3.

(Step 4) N- (5-Bromo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropionamide [N- (5-Bromo-2,3-dihydro-1H-inden-1 -yl) -3-methoxypropionamide] 55.0 mg (0.176 mmol) of N- (5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropionamide , 35% hydrochloric acid 5.6mL and water 8mL. To this, 1.41 g (21.5 mmol) of zinc powder was added and reacted at room temperature for 13.5 hours. To this reaction solution, 4.8 g of 98% sulfuric acid was added and reacted at room temperature for another hour. The reaction solution was filtered with a filter paper. The filtrate was poured into ice water, neutralized with 28% aqueous sodium hydroxide solution, and extracted multiple times with methylene chloride. The extract obtained by each extraction operation was put together and dried over magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography. 6.6 mg (0.022 mmol, 13%) of N- (5-bromo-2,3-dihydro-1H-inden-1-yl) -3-methoxypropionamide as a target product was obtained as a yellow oil.

(Example 19)
Synthesis of N- (5-bromo-2,3-dihydro-1H-inden-1-yl) acetamide [N- (5-bromo-2,3-dihydro-1H-inden-1-yl) acetamide] N- (5-Bromo-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide [N- (5-Bromo-3-oxo-2,3-dihydro-1H- inden-1-yl) acetamide] 1.07 g (4 mmol), potassium carbonate 2.75 g (20 mmol), hydrazine monohydrate 3.43 g (68 mmol), and diethylene glycol 18.4 mL were charged to the reactor, up to 85 ° C. Warmed up. To this reaction solution, 1.21 g (20 mmol) of potassium hydroxide was added, and the temperature was raised to 135 ° C. and reacted for 1 hour. After cooling, 40 mL of water, 40 mL of methanol, and 20 mL of chloroform were added to the reaction solution to separate the layers. The aqueous phase was extracted twice with 20 mL of chloroform and twice with 10 mL of chloroform. The extract obtained by each extraction operation was put together and dried with magnesium sulfate. The solvent was removed under reduced pressure. Water and chloroform were added to the obtained crude product and filtered through a filter paper. The filtrate was separated and the chloroform phase was dried over magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The obtained crude product was purified by column. As a result, 346 mg (1.36 mmol, yield 34%) of N- (5-bromo-2,3-dihydro-1H-inden-1-yl) acetamide was obtained.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 1.76-1.85 (m, 1H), 2.04 (s, 3H), 2.55-2.62 (m, 1H), 2.81-2.99 (m, 2H), 5.42 (q, 1H) , 5.61 (bs, 1H), 7.15 (d, 1H), 7.32 (d, 1H), 7.37 (s, 1H).
¹³ C-NMR (CDCl ₃ ) δ: 23.6, 30.2, 34.2, 54.2, 121.8, 125.4, 127.8, 129.7, 142.1, 145.5, 169.5.

(Example 20)
3-methoxy-N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro- 1H-Inden-1-yl) propanamide [3-methoxy-N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2 , 3-dihydro-1H-inden-1-yl) propanamide

  6 ml of sulfuric acid was cooled to 5 ° C. 3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydro there Isoxazole [3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole] 2. A solution prepared by dissolving 58 g (6 mmol) in 20.4 ml of 3-methoxypropionitrile was added dropwise in small portions over 5 minutes. When about half of the solution was added, the viscosity of the solution increased and it became difficult to stir. Therefore, the ice bath was removed and the rest was added dropwise. After dropping the entire amount, the mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was poured into ice water, and the product was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over magnesium sulfate. Thereafter, the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography. The target product, 3-methoxy-N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2, There were obtained 2.23 g (4.46 mmol, yield 74%) of 3-dihydro-1H-inden-1-yl) propanamide.

(Example 21)
N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-indene- 1-yl) propanamide [3-methoxy-N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro -1H-inden-1-yl) propanamide] (synthesis by liter reaction)
3- (1-Methoxy-2,3-dihydro-1H-inden-5-yl) -5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole (1 mmol) and propionitrile (13 mmol) were mixed, and 192 mg of sulfuric acid was added dropwise little by little. After dropwise addition of the entire amount, the mixture was stirred at room temperature for 2 hours, then the reaction solution was poured into ice water, and the product was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate, and then saturated brine, dried over magnesium sulfate, and the solvent was distilled off to purify the crude product obtained by silica gel column chromatography. The target N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro- 1H-Inden-1-yl) propanamide was obtained in 93% yield.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ7.88 (s, 1H), 7.81 (d, 1H), 7.69 (d, 1H), 7.44 -7.61 (m, 3H), 7.29 (d, 1H), 5.88-5.91 (br, 1H), 5.48 (dd, 1H), 4.13 (dd, 1H), 3.75 (dd, 1H), 2.80-3.02 (m, 2H), 2.54-2.64 (m, 1H), 2.26 ( q, 2H), 1.76-1.87 (m, 1H), 1.17 (t, 3H).

(Example 22)
The same liter reaction as in Example 21 was performed using butyronitrile, and N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5- Dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) butyrylamide [N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4, 5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) butyramide].
The yield of the target product was 93%.

The NMR analysis result of the obtained compound was as follows.
¹ H NMR (400 MHz, CDCl ₃ ) δ7.88 (s, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.44 -7.61 (m, 3H), 7.29 (d, 1H), 5.88 -5.92 (m, 1H), 5.49 (dd, 1H), 4.13 (dd, 1H), 3.75 (dd, 1H), 2.81-3.01 (m, 2H), 2.55-2.64 (m, 1H), 2.21 (t , 2H), 1.64-1.86 (m, 3H), 0.97 (t, 3H).

The same liter reaction as in (Example 21) was performed using cyclopropanecarbonitrile, and N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4 , 5-Dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) cyclopropanecarboxamide [N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) ) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) cyclopropanecarboxamide].
The yield of the target product was 89%.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.44 -7.61 (m, 3H), 7.32 (d, 1H), 6.00 -6.08 (m, 1H), 5.49 (dd, 1H), 4.13 (dd, 1H), 3.75 (d, 1H), 2.79-3.05 (m, 2H), 2.54-2.65 (m, 1H), 1.76-1.90 (m, 1H), 1.34-1.43 (m, 1H), 0.96-1.07 (m, 2H), 0.72-0.81 (m, 2H).

(Example 23)
The same liter reaction as in (Example 21) was performed using 3-methoxybutyronitrile, and 3-methoxy-N- (5- (5- (trifluoromethyl) -5- (3- (trifluoro Methyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) butyramide [3-methoxy-N- (5- (5- (trifluoromethyl)- 5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) butyramide] was synthesized.
The yield of the target product was 86%.

The same liter reaction as in (Example 21) was performed using 3,3,3-trifluoropropionitrile, and 3,3,3 trifluoro-N- (5- (5- (trifluoromethyl)- 5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) propanamide [3,3,3-trifluoro -N- (5- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -2,3-dihydro-1H-inden-1-yl) propanamide ] Was synthesized.
The yield of the target product was 46%.

(Example 24)
{5- [3- (3,5-dichlorophenyl) -4,4,4, -trifluoro-2-butenoyl] -2,3-dihydro-1H-inden-1-yl} -acetate [Acetic acid 5 -[3- (3,5-dichloro-phenyl) -4,4,4-trifluoro-but-2-enoyl] -2,3-dihydro-1H-inden-1-yl ester] (Step 1) Synthesis of (5-acetyl-2,3-dihydro-1H-inden-1-yl) acetate [Acetic acid 5-acetyl-2,3-dihydro-1H-inden-1-yl ester]

(5-Bromo-2,3-dihydro-1H-inden-1-yl) acetate was prepared from commercially available 5-bromo-1-indanone by a known method. 19.1 g of (5-bromo-2,3-dihydro-1H-inden-1-yl) acetate was dissolved in 200 ml of N, N-dimethylformamide and 50 ml of water. To this solution, 12.4 g of potassium carbonate, 0.84 g of palladium (II) acetate, 3.1 g of 1,3-bis (diphenylphosphino) propane, and 19 g of n-butyl vinyl ether were added. This was reacted with stirring overnight at 80 ° C. under a nitrogen atmosphere. The reaction mixture was ice-cooled, 160 ml of 2N hydrochloric acid was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent = ethyl acetate / n-hexane = 1/1 [volume ratio]) to obtain 13.8 g of the desired compound (yield 84%). )
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 2.08 (s, 3H), 2.10-2.19 (m, 1H), 2.50-2.61 (m, 1H), 2.60 (s, 1H), 2.88-2.98 (m, 1H) , 3.09-3.18 (m, 1H), 6.19-6.23 (m, 1H), 7.48 (d, 1H), 7.82-7.86 (m, 2H)

(Step 2) {5- [3- (3,5-dichlorophenyl) -4,4,4, -trifluoro-2-butenoyl] -2,3-dihydro-1H-inden-1-yl} -acetate Synthesis of [Acetic acid 5- [3- (3,5-dichloro-phenyl) -4,4,4-trifluoro-but-2-enoyl] -2,3-dihydro-1H-inden-1-yl ester]

4.28 g of (5-acetyl-2,3-dihydro-1H-inden-1-yl) acetate and 4.77 g of 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone in 10 ml of toluene Dissolved. To this solution was added 0.3 g of 1,8-diazabicyclo [5.4.0] undec-7-ene, and the mixture was stirred overnight under reflux. The reaction solution was poured into ice water and extracted with ethyl acetate, and the organic phase was washed with water, then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent = ethyl acetate / n-hexane = 3/2 [volume ratio]) to give 6.27 g (yield 75%) of the target compound. )
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 2.09 (s, 3H), 2.10-2.18 (m, 1H), 2.50-2.61 (m, 1H), 2.88-2.96 (m, 1H), 3.08-3.18 (m, 1H), 6.17-6.20 (m, 1H), 7.15-7.71 (m, 2H)

(Example 25)
3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1-yl ) Propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1 -yl) propanamide] (Step 1) 5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-one [5- (1-butoxyvinyl) -2,3-dihydro-1H- inden-1-one]

Under a nitrogen atmosphere, 0.62 g (1.50 mmol) of 1,3-bis (diphenylphosphino) propane and 0.17 g (0.76 mmol) of palladium acetate were aged with 60 ml of ethylene glycol at 50 ° C. for 20 minutes. To this was added 6.33 g (29.99 mmol) of 5-bromo-2,3-dihydro-1H-inden-1-one [5-bromo-2,3-dihydro-1H-inden-1-one], Aging was carried out at 55-60 ° C for 5 minutes. Thereafter, 9.17 g (90.62 mmol) of triethylamine was added dropwise and aged for 5 minutes. To this reddish brown solution, 9.06 g (90.46 mmol) of butyl vinyl ether was added dropwise. After completion of dropping, the mixture was aged at 65 to 75 ° C. for 25 hours.
After completion of the reaction, 60 ml of hexane was added and aged at 50-60 ° C. for 10 minutes. Thereafter, Celite (registered trademark) was filtered, and the residue was washed with 60 ml of hexane to obtain a filtrate. The ethylene glycol phase was separated from the filtrate and extracted with 20 ml of hexane. The hexane extract was washed with 90 ml of water and dried over magnesium sulfate. Thereafter, the solvent was distilled off to obtain 6.52 g (28.31 mmol, 94% yield) of 5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-one as a reddish brown oil. It was.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.62-7.73 (m, 3H), 4.78 (d, 1H), 4.34 (d, 1H), 3.88 (t, 2H), 3.15 (t, 2H), 2.71 (t, 2H), 1.77-1.85 (m, 2H), 1.49-1.58 (m, 2H), 1.00 (t, 3H).
¹³ C-NMR (400 MHz, CDCl ₃ ) δ: 7206.279, 158.876, 155.035, 142.627, 136.688, 124.677, 123.242, 123.085, 84.648, 67.768, 36.630, 31.189, 25.972, 19.635, 14.053.

(Step 2) 5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-ol [5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-ol] Composition

  197.2 mg (0.86 mmol) of 5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-one was dissolved in 4.3 ml of ethanol. To this, 32.3 mg (0.86 mmol) of sodium tetrahydroborate was added and reacted at 25-28 ° C. for 70 minutes. After completion of the reaction, 21.5 ml of water was added, and extraction was performed 3 times with 13.0 ml of methylene chloride. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 130.3 mg (5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-ol, which was the target product) as a yellow oil ( 0.56 mmol, yield 65%).

(Step 3) 1- (1- (t-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) ethanone [1- (1- (tert-butyldimethylsilyloxy) -2,3-dihydro -1H-inden-5-yl) ethanone)

2.26 g (9.7 mmol) of 5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-ol was dissolved in 20 ml of toluene. To this, 3.56 g (11.8 mmol) of a 50% toluene solution of t-butyldimethylsilyl chloride and 0.82 g (12.0 mmol) of imidazole were added and reacted at 47 to 52 ° C. for 80 minutes. After completion of the reaction, 15 ml of water was added, the pH was adjusted to 1 or lower with 35% hydrochloric acid under ice cooling, and 10 ml of toluene was added for liquid separation. The organic phase was washed with 10 ml of 10% brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography. The desired product 1- (1- (tert-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) ethanone is 1.33 g (4.6 mmol, 47% yield) as a yellow oil. Obtained.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.16 (s, 3H), 0.19 (s, 3H), 0.95 (s, 9H), 1.95 (tdd, 1H), 2.47 (tdd, 1H), 2.59 (s , 3H), 2.80 (td, 1H), 3.01 (ddd, 1H), 5.26 (t, 1H), 7.37 (d, 1H), 7.80 (s, 1H), 7.83 (d, 1H).

(Step 4) 1- (1- (t-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) -4,4,4-trifluoro-3- (3- (trifluoro Methyl) phenyl) but-2-en-1-one [1- (1- (tert-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) -4,4,4-trifluoro-3- Synthesis of (3- (trifluoromethyl) phenyl) but-2-en-1-one]

1- (1- (t-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) ethanone 0.58 g and 2,2,2-trifluoro-3 ′-(trifluoromethyl) 0.75 g (3.1 mmol) of acetophenone was dissolved in 2.0 ml of toluene. To this, 65.5 mg of tetra n-butylammonium bromide and 0.28 g (2.0 mmol) of potassium carbonate were added and reacted at reflux temperature for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and 6.0 ml of toluene was added. The reaction solution was washed twice with 2.0 ml of water and then with 2.0 ml of 10% brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography. 1- (1- (t-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) -4,4,4-trifluoro-3- (3- (trifluoro The two isomers A and B of methyl) phenyl) but-2-en-1-one were 0.81 g (1.6 mmol, 79% yield) and 0.06 g (0.1 mmol, 6% yield), respectively. ) Obtained.
The NMR analysis results of the obtained compound were as follows.

(Isomer A)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.15 (s, 3H), 0.17 (s, 3H), 0.94 (s, 9H), 1.92 (tdd, 1H), 2.45 (tdd, 1H), 2.76 (td , 1H), 2.97 (ddd, 1H), 5.22 (t, 1H), 7.34 (d, 1H), 7.39-7.47 (m, 3H), 7.54 (s, 1H), 7.56 (d, 1H), 7.65 ( s, 1H), 7.70 (d, 1H).
(Isomer B)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.18 (s, 3H), 0.20 (s, 3H), 0.97 (s, 9H), 1.99 (tdd, 1H), 2.51 (tdd, 1H), 2.84 (td , 1H), 3.05 (ddd, 1H), 5.29 (t, 1H), 6.88 (s, 1H), 7.45 (d, 1H), 7.60 (t, 1H), 7.72-7.76 (m, 2H), 7.80 ( s, 1H), 7.84 (s, 1H), 7.85 (d, 1H).

(Step 5-1) 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H -Inden-1-yl) propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro Of -1H-inden-1-yl) propanamide]

1- (1- (t-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) -4,4,4-trifluoro-3- (3- (tri 0.78 g (1.5 mmol) of isomer A of fluoromethyl) phenyl) but-2-en-1-one was dissolved in 3.0 ml of 3-methoxypropionitrile. To this was added 0.29 g (2.9 mmol) of concentrated sulfuric acid and allowed to react at 18 ° C. for 3 hours. After completion of the reaction, the reaction solution was added dropwise to 10 ml of ice water, neutralized with 28% aqueous sodium hydroxide solution, and extracted twice with 10 ml of methylene chloride. Each extract was washed with 5 ml of 10% saline solution, and then combined into one and dried over magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography, and crystallized from ethyl acetate and hexane. 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-indene which is the target product As a result, 0.48 g (1.0 mmol, yield 65%) of isomer A of -1-yl) propanamide was obtained.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78 (tdd, 1H), 2.50 (t, 2H), 2.59 (tdd, 1H), 2.83 (td, 1H), 2.95 (ddd, 1H), 3.33 (s , 3H), 3.65 (td, 2H), 5.47 (q, 1H), 6.61 (d, 1H), 7.29 (d, 1H), 7.38-7.47 (m, 3H), 7.51 (s, 1H), 7.56 ( d, 1H), 7.63 (s, 1H), 7.64 (d, 1H).

(Step 5-2) 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H -Inden-1-yl) propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro -1H-inden-1-yl) propanamide] 1- (1- (t-butyldimethylsilyloxy) -2,3-dihydro-1H-inden-5-yl) obtained in Step 4 From 0.05 g (0.12 mmol) of isomer B of -4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-en-1-one to step 5-1. In the same way as described, 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoy 0.04 g (0.08 mmol, 71% yield) of isomer B of (l) -2,3-dihydro-1H-inden-1-yl) propanamide was obtained as an oil.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.86 (tdd, 1H), 2.54 (t, 2H), 2.67 (tdd, 1H), 2.94 (td, 1H), 3.05 (ddd, 1H), 3.36 (s , 3H), 3.68 (t, 2H), 5.56 (q, 1H), 6.57 (d, 1H), 6.88 (s, 1H), 7.41 (d, 1H), 7.61 (t, 1H), 7.71-7.76 ( m, 2H), 7.78-7.85 (m, 3H).

(Example 26)
3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1-yl ) Propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1 -yl) propanamide] (step 1) 1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) ethanone [1- (1-methoxy-2,3-dihydro-1H-inden -5-yl) ethanone)

130.3 mg (0.56 mmol) of 5- (1-butoxyvinyl) -2,3-dihydro-1H-inden-1-ol was dissolved in 5.6 ml of methanol. To this, 431.8 mg of 14% hydrogen chloride-dioxane solution was added and reacted at 40 to 45 ° C. for 1.5 hours. After completion of the reaction, 30 ml of water was added, and extraction was performed twice with 20 ml of methylene chloride. The extract was dried over magnesium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure was purified by thin layer chromatography. As a result, 85.6 mg (0.45 mmol, 80% yield) of 1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) ethanone was obtained.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.06-2.14 (m, 1H), 2.36-2.45 (m, 1H), 2.60 (s, 3H), 2.86 (ddd, 1H), 3.10 (ddd, 1H) , 3.43 (s, 3H), 4.84 (dd, 1H), 7.47 (d, 1H), 7.82-7.84 (m, 2H).

(Step 2) 4,4,4-trifluoro-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) but-2 -En-1-one (4,4,4-trifluoro-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) but-2 -en-1-one]

From 85.6 mg (0.45 mmol) of 1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) ethanone in the same manner as described in Example 25, 4,4,4- 113.5 mg of trifluoro-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) but-2-en-1-one (0.27 mmol, 61% yield).
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.02-2.11 (m, 1H), 2.34-2.43 (m, 1H), 2.81 (td, 1H), 3.05 (ddd, 1H), 3.41 (s, 3H) , 4.81 (dd, 1H), 7.39-7.46 (m, 4H), 7.53-7.58 (m, 2H), 7.67-7.70 (m, 2H).

(Step 3) 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-indene -1-yl) propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H -inden-1-yl) propanamide] (synthesis by liter reaction)

4,4,4-trifluoro-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) but-2-ene-1 -On from 40.86 g (98.6 mmol) in the same manner as described in Example 25, step 5-1, 3-methoxy-N- (5- (4,4,4-trifluoro-3- 40.91 g (84.3 mmol, 85% yield) of (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1-yl) propanamide were obtained as crystals. It was.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.20-7.68 (m, 8H), 6.41 (d, 1H), 5.51 (d, 1H), 3.67 (t, 2H), 3.69 (s, 3H), 2.75 -3.05 (m, 2H), 2.57-2.70 (m, 1H), 2.52 (t, 2H), 1.71-1.86 (m, 1H).

4,4,4-trifluoro-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3,5-dichlorophenyl) butamate in the same manner as in step 2 above. -2-en-1-one [4,4,4-trifluoro-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3,5-dichlorophenyl) but- 2-en-1-one] was synthesized.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.85 -7.86 (m, 7H), 4.83 (t, 1H), 3.43 (s, 3H), 3.03-3.19 (m, 1H), 2.78-2.94 (m, 1H), 2.35-2.49 (m, 1H), 2.02-2.18 (m, 1H).

(Example 27)
3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1-yl ) Propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1 -yl) propanamide] (Step 1) 4,4,4-trifluoro-1- (1-hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoro Methyl) phenyl) but-2-en-1-one [4,4,4-trifluoro-1- (1-hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (3- ( Synthesis of trifluoromethyl) phenyl) but-2-en-1-one]

From 0.88 g (5.0 mmol) of 1- (1-hydroxy-2,3-dihydro-1H-inden-5-yl) ethanone in the same manner as described in Example 25, 4,4,4- 0.45 g of trifluoro-1- (1-hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) but-2-en-1-one (1.1 mmol, 22% yield).
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-2.15 (m, 2H), 2.49-2.58 (m, 1H), 2.81 (td, 1H), 3.03 (ddd, 1H), 5.23 (t, 1H) , 7.39-7.47 (m, 4H), 7.53 (s, 1H), 7.57 (d, 1H), 7.67 (s, 1H), 7.70 (d, 1H).

(Step 2) 5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-5-yl acetate [ Synthesis of 5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1-yl acetate]

4,4,4-trifluoro-1- (1-hydroxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) but-2-ene-1 -0.51 g (1.1 mmol) of ON was dissolved in 5.6 ml of methylene chloride and cooled to 5 ° C. To this, 13.7 mg (0.1 mmol) of N, N-dimethylaminopyridine, 171 mg (1.7 mmol) of acetic anhydride and 133 mg (1.7 mmol) of pyridine were added and reacted at 5 ° C. for 1.5 hours. After completion of the reaction, 5.6 ml of methylene chloride was added, washed twice with 2.2 ml of water, and dried over magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography. The desired 5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-5-yl acetate is obtained. 297 mg (0.67 mmol, 64% yield) was obtained.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.06-2.15 (m, 1H), 2.08 (s, 3H), 2.53 (tdd, 1H), 2.88 (ddd, 1H), 3.10 (ddd, 1H), 6.16 (dd, 1H), 7.40-7.47 (m, 4H), 7.52 (s, 1H), 7.57 (d, 1H), 7.68 (d, 1H), 7.70 (s, 1H).

(Step 3) 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-indene -1-yl) propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H -inden-1-yl) propanamide] (synthesis by liter reaction)

  5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-5-yl acetate 295 mg (0.67 mmol) ) To 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3-trifluoromethyl) phenyl) but-2-ene in the same manner as described in step 5-1. 254 mg (0.52 mmol, yield 79%) of enoyl) -2,3-dihydro-1H-inden-1-yl) propanamide was obtained.

(Example 28)
3-methoxy-N- (5- (5-trifluoromethyl-5- (3- (trifluoromethyl) phenyl) -4,5-dihydro-isoxazol-3-yl] -2,3-dihydro-1H -Inden-1-yl) propanamide [3-methoxy-N- {5- [5-trifluoromethyl-5- (3-trifluoromethyl-phenyl) -4,5-dihydro-isoxazol-3-yl] -2,3 -dihydro-1H-inden-1-yl} -propionamide]

  To 2 ml of toluene, 3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl] -2,3-dihydro-1H- Inden-1-yl) propanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro- 1H-inden-1-yl) propanamide] 90 mg (0.186 mmol), 50% aqueous hydroxylamine solution 36.7 mg (0.556 mmol), and tetrabutylammonium bromide 5.9 mg (10 mol%) were dissolved. While stirring the obtained toluene solution, 0.5 mL of 50% aqueous potassium hydroxide solution was added dropwise, and after stirring at room temperature for 15 hours, water was added and extraction was performed with a toluene solvent. Column purification (developing solvent = hexane / ethyl acetate = 1/1 To obtain the desired product (91% yield) through the volume ratio]).

(Example 29)
3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl] -2,3-dihydro-1H-indene-1- Yl) butanamide [3-methoxy-N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1 -yl) butanamide] (synthesis by liter reaction)

  4,4,4-trifluoro-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) but-2-ene-1 -One (1 mmol) and 3-methoxybutyronitrile (13 mmol) were mixed, and 192 mg of sulfuric acid was added dropwise little by little. After dropwise addition of the entire amount, the mixture was stirred at room temperature for 2 hours, then the reaction solution was poured into ice water, and the product was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate and then saturated brine, dried over magnesium sulfate, and the crude product obtained by distilling off the solvent was purified by silica gel column chromatography. % Yield.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.28-7.70 (m, 8H), 6.56 (t, 1H), 5.49 (dd, 1H), 3.65-3.81 (m, 1H), 3.32, 3.31 (s x2 , 3H, diastereomer), 2.80-3.02 (m, 2H), 2.57-2.67 (m, 1H), 2.34-2.48 (m, 2H), 1.65-1.85 (m, 1H), 1.22 (t, 3H).

  The same liter reaction as described above was performed using 3,3,3-trifluoropropionitrile and 3,3,3-trifluoro-N- (5- (4,4,4-trifluoro-3- (3 -(Trifluoromethyl) phenyl) but-2-enoyl] -2,3-dihydro-1H-inden-1-yl) propanamide [3,3,3-trifluoro-N- (5- (4,4, 4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1-yl) propanamide] was synthesized at a yield of 85%. there were.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.22-7.68 (m, 8H), 5.92 (d, 1H), 5.52 (d, 1H), 3.12 (q, 2H), 2.82-3.04 (m, 2H) , 2.57-2.69 (m, 1H), 1.77-1.88 (m, 1H).

  The same liter reaction as described above was performed using acetonitrile, and N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl] -2, 3-Dihydro-1H-inden-1-yl) acetamide [N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro -1H-inden-1-yl) acetamide] The yield of the desired product was 75%.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.65-7.27 (m, 8H), 5.79 (d, 1H), 5.48 (d, 1H), 3.00-2.90 (m, 1H), 2.86-2.79 (m, 1H), 2.62-2.56 (m, 1H), 2.25 (t, 2H), 1.81-1.76 (m, 1H), 1.18 (t, 3H).

  The same liter reaction as described above was performed using propionitrile, and N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl]- 2,3-dihydro-1H-inden-1-yl) propanamide [N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2, 3-dihydro-1H-inden-1-yl) propanamide] was synthesized with a yield of 77%.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.66-7.28 (m, 8H), 5.71 (d, 1H), 5.48 (d, 1H), 3.01-2.91 (m, 1H), 2.89-2.78 (m, 1H), 2.62-2.52 (m, 1H), 2.21 (t, 2H), 1.81-1.67 (m, 3H), 0.98 (t, 3H).

  The same liter reaction as described above was performed using cyclopropanecarbonitrile, and N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl] -2,3-dihydro-1H-inden-1-yl) cyclopropanecarboxamide [N- (5- (4,4,4-trifluoro-3- (3- (trifluoromethyl) phenyl) but-2-enoyl) -2,3-dihydro-1H-inden-1-yl) cyclopropanecarboxamide] The yield of the desired product was 77%.

The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.66-7.31 (m, 8H), 5.91 (d, 1H), 5.50 (d, 1H), 3.00-2.92 (m, 1H), 2.90-2.78 (m, 1H), 2.65-2.50 (m, 1H), 1.84-1.72 (m, 1H), 1.38-1.30 (m, 1H), 1.10-0.95 (m, 1H), 0.82-0.71 (m, 1H).

(Example 30)
N- {5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-2-butenoyl] -2,3-dihydro-1H-inden-1-yl} -propionic acid amide [N -{5- [3- (3,5-dichloro-phenyl) -4,4,4-trifluoro-but-2-enoyl] -2,3-dihydro-1H-inden-1-yl} -propionamide] Manufacturing (Process 1)
N- (5-acetyl-2,3-dihydro-1H-inden-1-yl) propionamide [N- (5-acetyl-2,3-dihydro-1H-inden-1-yl) -propionamide] Synthesis From a commercially available 5-bromo-1-indanone via known methods such as reductive amination and reaction with acid chloride, N- (5-bromo-2,3-dihydro-1H-indene- 1 g of 1-yl) propionic acid amide was prepared. 2 g of the obtained N- (5-bromo-2,3-dihydro-1H-inden-1-yl) propionic acid amide was dissolved in 20 ml of N, N-dimethylformamide and 5 ml of water. To this solution, 1.24 g of potassium carbonate, 84 mg of palladium (II) acetate, 0.31 g of 1,3-bis (diphenylphosphino) propane, and 1.9 g of n-butyl vinyl ether were added. This was reacted with stirring overnight at 80 ° C. under a nitrogen atmosphere. The reaction solution was ice-cooled, and 16 ml of 2N hydrochloric acid was added dropwise thereto. Then, it stirred at room temperature for 2 hours. The resulting reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent = ethyl acetate / n-hexane = 1/1 [volume ratio]) to obtain 1.2 g of the target compound (yield 69%). )
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (t, 3H), 1.56-1.86 (m, 1H), 2.26 (q, 2H), 2.59 (s, 3H), 2.60-2.70 (m, 1H), 2.89 -3.05 (m, 2H), 5.53-5.59 (m, 2H), 7.35 (d, 1H), 7.80-7.83 (m, 2H)

(Process 2)
N- {5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-3-hydroxybutanoyl] -2,3-dihydro-1H-inden-1-yl} -propionic acid amide [N- {5- [3- (3,5-dichloro-phenyl) -4,4,4-trifluoro-3-hydroxy-butyryl] -2,3-dihydro-1H-inden-1-yl} -propionamide ]

N- (5-acetyl-2,3-dihydro-1H-inden-1-yl) propionic acid amide (1.21 g) and 3 ′, 5′-dichloro-2,2,2-trifluoroacetophenone (1.4 g) in toluene Dissolved in 10 ml. To this solution, 0.48 g of tri-n-butylamine was added and stirred at 60 ° C. overnight. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent = ethyl acetate / n-hexane = 3/2 [volume ratio]) to give 1.22 g of the desired compound (yield 49%). )
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (t, 3H), 1.80-1.89 (m, 1H), 2.29 (q, 2H), 2.64-2.71 (m, 1H), 2.88-3.10 (m, 2H) , 3.65 (d, 1H), 3.83 (d, 1H), 5.52-5.62 (m, 2H), 5.86 (s, 1H), 7.33-7.80 (m, 6H)

(Process 3)
N- {5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-2-butenoyl] -2,3-dihydro-1H-inden-1-yl} -propionic acid amide [N -{5- [3- (3,5-dichloro-phenyl) -4,4,4-trifluoro-but-2-enoyl] -2,3-dihydro-1H-inden-1-yl} -propionamide] Composition

N- {5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-3-hydroxybutanoyl] -2,3-dihydro-1H-inden-1-yl} -propionic acid amide 1.22 g was dissolved in 10 ml of toluene. To this solution, 0.53 g of triethylamine and 30 mg of N, N-dimethylaminopyridine were added. The solution was ice-cooled, 0.53 g of acetic anhydride was added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate, and the organic phase was washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent = ethyl acetate / n-hexane = 3/2 [volume ratio]) to give 1.04 g (yield 89%) of the target compound. )
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (t, 3H), 1.74-1.88 (m, 1H), 2.30 (q, 2H), 2.59-2.70 (m, 1H), 2.86-3.05 (m, 2H) , 5.50-5.61 (m, 2H), 7.14-7.68 (m, 7H)

(Example 31)
N- {5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2,3-dihydro-1H-inden-1-yl} -propionic acid amide [[N- {5- [5-trifluoromethyl-5- (3,5-dichloro-phenyl) -4,5-dihydroisoxazol-3-yl] -2,3-dihydro-1H-inden-1-yl}- propionamide]

32 mg of N- {5- [3- (3,5-dichlorophenyl) -4,4,4-trifluoro-2-butanoyl] -2,3-dihydro-1H-inden-1-yl} -propionic acid amide , Dissolved in 2 ml of 1,2-dimethoxyethane and 0.5 ml of water. To this was added 9 mg of hydroxylammonium chloride. The reaction was stirred at room temperature for 30 minutes. Thereafter, 11 mg of lithium hydroxide monohydrate was added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate, and the organic phase was washed with water, then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 32 mg (yield 100%) of the target compound.
The NMR analysis result of the obtained compound was as follows.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (t, 3H), 1.74-1.84 (m, 1H), 2.27 (q, 2H), 2.61-2.67 (m, 1H), 2.86-3.01 (m, 2H) , 3.68 (d, 1H), 4.08 (d, 1H), 5.51-5.60 (m, 2H), 7.31-7.58 (m, 6H)

(Example 32)
Methyl 3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3-oxopropionate [methyl 3- (1-methoxy-2,3-dihydro-1H-inden-5- (yl) -3-oxopropanoate]

(Step 1) Synthesis of 5-bromo-1-hydroxy-2,3-dihydro-1H-indene 10.55 g of 5-bromo-1-indanone was suspended in 50 ml of methanol and stirred at 0 ° C. To this, 1.89 g of sodium tetrahydroborate was slowly added, and then stirred at 0 ° C. for 2 hours. To this, 3N hydrochloric acid was slowly added to adjust the pH to 2. This was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, dried and filtered. The solvent was distilled off with an evaporator to obtain 10.92 g of crude 5-bromo-1-hydroxy-2,3-dihydro-1H-indene. The resulting material was used in the next step without further purification.

(Step 2) Synthesis of 5-bromo-1-methoxy-2,3-dihydro-1H-indene 100 ml of methanol was added to 10.92 g of crude 5-bromo-1-hydroxy-2,3-dihydro-1H-indene, 9.61 g of methanesulfonic acid was slowly added dropwise. Then, it stirred at room temperature overnight and then stirred at 40 degreeC for 4 hours. The mixture was cooled to room temperature and adjusted to pH 8.6 by adding saturated sodium bicarbonate water. This was extracted with methylene chloride, dried over magnesium sulfate, dried and filtered. The solvent was distilled off with an evaporator. 10.36 g of 5-bromo-1-methoxy-2,3-dihydro-1H-indene was obtained. The resulting material was used in the next step without further purification.

(Step 3) Synthesis of 5-cyano-1-methoxy-2,3-dihydro-1H-indene 5-bromo-1-methoxy-2,3-dihydro-1H-indene 5.04 g, copper cyanide 3.98 g And 20 ml of N-methylpyrrolidone was put into the reactor and stirred at 140 ° C. for 20 hours. This was cooled to room temperature. Next, the mixture was diluted with 30 ml of ethyl acetate, and 15 ml of 28% aqueous ammonia was slowly added dropwise. Stir at room temperature for 30 minutes. Thereafter, Celite (registered trademark) was filtered. The filtrate was separated and the aqueous phase was extracted several times with ethyl acetate. The organic phases obtained by each extraction operation were combined together, washed with water, dehydrated and dried over magnesium sulfate, and filtered. The solvent was distilled off with an evaporator. The residue was purified by silica gel column chromatography to obtain 2.85 g of 5-cyano-1-methoxy-2,3-dihydro-1H-indene.

The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (CDCl ₃ ) δ: 7.5 (m, 3H), 4.8 (m, 1H), 3.4 (m, 3H), 3.1 (m, 1H), 2.8 (m, 1H), 2.4 (m, 1H ), 2.1 (m, 1H)

(Step 4) Synthesis of methyl 3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3-oxopropionate 0.38 g of zinc was put into a reactor, and the inside of the reactor was nitrogen. Replaced. A catalytic amount of methanesulfonic acid and 4 ml of dehydrated tetrahydrofuran were added and refluxed for 10 minutes. To this, 4 drops of methyl bromoacetate was added and stirred for another 30 minutes. To this was added 0.50 g of 5-cyano-1-methoxy-2,3-dihydro-1H-indene, and 0.66 g of methyl bromoacetate was added dropwise over 1 hour while refluxing. After completion of dropping, the mixture was aged for 1 hour. This was cooled to room temperature, 2 ml of 50% aqueous potassium carbonate solution and 9 ml of tetrahydrofuran were added, and the mixture was vigorously stirred at room temperature. The organic phase was separated and the aqueous phase was extracted with tetrahydrofuran. To this solution, 9 ml of 1N hydrochloric acid was added and stirred at room temperature for 4 hours. The solvent was distilled off with an evaporator and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and filtered. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 0.33 g of methyl 3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3-oxopropionate.

The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (CDCl ₃ ) δ: 12.5 (s, 0.15H), 7.8-7.47 (m, 3H), 5.6 (s, 0.16H), 4.8 (m, 1H), 4.0 (s, 1.7H), 3.8 (s, 0.6H), 3.7 (s, 2.6H), 2.9 (s, 3H), 3.0 (m, 1H), 2.8 (m, 1H), 2.4 (m, 1H), 2.1 (m, 1H)

(Example 33)
4,4,4-trifluoro-3-hydroxy-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) butane-1 -On (4,4,4-trifluoro-3-hydroxy-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3- (trifluoromethyl) phenyl) butan-1 -one)

  0.12 g of methyl 3- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3-oxopropionate and 1 ml of water were mixed and heated to 40 ° C. 0.1 g of 28% sodium hydroxide was added dropwise, and the mixture was stirred at 40 ° C. for 4 hours. To this, 0.05 g of benzyltributylammonium chloride and 0.12 g of 2,2,2-trifluoro-3 ′-(trifluoromethyl) acetophenone were added, and then adjusted to pH 8.0 by adding 1N hydrochloric acid. Stir at 0 ° C. for 3 hours. The pH was adjusted to 3 with 1N hydrochloric acid. Then, it stirred for 30 minutes. Extraction was performed with ethyl acetate, and the organic phase was dried over magnesium sulfate and filtered. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to give 4,4,4-trifluoro-3-hydroxy-1- (1-methoxy-2,3-dihydro-1H-inden-5-yl) -3- (3 0.07 g of-(trifluoromethyl) phenyl) butan-1-one was obtained.

The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (CDCl ₃ ) δ: 7.92 (br s, 1H), 7.82-7.76 (m, 3H), 7.60 (d, J = 8.0 Hz, 1H), 7.52-7.46 (m, 2H), 5.90 ( d, 1H, J = 2.4Hz), 4.85 (m, 1H), 3.97 (d, J = 17.6Hz, 1H), 3.69 (d, J = 17.6Hz, 1H), 3.09 (m, 1H), 2.88 ( m, 1H), 2.41 (m, 1H), 2.10 (m, 1H)

(Example 34)
Synthesis of 2,2,2-trifluoro-1- (3- (trifluoromethyl) phenyl) ethanone [2,2,2-trifluoro-1- (3- (trifluoromethyl) phenyl) ethanone] (Step 1) Trimethyl (2,2,2-trifluoro-1-methoxy-1- (3- (trifluoromethyl) phenyl) ethoxy) silane [trimethyl (2,2,2-trifluoro-1-methoxy-1- (3- ( Synthesis of trifluoromethyl) phenyl) ethoxy) silane] 92.6 mg (0.696 mmol) of cesium fluoride was added to 4.30 g (21.1 mmol) of 3-trifluoromethylbenzoic acid methyl ester, and then −10 ° C. Cooled to: About 4 mL (about 27 mmol) of trifluoromethyltrimethylsilane was added dropwise thereto at -10 ° C or lower. The mixture was stirred at -10 ° C for 1 hour and further at room temperature for 1 hour. Thereafter, water and methylene chloride were added to the reaction solution for extraction. The organic phase was dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (developing solvent = n-hexane / ethyl acetate = 98/2 [volume ratio]). When a portion corresponding to an Rf value of about 0.9 is collected and concentrated, trimethyl (2,2,2-trifluoro-1-methoxy-1- (3- (trifluoromethyl) phenyl) ethoxy) silane is obtained as a colorless transparent liquid. 4.46 g (65%) was obtained. Note that Rf is a ratio (relative movement distance) of the distance that the target sample has moved from the origin to the distance from the origin to the tip of the solvent.
The NMR analysis results of the obtained compound were as follows.
¹ H-NMR (CDCl ₃ ) δ: 0.28 (9H, s), 3.23 (3H, s), 7.5 to 7.9 (4H, m)

(Step 2) Synthesis of 2,2,2-trifluoro-1- (3- (trifluoromethyl) phenyl) ethanone [2,2,2-trifluoro-1- (3- (trifluoromethyl) phenyl) ethanone] 4.34 g of (2,2,2-trifluoro-1-methoxy-1- (3- (trifluoromethyl) phenyl) ethoxy) silane was dissolved in 12 mL of methanol, and 0.67 g of 36% hydrochloric acid was added. This was stirred at about 60 ° C. for 2 hours. Then, it concentrated and methanol was removed almost completely. Water and hexane were added to the residue and extracted. The organic phase was dried over magnesium sulfate and then concentrated. The residue was distilled at 65 ° C. under reduced pressure to less than 23 kPa. As a colorless transparent liquid, 2.19 g (63%) of 2,2,2-trifluoro-1- (3- (trifluoromethyl) phenyl) ethanone was obtained.

  By using the condensed ring compound, an isoxazoline derivative A useful as a pest control agent can be produced industrially stably and efficiently.

Claims (4)

A condensed ring compound represented by the formula (I).

(In formula (I), X ″ represents a halogen atom or a C 1-6 haloalkyl group .
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
R ¹ represents a C 1-6 haloalkyl group .
R ² represents a C 1-6 alkoxy group or a tri C 1-6 alkyl-substituted silyloxy group .
R ³ represents a hydrogen atom .
q represents the number of carbon atoms and is 1 or 2.
p represents the number of substitutions of R ³ and is 1 .
The bond between carbon atom 1 and carbon atom 2 represents a single bond . ). A condensed ring compound represented by the formula (VII).

(In formula (VII), X ″ represents a halogen atom or a C 1-6 haloalkyl group .
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
R ¹ represents a C 1-6 haloalkyl group .
R ²¹ represents a C 1-6 alkoxy group or a tri C 1-6 alkyl-substituted silyloxy group .
R ³¹ represents a hydrogen atom .
q represents the number of carbon atoms and is 1 or 2.
p ′ represents the number of substitutions of R ³¹ and is 1 .
The bond between carbon atom 1 and carbon atom 2 represents a single bond .
The bond represented by the wavy line indicates a trans conformation or cis conformation with respect to R ¹ .
Z represents an oxygen atom . ) Fused ring compound represented by formula (X)

(In formula (X), X ″ represents a halogen atom or a C 1-6 haloalkyl group .
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
R ¹ represents a C 1-6 haloalkyl group .
R ²² represents a C 1-6 alkoxy group or a tri C 1-6 alkyl-substituted silyloxy group .
q represents the number of carbon atoms and is 1 or 2. A C1-6 alkyl cyanide compound, a C3-8 cycloalkyl C1-6 alkyl cyanide compound, a C1-6 haloalkyl cyanide compound, or a C1-6 alkoxy C1-6 alkyl cyanide compound , a protonic acid or Reaction in the presence of Lewis acid,
Fused ring compound represented by formula (XI)

(In formula (XI), X ″, n ¹ , R ¹ , and q have the same meaning as described above.
R ²³ represents a C 1-6 alkyl group, a C 3-8 cycloalkyl C 1-6 alkyl group, a C 1-6 haloalkyl group, or a C 1-6 alkoxy C 1-6 alkyl group . How we manufacture a). Fused ring compound represented by formula (XII)

(In formula (XII), X ″ represents a halogen atom or a C 1-6 haloalkyl group .
n represents the number of substitutions of X ″ and is an integer of 0 to 5. When n is 2 or more, X ″ may be the same as or different from each other.
R ¹ represents a C 1-6 haloalkyl group .
R ²² represents a C 1-6 alkoxy group or a tri C 1-6 alkyl-substituted silyloxy group .
q represents the number of carbon atoms and is 1 or 2.
The bond represented by the wavy line indicates a trans conformation or cis conformation with respect to R ¹ .
Z represents an oxygen atom . A C1-6 alkyl cyanide compound, a C3-8 cycloalkyl C1-6 alkyl cyanide compound, a C1-6 haloalkyl cyanide compound, or a C1-6 alkoxy C1-6 alkyl cyanide compound , a protonic acid or Reaction in the presence of Lewis acid,
Fused ring compound represented by formula (XIII)

(In formula (XIII), X ″, n ¹ , R ¹ , q, Z and the bond represented by a broken line have the same meaning as described above.
R ²³ represents a C 1-6 alkyl group, a C 3-8 cycloalkyl C 1-6 alkyl group, a C 1-6 haloalkyl group, or a C 1-6 alkoxy C 1-6 alkyl group . How we manufacture a).