JP2002220372A - Novel piperidine derivative and insecticide containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a piperidine derivative having a remarkably excellent insecticidal activity at a lower dose than a conventional piperidine compound. SOLUTION: The piperingin derivative represented by the general formula (I), its N-oxide or its salt, and an insecticide, miticide or nematicide containing each of them as an active ingredient. Wherein two R _{1 s} may be the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkyl group, a lower haloalkoxy group or a lower alkylsulfonyloxy group; ₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxyalkyl group or a lower alkylcarbonyl group;
Represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, R ₃ represents an unsubstituted or substituted lower alkenyl group or lower alkynyl group (the substituent is a hydroxy group, a halogen atom, a lower Represents an alkoxy group) or a lower cycloalkenyl group]

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel piperidine derivative useful as an insecticide and an insecticide characterized by containing this derivative as an active ingredient.

[0002]

The following compounds are known as compounds similar to the piperidine derivatives of the general formula (I) according to the present invention.

(1) US Pat. No. 5,556,964 discloses that
It is described that the compound represented by the following general formula (A) has insecticidal activity.

[0004] (In the formula, n represents an integer of 1 to 3, R ₁ and R ₂ represent an optionally substituted phenyl group, and R ₃ represents a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group, a haloalkyl group,
It represents an alkenyl group, an alkynyl group, an alkoxy group, an alkylcarbonylamino group, an alkoxycarbonylamino group, or the like. However, US Pat. No. 5,556,964 does not disclose any compound in which R ₃ in the general formula (A) is an alkenyloxycarbonylamino group or an alkynyloxycarbonylamino group.

(2) US Pat. No. 5,639,763 discloses that
It is described that the compound represented by the following general formula (B) has insecticidal activity.

[0006] (Wherein, n represents an integer of 1 to 3, R ₁ and R ₂ represent an optionally substituted phenyl group, and W and X together form —OCH ₂ CH ₂ O—, —CH ₂ C (CH ₃ ) ₂ O— and the like.) However, U.S. Pat. No. 5,639,763 completely describes compounds in which X in the general formula (B) is an alkenyloxycarbonylamino group or an alkynyloxycarbonylamino group. Not.

(3) Japanese Patent Publication No. 9-505080 describes that a compound represented by the following formula (C) has insecticidal activity.

[0008] (Wherein, n represents an integer of 1 to 3, R ₁ and R ₂ represent a phenyl group substituted by a haloalkyl group or a haloalkoxy group, and R ₃ represents a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group, Examples thereof include a haloalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylcarbonylamino group, and an alkoxycarbonylamino group.) However, JP-A-9-505080 discloses that R ₃ in the general formula (C) is alkenyloxy. No mention is made of compounds which are a carbonylamino group or an alkynyloxycarbonylamino group.

(4) US Pat. No. 6,017,793 discloses that
It is described that the compound represented by the following formula (D) has insecticidal activity.

[0010] (In the formula, n represents an integer of 1 to 3, R ₁ and R ₂ represent an optionally substituted phenyl group, and R ₃ represents an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a cycloalkylalkoxy group, an alkoxyl group. A carbonylamino group, a haloalkoxycarbonylamino group, a cycloalkylalkoxycarbonylamino group, a halocycloalkylalkoxycarbonylamino group, a cyanoalkoxycarbonylamino group, and the like are shown.) However, US Pat. The compound in which R ₃ in D) is an alkenyloxycarbonylamino group or an alkynyloxycarbonylamino group is not described at all.

(5) JP-T-11-509524 describes that a compound represented by the following formula (E) has insecticidal activity.

[0012] (Wherein, n represents an integer of 1 to 3, R ₁ and R ₂ represent a phenyl group or a pyridyl group substituted by a haloalkyl group or a haloalkoxy group, and R ₃ is a 5-membered optionally substituted group. Or 6-membered heterocycle, etc.) (6) International Patent Publication WO99 / 14193 describes that a compound represented by the following formula (F) has insecticidal activity.

[0013] (Wherein, R represents a hydrogen atom, a halogen atom, an alkyl group, etc., R ₁ represents a hydrogen atom, an alkyl group, a haloalkyl group, etc., X represents an oxygen atom, NR ₂ , and n represents 0 or 1
And Z represents a halogen atom, a haloalkyl group, a haloalkoxy group, or the like. (7) JP-A No. 12-178272 describes that a compound represented by the following general formula (G) has insecticidal activity.

[0014] (Wherein R ₁ is a halogen atom, a C1-4 haloalkyl group, a C1
-4 shows a like haloalkoxy group, R ₂ represents a hydrogen atom, hydroxy group, halogen atom, C1-4 alkyl group, etc. C1-4 alkoxy group, R ₃ is a halogen atom, C1-4 alkyl group, C1- 4 represents an alkoxy group or the like, Z is an oxygen atom,
S (O) p- (p is 0 to 2) or the like, m is an integer of 0 to 2, and n is 0 or 1. (8) JP-A-62-169763 describes that a compound represented by the following general formula (H) has an activity such as cardiovascular dilation, an antihistamine activity, and a secretion inhibitory activity such as gastric juice. ing.

[0015] (Where p represents 0, 1, 2; z represents 0 or 1;
A is a hydrogen atom, Are shown, m represents an Less than six, Q is _{= CH -, - CH 2 -} , - CH (OH)
-, D and n represent 0 or 1, and Ar, D and R represent X, Y and Z represent a hydrogen atom, a lower alkyl group, a halogen atom, And B represents an oxygen atom, a sulfur atom, Wherein R ₁ represents a hydrogen atom, a lower alkyl group, a phenyl group or a phenyl lower alkyl group, and R ₂ represents a lower alkyl group, a phenyl group or a phenyl lower alkyl group. ) However, in JP-A-62-169763, there is no description about the insecticidal activity and a compound wherein R ₂ is a lower alkenyl group and lower alkynyl group of the are not described at all.

(9) British Patent Publication No. 2319524 describes that a compound represented by the following general formula (K) has insecticidal activity.

[0017] (In the formula, A represents —CH ₂ CH ₂ — and the like, Ar ₁ and Ar ₂ represent an optionally substituted phenyl group and the like, and R represents an optionally substituted aralkyl group and the like.)

[0018]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a piperidine derivative having a remarkably superior insecticidal activity as compared with conventional piperidine compounds.

Further, the present invention shows an excellent control effect against resistant pests, does not harm beneficial insects, is safe and does not adversely affect the environment, and is effective against mammals. An object of the present invention is to provide a piperidine derivative having low toxicity.

[0020]

Means for Solving the Problems In order to solve the above problems, the present inventors have synthesized a large number of novel piperidine derivatives and examined their insecticidal activity. As a result, they have found that a novel piperidine derivative represented by the following general formula (I) has excellent insecticidal activity at a low dose. In addition, they have found that they have significantly superior immediate insecticidal activity at a lower dose than conventional piperidine compounds. The present invention has been completed based on these findings.

That is, the present invention provides the following general formula (I) [In the formula, two R _{1 s} may be the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkyl group, a lower haloalkoxy group or a lower alkylsulfonyloxy group; ₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxyalkyl group or a lower alkylcarbonyl group, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, and R ₃ is unsubstituted Or a lower alkenyl group or a lower alkynyl group having a substituent (the substituent is a hydroxy group, a halogen atom, a lower alkoxy group, a lower haloalkoxy group, a lower alkylthio group,
A lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower cycloalkyl group, a lower alkoxyalkoxy group, an amino group, a lower alkylamino group, a lower dialkylamino group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a trimethylsilyl group or a phenyl group is there)
Or a lower cycloalkenyl group]], its N-oxide or its salt.

Furthermore, the present invention provides a compound represented by the following general formula (I): [In the formula, two R _{1 s} may be the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkyl group, a lower haloalkoxy group or a lower alkylsulfonyloxy group; ₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxyalkyl group or a lower alkylcarbonyl group, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, and R ₃ is unsubstituted Or a lower alkenyl group having a substituent or a lower alkynyl group (the above substituent is a hydroxy group, a halogen atom, a lower alkoxy group, a lower haloalkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, Cycloalkyl group, lower alkoxyalkoxy group, amino group, lower Alkylamino group, a lower dialkylamino group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a trimethylsilyl group or a phenyl group)
Or a lower cycloalkenyl group], an insecticide, an acaricide or a nematicide containing the N-oxide form or a salt thereof as an active ingredient.

In the general formula (I), R ₁ and R ₂
And the groups represented by R ₃ is specifically can include the following.

The "lower alkyl group" includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-
Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2 -Methylpentyl group, 3,3-dimethylbutyl group, 1,1-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group,
1 to 6 carbon atoms, such as 1-methyl-1-ethylpropyl group, 1,2-dimethylbutyl group, 2-methyl-1-ethylpropyl group, 2,2-dimethylbutyl group, etc. Or a branched alkyl group can be mentioned, and a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group are preferable.

The "lower alkenyl group" includes, for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-methyl-2
-Propenyl group, 2-methyl-2-propenyl group, 2-ethyl-2
-Propenyl group, 2-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-ethyl-2-butenyl group,
3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl or 4-
Such as a hexenyl group, may be a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, preferably 1-propenyl group, 2-propenyl group, 1-methyl-2-propenyl group , 2-methyl-2-propenyl group, 2-ethyl-2-propenyl group, 2-butenyl group, and 3-butenyl group.

The “lower alkynyl group” includes, for example, 2-
Propynyl group, 1-methyl-2-propynyl group, 2-butynyl group, 1-methyl-2-butynyl group, 1-ethyl-2-butynyl group,
3 carbon atoms such as 3-butynyl group, 2-methyl-3-butynyl group, 2-pentynyl group, 4-pentynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group or 5-hexynyl group To 6 linear or branched alkynyl groups, preferably a 2-propynyl group, 1-methyl
A 2-propynyl group, a 2-butynyl group, and a 3-butynyl group.

As the "lower cycloalkenyl group", for example, 2-cyclopropenyl group, 1-cyclobutenyl group, 2-cyclopropenyl group,
Examples thereof include cycloalkenyl groups having 3 to 6 carbon atoms such as cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 1-cyclohexenyl, and 2-cyclohexenyl.

As the "lower cycloalkyl group", for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 2-methylcyclopropyl group,
Such as a 2-methylcyclopentyl group or a 2-methylcyclohexyl group, there may be mentioned a cycloalkyl group having 3 to 7 carbon atoms which may have a branched chain having 1 to 6 carbon atoms, and preferably a cycloalkyl group. Propyl group.

As the "halogen atom", fluorine, chlorine,
Each atom of bromine or iodine can be mentioned.

The "lower haloalkyl group" includes, for example, trifluoromethyl group, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, dichloromethyl group, trichloromethyl group,
2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 1-fluoroethyl group, 1,1-difluoroethyl group,
2,2,2-trifluoroethyl group, pentafluoroethyl group, 1-fluoropropyl group, 3-fluoropropyl group, 2-
Chloropropyl group, 3-chloropropyl group, 3-iodopropyl group, 1-fluorobutyl group, 4-fluorobutyl group, 1-
A lower alkyl group in which a halogen atom such as fluorine, chlorine, bromine or iodine is bonded to the above lower alkyl group such as chlorobutyl group, etc., is preferably a trifluoromethyl group.

As the “lower alkoxy group”, for example,
Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, etc. And a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group and an ethoxy group.

As the "lower haloalkoxy group", for example, a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, an iodomethoxy group, a difluoromethoxy group,
Trifluoromethoxy group, 1-fluoroethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group, 1-fluoropropoxy group, 3-fluoropropoxy group , 2-chloropropoxy group, 3-chloropropoxy group, 1-fluorobutoxy group, 4-fluorobutoxy group, linear or branched haloalkoxy having 1 to 6 carbon atoms such as 1-chlorobutoxy group And a trifluoromethoxy group and a difluoromethoxy group.

As the "lower alkylthio group", for example, a methylthio group, an ethylthio group, an n-propylthio group,
An isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, a straight-chain or branched alkylthio group having 1 to 4 carbon atoms such as a tert-butylthio group, and the like, preferably , A methylthio group.

The "lower alkylsulfinyl group" includes, for example, methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group The alkyl moiety has 1 to 4 carbon atoms, such as a butylsulfinyl group.
And a straight or branched alkylsulfinyl group, preferably a methylsulfinyl group.

As the "lower alkylsulfonyl group",
For example, methylsulfonyl group, ethylsulfonyl group, n-
Propylsulfonyl group, isopropylsulfonyl group, n-
A butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, and the like, wherein the alkyl portion can be a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms, Preferably, it is a methylsulfonyl group.

As the "lower alkoxyalkoxy group", for example, methoxymethoxy group, ethoxymethoxy group, n-propoxymethoxy group, isopropoxymethoxy group, n-butoxymethoxy group, isobutoxymethoxy group,
sec-butoxymethoxy group, tert-butoxymethoxy group, n
-Pentyloxymethoxy group, isopentyloxymethoxy group, n-hexyloxymethoxy group, methoxyethoxy group, ethoxyethoxy group, n-propoxyethoxy group,
Isopropoxyethoxy group, n-butoxyethoxy group, isobutoxyethoxy group, sec-butoxyethoxy group, tert
Each alkoxy moiety has 1 to 6 carbon atoms, such as butoxyethoxy group, methoxypropoxy group, ethoxypropoxy group, n-propoxypropoxy group, isopropoxypropoxy group, n-butoxypropoxy group; Examples thereof include a branched alkoxyalkoxy group, and preferred are a methoxymethoxy group and an ethoxymethoxy group.

The "lower alkylamino group" includes, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino group, tert- Butylamino group, n-pentylamino group, isopentylamino group,
2-methylbutylamino group, neopentylamino group, n-
Hexylamino group, 4-methylpentylamino group, 3-methylpentylamino group, 2-methylpentylamino group, 3,3-
Dimethylbutylamino group, 1,1-dimethylbutylamino group, 1,3-dimethylbutylamino group, 2,3-dimethylbutylamino group, 1-ethylbutylamino group, 1-methyl-1-ethylpropylamino group, 1,2-dimethylbutylamino group, 2-
Examples thereof include a linear or branched alkylamino group having 1 to 6 carbon atoms, such as a methyl-1-ethylpropylamino group and a 2,2-dimethylbutylamino group. Group.

The "lower dialkylamino group" includes, for example, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, ethylmethylamino, n-propylmethylamino , Isopropylmethylamino group, n-butylmethylamino group, ethyl n-propylamino group, ethylisopropylamino group, ethyl n-butylamino group, etc. Or a branched or dialkylamino group, preferably,
It is a dimethylamino group.

The "lower alkoxycarbonyl group" includes, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group An alkoxy moiety such as, tert-butoxycarbonyl group, etc.
Examples thereof include 1 to 6 linear or branched alkoxycarbonyl groups, and preferably a methoxycarbonyl group and an ethoxycarbonyl group.

As the “lower alkoxyalkyl group”,
For example, methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, isopropoxymethyl group, n-butoxymethyl group, isobutoxymethyl group, sec-butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group , Isopentyloxymethyl group, n-hexyloxymethyl group, methoxyethyl group, ethoxyethyl group, n-propoxyethyl group, isopropoxyethyl group, n-butoxyethyl group, isobutoxyethyl group, sec-butoxyethyl group, tert-butoxyethyl group, methoxypropyl group, ethoxypropyl group, n-propoxypropyl group, isopropoxypropyl group, n-butoxypropyl group, etc., the alkoxy portion is a straight or branched chain having 1 to 6 carbon atoms. Alkoxyalkyl group, preferably a methoxymethyl group, an ethoxymethyl group. A Le group.

As the "lower alkylcarbonyl group",
For example, methylcarbonyl group, ethylcarbonyl group, n-
Propylcarbonyl group, isopropylcarbonyl group,
n-butylcarbonyl group, isobutylcarbonyl group, sec-
Examples thereof include a linear or branched alkylcarbonyl group having 1 to 6 carbon atoms such as a butylcarbonyl group and a tert-butylcarbonyl group, and a methylcarbonyl group is preferable.

Next, specific examples of the compounds included in the general formula (I) according to the present invention include the compounds shown in Table 1 below. However, the present invention is not limited to these specific examples.

[0043]

[0044]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing a piperidine derivative of the general formula (I) according to the present invention will be described in detail.

The piperidine derivative of the general formula (I) according to the present invention can be produced, for example, by the method of the following reaction step (A).

[0046] (Wherein, R ₁ , R ₂ , R ₃ , X and Y have the same meaning as described above, and Z represents a halogen atom.) That is, in the reaction step (A), the benzyl halide represented by the formula (II) And a piperidine compound represented by the formula (III), if necessary, in the presence of a solvent and a base,
By reacting, the piperidine derivative represented by the general formula (I) of the present invention can be produced.

In this reaction, the ratio of the piperidine compound represented by the formula (III) to the benzyl halide represented by the formula (II) is not particularly limited and can be appropriately selected from a wide range. It should be near that.

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, halogenation such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride Hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N,
N-dimethylformamide, N, N-dimethylacetamide,
An amide such as N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, pyridine, acetic acid, water, or the like can be used, or a mixed solvent thereof can also be used. Preferably, it is N, N-dimethylformamide, dimethylsulfoxide, chloroform, acetone, tetrahydrofuran or acetonitrile.

This reaction does not necessarily require a base, but may be carried out in the presence of a base. As the base used, for example, triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] Organic tertiary amines such as -7-undecene, sodium methoxide,
Alkali metal alkoxides such as sodium ethoxide or potassium tert-butoxide, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkali metal hydrides such as sodium hydride or potassium hydride But preferably, triethylamine, diisopropylethylamine, pyridine,
Sodium carbonate or potassium carbonate. The amount of the base used is not particularly limited and can be appropriately selected from a wide range. However, it is usually sufficient to use a stoichiometric amount or an excess amount, and preferably a stoichiometric amount or about 1 to 5 times the amount. An excessive amount may be used. When organic bases such as triethylamine and pyridine are used, they can be used as a solvent in a large excess.

In the present reaction, the reaction is carried out at a temperature of -30 ° C to the reflux temperature of the reaction system, preferably at -10 ° C to 80 ° C.
° C.

The reaction time varies depending on the reaction temperature and the reaction substrate, but the reaction is usually completed in 30 minutes to 24 hours.

The compound of the formula (I) obtained in the reaction step (A) is collected from the reaction solution by a usual post-treatment.
For example, it can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water to the reaction solution, washing with water, and distilling off the solvent. The obtained compound of the formula (I) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

In the reaction step (A), the piperidine compound represented by the formula (III) used as a raw material is a known compound, such as, for example, US Pat. No. 5,556,664, JP-T-11-509524 and the like. Can be easily synthesized according to the method described in (1). Further, specific production examples are shown in Reference Production Examples 5 and 6 described below.

The benzyl halide represented by the formula (II) is
For example, it can be produced as a compound of the formula (IIa) in the reaction step (C) described later and a compound of the formula (IIb) in the reaction step (F).

The piperidine derivative N-oxide of the general formula (Ia) and the piperidine derivative salt of the general formula (Ib) according to the present invention can be produced, for example, by the method of the following reaction step (B).

[0056] (In the formula, R ₁ , R ₂ , R ₃ , X and Y have the same meaning as described above, and AH represents an adduct.) That is, in the reaction step (B), the piperidine derivative represented by the formula (I) And an oxidizing agent in the presence of a solvent and, if necessary, a catalyst to produce an N-oxide of a piperidine derivative represented by the general formula (Ia) of the present invention.

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, esters such as ethyl acetate and ethyl propionate, and ethers such as diethyl ether, tetrahydrofuran and dioxane. Ketones such as acetone or methyl ethyl ketone, halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N, N-dimethylformamide, N , N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-
Amides such as imidazolidinone, dimethyl sulfoxide and the like can be used, or a mixed solvent thereof can also be used. Preferably, it is chloroform or methylene chloride.

As the oxidizing agent used in this reaction, for example, m-chloroperbenzoic acid, hydrogen peroxide, sodium periodate, tert-butyl hypochlorite or sodium hypochlorite can be used. Preferably, it is m-chloroperbenzoic acid.

The amount of the oxidizing agent is not particularly limited.
Although it can be appropriately selected from a wide range, it is usually sufficient to use a stoichiometric amount or an excess amount, and preferably, a stoichiometric amount or about 1 to 3 times excess amount.

As a catalyst that can be used as required, for example, sodium tungstate or ammonium molybdate is used.

The amount of the catalyst used is not particularly limited and can be appropriately selected from a wide range. It is usually 0.0001 to 1 times the stoichiometric amount, preferably about 0.01 to 1 times the stoichiometric amount. And it is sufficient.

In this reaction, the reaction is carried out at a temperature of from -30 ° C to the reflux temperature of the reaction system, preferably from -10 ° C to 80 ° C.
° C.

The reaction time varies depending on the reaction temperature and the reaction substrate, but the reaction is usually completed in 10 minutes to 24 hours.

The compound of the general formula (Ia) obtained in the reaction step (B) is collected from the reaction solution by a usual post-treatment. For example, it can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water to the reaction solution, washing with water, and distilling off the solvent. The obtained compound of the general formula (Ia) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

In the reaction step (B), the compound of the formula (I)
The piperidine derivative represented by the formula (Ib) of the present invention is produced by reacting the piperidine derivative represented by the formula with an adduct represented by AH in the presence of a solvent, if necessary.

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, methylene chloride, dichloroethane, chloroform or carbon tetrachloride Halogenated hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N, N-dimethylformamide, N, N-
Dimethylacetamide, N-methyl-2-pyrrolidone or
Amides such as 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, pyridine, acetic acid, water or the like can be used, or a mixed solvent thereof can also be used. Preferably, diethyl ether, hexane, toluene, acetone, tetrahydrofuran or ethanol is used.

As the compound represented by AH, for example,
Inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid; organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, malonic acid, fumaric acid, maleic acid, phthalic acid, salicylic acid, and D-glucuronic acid; Sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid and p-toluenesulfonic acid, alcohols such as methanol, ethanol and ethylene glycol, and water can be used. Preferred are hydrochloric acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethanol, water and the like.

The amount of AH to be used is not particularly limited and can be appropriately selected from a wide range. The amount may be usually a stoichiometric amount or an excess amount, preferably a stoichiometric amount or more. The amount may be about 1 to 3 times excess.

The reaction is carried out at a reaction temperature of -30 ° C to the reflux temperature of the reaction system, preferably -10 ° C to 80 ° C.
° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 10 minutes to 24 hours.

The compound of the general formula (Ib) obtained in the reaction step (B) is collected from the reaction solution by a usual post-treatment. For example, it can be obtained by isolating the precipitated crystal by a filtration operation or distilling off the reaction solvent. The obtained compound of the general formula (Ib) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

In the piperidine derivative represented by the formula (I), the piperidine derivative represented by the formula (Ic) wherein R ₂ is a hydrogen atom can be produced, for example, by the method of the following reaction step (C).

[0073] (In the formula, R ₁ , R ₃ , X and Y have the same meaning as described above, and Z represents a halogen atom.) That is, in the reaction step (C), first, tolyl isocyanate represented by the formula (V) or The benzyl halide represented by the formula (IV) can be produced by reacting tolyl isothiocyanate with a halogenating agent in the presence of a solvent and, if necessary, a catalyst.

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, halogenation such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride Hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N,
N-dimethylformamide, N, N-dimethylacetamide,
An amide such as N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, or the like, or a mixed solvent thereof can also be used. Preferably, it is carbon tetrachloride.

Examples of the halogenating agent used in this reaction include imides such as N-chlorosuccinimide or N-bromosuccinimide, and halogens such as chlorine and bromine.

The amount of the halogenating agent to be used is not particularly limited and can be appropriately selected from a wide range. The stoichiometric amount or an excess amount may be usually used, preferably the stoichiometric amount or more. The amount may be about 1 to 3 times excess.

As the catalyst used in this reaction, for example, when an imide is used as a halogenating agent,
Nitriles such as 2'-azobis (isobutyronitrile) or peroxides such as benzoyl peroxide can be used.

The amount of the catalyst used is 0.005 of the stoichiometric amount.
The stoichiometric amount is preferably 0.01 to 1 time, preferably 0.01 to 1 time.
What is necessary is just to about 1 time amount.

When a halogen is used as a halogenating agent, the reaction can be performed under light irradiation.

In this reaction, the reaction is carried out at a temperature of -30 ° C. to the reflux temperature of the reaction system, preferably at -10 ° C. to 80 ° C.
° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

The compound of the formula (IV) thus obtained is collected from the reaction solution by a usual post-treatment. For example, it can be obtained by adding an extraction solvent such as carbon tetrachloride or chloroform and water to a reaction solution, washing with water, and distilling off the solvent. The obtained compound of the formula (IV) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

Next, in the reaction step (C), the compound represented by the formula (IV)
Is reacted with an alcohol or a mercaptan of the formula (VI), if necessary, in the presence of a solvent and a catalyst to produce a carbamate of the formula (IIa).

In this reaction, a solvent is not necessarily required, but the reaction may be carried out in the presence of a solvent. As the solvent used, for example, aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene, a compound represented by the formula (VI)
Represented by alcohols or mercaptans, nitriles such as acetonitrile or propionitrile, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, methylene chloride , Dichloroethane, halogenated hydrocarbons such as chloroform or carbon tetrachloride, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2 Amides such as -pyrrolidone or 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide, or a mixed solvent thereof can be used. Preferred are N, N-dimethylformamide, acetonitrile, chloroform and the like.

In this reaction, the ratio of the compound of the formula (IV) to the compound of the formula (VI) is not particularly limited and can be appropriately selected from a wide range, but is usually at or near an equimolar ratio. . Further, the compound of the formula (VI) can be used as a solvent using a large excess.

In this reaction, a catalyst is not necessarily required, but the reaction may be carried out in the presence of a catalyst. As the catalyst used, for example, triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] There are organic tertiary amines such as -7-undecene, but preferably,
Triethylamine, diisopropylethylamine, pyridine and the like.

The amount of the catalyst used was 0.005 of the stoichiometric amount.
The stoichiometric amount is preferably 0.01 to 1 time, preferably 0.01 to 1 time.
What is necessary is just to about 1 time amount.

The reaction is carried out at a temperature from -30 ° C to the reflux temperature in the reaction system, preferably from -10 ° C to 80 ° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

The compound of the formula (IIa) thus obtained is collected from the reaction solution by a usual post-treatment.
For example, it can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water to the reaction solution, washing with water, and distilling off the solvent. The obtained compound of the formula (IIa) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

In the final step of the reaction step (C), the benzyl halide represented by the formula (IIa) and the piperidine compound represented by the formula (III) are reacted, if necessary, in the presence of a solvent and a base. Thus, the piperidine derivative represented by the general formula (Ic) of the present invention can be produced.

The reaction operation can be carried out in the same manner as in the reaction step (A).

In the reaction step (C), the compound of the formula (Ic) can be produced from the compound of the formula (IV) in a one-pot manner without isolating the intermediate compound of the formula (IIa). .

In the present reaction, the compound of the formula (IIa) is reacted with the alcohol or the mercaptan of the formula (VI) in the presence of a solvent and a catalyst, if necessary, to give a carbamate intermediate of the formula (IIa). The body can be manufactured.

In this reaction, a solvent is not necessarily required, but the reaction may be carried out in the presence of a solvent. As the solvent used, for example, aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene, nitriles such as acetonitrile or propionitrile, esters such as ethyl acetate or ethyl propionate,
Ethers such as diethyl ether, tetrahydrofuran or dioxane; ketones such as acetone or methyl ethyl ketone; halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, or dimethylsulfoxide and the like. Or a mixed solvent thereof can also be used. Preferred are N, N-dimethylformamide, acetonitrile, chloroform and the like.

In this reaction, the ratio of the compound of the formula (IV) to the compound of the formula (VI) is not particularly limited and can be appropriately selected from a wide range, but is usually at or near an equimolar ratio. .

In the present reaction, a catalyst is not always required, but the reaction may be carried out in the presence of a catalyst. As the catalyst used, for example, triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] There are organic tertiary amines such as -7-undecene, but preferably,
Triethylamine, diisopropylethylamine, pyridine and the like.

The amount of the catalyst used is 0.005 of the stoichiometric amount.
The stoichiometric amount is preferably 0.01 to 1 time, preferably 0.01 to 1 time.
What is necessary is just to about 1 time amount.

The reaction is carried out at a temperature from -30 ° C to the reflux temperature in the reaction system, preferably from -10 ° C to 80 ° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

Next, the reaction mixture containing the obtained compound of the formula (IIa) and the piperidine compound of the formula (III) are reacted, if necessary, in the presence of a solvent and a base to obtain the compound of the formula (II) The piperidine derivative represented by I) can be produced.

The reaction operation can be carried out in the same manner as in the reaction step (A).

The starting material, tolyl isocyanate or tolyl isothiocyanate represented by the formula (V) used in the reaction step (C) is a well-known compound in the field of organic chemistry. ).

The benzyl halide represented by the formula (IV) used in the reaction step (C) is a known compound, for example, Journal of Heterocyclic Chemistry, No. 31
Volume, 457-479 (1994), Synthesis (Synthe
sis) pp. 376-377 (1978), Collection of Czechoslovak Chemical Communicatio
ns), Vol. 55, pp. 752-760 (1990), JP-A-51
It can be easily produced according to the method described in US Pat. No. -19756 and British Patent Publication No. 752931. Further, specific production examples are shown in Reference Production Examples 1 and 4 described below.

The alcohol or mercaptan represented by the formula (VI) used in the reaction step (C) is a well-known compound in the field of organic chemistry, and can be obtained as a reagent from Tokyo Chemical Industry Co., Ltd., for example. .

The benzyl halide represented by the formula (IIa) can be produced as shown in the reaction step (C), and a specific production example is shown in Reference Production Example 1 described later.

In the compound of the formula (IV) in the reaction step (C), in particular, the isocyanate compound of the formula (IVa) wherein X is an oxygen atom can be produced, for example, by the method of the reaction step (D).

[0108] (In the formula, Z represents a halogen atom.) That is, in the reaction step (D), first, the formula (VIII)
Is reacted with sodium azide in the presence of a solvent to produce an acid azide compound represented by the formula (VII).

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, halogenation such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride Hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N,
N-dimethylformamide, N, N-dimethylacetamide,
An amide such as N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, pyridine, acetic acid, water, or the like can be used, or a mixed solvent thereof can also be used. Preferred are N, N-dimethylformamide, acetone, tetrahydrofuran, diethyl ether, dioxane and the like.

The amount of sodium azide to be used is not particularly limited and can be appropriately selected from a wide range. The amount may be usually a stoichiometric amount or an excess amount, preferably a stoichiometric amount or more. The amount may be about 1 to 3 times excess.

The reaction is carried out at a temperature from -30 ° C to the reflux temperature in the reaction system, preferably from -10 ° C to 80 ° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

The compound of the formula (VII) thus obtained is collected from the reaction solution by a usual post-treatment.
For example, it can be obtained by adding an extraction solvent such as toluene and diethyl ether and water to a reaction solution, washing with water, and distilling off the solvent. The obtained compound of the formula (VII) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

In the reaction step (D), the compound of the formula (VI)
The compound of formula (IVa) can be produced by subjecting the compound of I) to a heat reaction in the presence of a solvent, if necessary.

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, halogenation such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride Hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N,
N-dimethylformamide, N, N-dimethylacetamide,
An amide such as N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, pyridine, acetic acid, water, or the like can be used, or a mixed solvent thereof can also be used. Preferably, benzene, toluene and the like are used.

The reaction is carried out at a temperature from -30 ° C to the reflux temperature of the reaction system, preferably from 60 ° C to 120 ° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

In the reaction step (D), the compound of the formula (VII) can be obtained without isolation of the intermediate compound of the formula (VII).
The compound of formula (IVa) can also be prepared from the compound of I) in one pot.

In the reaction step (D), the acid halide compound represented by the formula (VIII) is a well-known compound in the field of organic chemistry, and can be obtained as a reagent from Tokyo Chemical Industry Co., Ltd., for example.

The production of the isocyanate compound represented by the formula (IVa) by the reaction step (D) can be carried out, for example, by the method described in Inorganic Chemistry, No. 23.
Volume, pages 961 to 969 (1984). Further, a specific production example is shown in Reference Production Example 3 described later.

When R ₂ is not a hydrogen atom in the piperidine derivative represented by the formula (I), the piperidine derivative represented by the formula (Id) can be produced, for example, by the method of the following reaction step (E). .

[0122] (Wherein, R ₁ , R ₃ , X and Y have the same meanings as described above;
R ₂ a represents an R ₂ having the same meaning as above except hydrogen atom, Z
Represents a halogen atom. That is, in the reaction step (E), a compound of the formula (Ic) is reacted with a halide compound of the formula (IX) in the presence of a solvent and a base, if necessary, to obtain a compound of the formula (Id)
Can be produced.

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, halogenation such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride Hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N,
N-dimethylformamide, N, N-dimethylacetamide,
Amides such as N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, pyridine, acetic acid or water can be used, or a mixed solvent thereof can be used. Preferred are toluene, acetonitrile, chloroform, N, N-dimethylformamide and the like.

This reaction does not necessarily require a base, but may be carried out in the presence of a base. As the base used, for example, triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] Organic tertiary amines such as -7-undecene, sodium methoxide,
Alkali metal alkoxides such as sodium ethoxide or potassium tert-butoxide, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkali metal hydrides such as sodium hydride or potassium hydride But preferably triethylamine, sodium hydride, sodium carbonate or potassium carbonate. The amount of the base to be used is not particularly limited and can be appropriately selected from a wide range. An excessive amount may be used. When organic bases such as triethylamine and pyridine are used, they can be used as a solvent in a large excess.

The amount of the compound of the formula (IX) to be used in this reaction is not particularly limited and can be appropriately selected from a wide range, but may be usually a stoichiometric amount or an excess thereof, preferably a stoichiometric amount. The amount may be stoichiometric or an excess of about 1 to 5 times.

In this reaction, the reaction is carried out at a temperature of -30 ° C to the reflux temperature of the reaction system, preferably at -10 ° C to 80 ° C.
° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

The compound of the formula (Id) obtained in the reaction step (E) is collected from the reaction solution by usual post-treatment.
For example, it can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water to the reaction solution, washing with water, and distilling off the solvent. The obtained compound of the formula (Id) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

In the reaction step (E), the halide compound represented by the formula (IX) is a well-known compound in the field of organic chemistry, and can be obtained as a reagent from Tokyo Chemical Industry Co., Ltd., for example.

The compound of formula (Id) can also be prepared in reaction step (F)
It can also be manufactured by the method described above.

[0131] (And _{wherein, R 1, R 3, X} , Y are as defined above, R ₂
a represents R ₂ having the same meaning as described above except for a hydrogen atom;
V represents a halogen atom. That is, in the reaction step (F), first, the formula (XIII)
Is reacted with a carbamoylating agent in the presence of a solvent, if necessary, to produce a carbamoyl halide represented by the formula (XII).

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, halogenation such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride Hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N,
N-dimethylformamide, N, N-dimethylacetamide,
An amide such as N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, pyridine or acetic acid can be used, or a mixed solvent thereof can be used. Preferably, it is toluene.

The carbamoylating agent includes phosgene and its multimers, thiophosgene and the like. The amount used is not particularly limited and can be appropriately selected from a wide range, but may be usually stoichiometric or an excess thereof, preferably stoichiometric or an excess of about 1 to 3 times the amount. And it is sufficient.

The reaction is carried out at a temperature from -30 ° C to the reflux temperature in the reaction system, preferably from 20 ° C to the reflux temperature in the reaction system.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

The obtained compound of the formula (XII) is collected from the reaction solution by a usual post-treatment. For example, it can be obtained by distilling off the solvent. The obtained compound of the formula (XII) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

Next, the compound of the formula (XI) can be produced by reacting the compound of the formula (XII) with a halogenating agent in the presence of a solvent and, if necessary, a catalyst.

Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic alcohols such as methyl alcohol, ethyl alcohol and tert-butyl alcohol, acetonitrile and propionyl. Nitriles such as nitriles, esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, halogenation such as methylene chloride, dichloroethane, chloroform or carbon tetrachloride Hydrocarbons, aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N,
N-dimethylformamide, N, N-dimethylacetamide,
An amide such as N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, or the like, or a mixed solvent thereof can also be used. Preferably, it is carbon tetrachloride.

Examples of the halogenating agent used in this reaction include imides such as N-chlorosuccinimide and N-bromosuccinimide, and halogens such as chlorine and bromine.

The amount of the halogenating agent used is not particularly limited and can be appropriately selected from a wide range, but may be usually a stoichiometric amount or an excess thereof, preferably a stoichiometric amount or more. The amount may be about 1 to 3 times excess.

As a catalyst used in this reaction, for example, when imides are used as a halogenating agent,
Nitriles such as 2'-azobis (isobutyronitrile) or peroxides such as benzoyl peroxide can be used.

The amount of the catalyst used was 0.005 of the stoichiometric amount.
The stoichiometric amount is preferably 0.01 to 1 time, preferably 0.01 to 1 time.
What is necessary is just to about 1 time amount.

When a halogen is used as the halogenating agent, the reaction can be performed under light irradiation.

In this reaction, the reaction is carried out at a temperature of -30 ° C to the reflux temperature of the reaction system, preferably at -10 ° C to 80 ° C.
° C.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

The compound of the formula (XI) thus obtained is collected from the reaction solution by a usual post-treatment. For example, it can be obtained by adding an extraction solvent such as carbon tetrachloride or chloroform and water to a reaction solution, washing with water, and distilling off the solvent. The obtained compound of the formula (XI) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

Next, the compound of the formula (II) is reacted with an alcohol or a mercaptan of the formula (VI) in the presence of a solvent and a base, if necessary.
The carbamate shown in b) can be produced.

In this reaction, examples of the solvent used include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, alcohols or mercaptans represented by the formula (VI), nitriles such as acetonitrile and propionitrile. , Esters such as ethyl acetate or ethyl propionate, ethers such as diethyl ether, tetrahydrofuran or dioxane, ketones such as acetone or methyl ethyl ketone, methylene chloride, dichloroethane, halogenated hydrocarbons such as chloroform or carbon tetrachloride, Aliphatic hydrocarbons such as pentane, hexane, heptane or cyclohexane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-
Amides such as dimethyl-2-imidazolidinone, dimethylsulfoxide or pyridine can be used, or a mixed solvent thereof can also be used. Preferred are N, N-dimethylformamide, acetonitrile, tetrahydrofuran and the like.

In this reaction, the ratio of the compound of the formula (XI) to the compound of the formula (VI) is not particularly limited and can be appropriately selected from a wide range, but is usually at or near an equimolar ratio. . Further, the compound of the formula (VI) can be used as a solvent using a large excess.

The base used in this reaction includes, for example, triethylamine, diisopropylethylamine, tributylamine, 4-dimethylaminopyridine, pyridine, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo Organic tertiary amines such as [5,4,0] -7-undecene, alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or carbonic acid Examples thereof include alkali metal carbonates such as potassium hydrogen, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, and alkali metal hydrides such as sodium hydride or potassium hydride. , Sodium hydride. The amount of the base used is not particularly limited and can be appropriately selected from a wide range. However, it is usually sufficient to use a stoichiometric amount or an excess amount, and preferably a stoichiometric amount or about 1 to 5 times the amount. An excessive amount may be used.

In this reaction, the reaction is carried out at a temperature from -30 ° C to the reflux temperature in the reaction system, preferably from 20 ° C to the reflux temperature in the reaction system.

Although the reaction time varies depending on the reaction temperature and the reaction substrate, the reaction is usually completed in 30 minutes to 24 hours.

The obtained compound of the formula (IIb) is collected from the reaction solution by usual post-treatment. For example, it can be obtained by adding an extraction solvent such as toluene, ethyl acetate or chloroform and water to the reaction solution, washing with water, and distilling off the solvent. The obtained compound of the formula (IIb) can be purified, if necessary, by an operation such as column chromatography or recrystallization.

In the final step of the reaction step (F), the compound of the formula (IIb) is reacted with the compound of the formula (III) in the presence of a solvent and a base, if necessary, to obtain the compound of the formula (I) The piperidine derivative represented by Id) can be produced.

The reaction operation can be performed in the same manner as in the reaction step (A).

In the reaction step (F), the compounds represented by the formulas (XII) and (X
Specific production examples of the compounds (I) and (IIb) are shown in Reference Production Example 2 below.

Next, a general method for preparing a piperidine derivative of the general formula (I) according to the present invention will be described in detail.

When the compound of the present invention is used as an active ingredient of an insecticide, the compound of the present invention may be used as it is, but a carrier, a surfactant and other auxiliaries generally used for formulation as an agricultural chemical adjuvant. Formulation, emulsion,
Suspensions, powders, granules, tablets, wettable powders, aqueous solvents, liquids, flowables, wettable powders, aerosols, pastes,
It can be formulated in various forms such as oils and emulsions.
The proportions of these are usually 0.1 to 90 parts by weight of the active ingredient and 10 to 99.9 parts by weight of the pesticide adjuvant.

Carriers that can be used in the formulation include
As long as it is commonly used for agricultural and horticultural drugs, either a solid carrier or a liquid carrier can be used, and there is no particular limitation.

Examples of such solid carriers include, for example, starch, activated carbon, soy flour, wheat flour, wood flour,
Examples include animal and plant powders such as fish meal and milk powder, and mineral powders such as talc, kaolin, bentonite, zeolite, diatomaceous earth, white carbon, clay, alumina, calcium carbonate, potassium chloride, and ammonium sulfate.

Examples of the liquid carrier include water; alcohols such as isopropyl alcohol and ethylene glycol; ketones such as cyclohexanone and methyl ethyl ketone; ethers such as propylene glycol monomethyl ether and diethylene glycol mono-n-butyl ether; kerosene and light oil. Aliphatic hydrocarbons; Aromatic hydrocarbons such as xylene, trimethylbenzene, tetramethylbenzene, methylnaphthalene and solvent naphtha; Amides such as N-methyl-2-pyrrolidone; Esters such as glycerin esters of fatty acids; Vegetable oils such as soybean oil and rapeseed oil are included. Two or more of these carriers can be used in combination.

The surfactants that can be used in the formulation include nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, and the like. Can be used.

Examples of nonionic surfactants include, for example, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl phenyl ether, polyoxyethylene alkyl ester, polyoxyethylene sorbitan alkylate, Oxyethylene phenyl ether polymer,
Examples include polyoxyethylene alkylene aryl phenyl ether, polyoxyethylene alkylene glycol, and polyoxyethylene polyoxypropylene block polymer.

Examples of anionic surfactants include, for example, lignin sulfonate, alkyl aryl sulfonate, dialkyl sulfosuccinate, polyoxyethylene alkyl aryl ether sulfate, alkyl naphthalene sulfonate, polyoxyethylene styryl Phenyl ether sulfate and the like.

Examples of the cationic surfactant include, for example, an alkylamine salt.

Examples of the amphoteric surfactant include, for example, quaternary ammonium salt alkyl betaine, amine oxide and the like.

The surfactants that can be used in the preparation are not limited to these, and two or more surfactants can be used in combination.

As other auxiliaries, binders, thickeners,
Fixing agents, preservatives and fungicides, solvents, stabilizers for pesticidal active ingredients, antioxidants, UV inhibitors, crystal precipitation inhibitors, defoamers, physical property improvers, coloring agents, etc. are added as required. However, the present invention is not limited to the auxiliary agents exemplified here.

The binder, thickener and fixing agent are not particularly limited, but include, for example, the following. Starch, dextrin, cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,
Carboxymethyl starch, pullulan, sodium alginate, ammonium alginate, propylene glycol alginate, guar gum, locust bean gum, gum arabic, xanthan gum, gelatin, casein, polyvinyl alcohol, polyethylene oxide, polyethylene glycol, ethylene propylene block polymer, polyacrylic acid Sodium, polyvinylpyrrolidone and the like.

The formulation of the insecticide of the present invention obtained by the above method is used as follows.

That is, it can be used as it is or diluted to a predetermined concentration with a diluent such as water. The application of various preparations containing the compound of the present invention, or a dilution thereof, is carried out by a generally used application method, that is, spraying (for example, spraying, misting, atomizing, dusting, dusting, water application, box application). Etc.), soil application (e.g., mixing, irrigation, etc.), surface application (e.g., application, dressing, coating, etc.), immersion, bait and the like.

The application rate of the insecticide of the present invention is not particularly limited.
The extent of the damage by pests, application place, application method, application time, the amount of such agents or fertilizers mix combination can be suitably selected from a wide range depending on various conditions such as the type, usually 100 m ² per 0.001~100g And preferably about 0.01 to 50 g.

When an emulsion, wettable powder, flowable or the like is diluted with water and used, its application concentration is about 0.1 to 1000 ppm, preferably about 1 to 500 ppm, but is not limited thereto. Absent. Granules, powders and the like are applied as they are without dilution.

It is needless to say that the pesticide preparation of the present invention is effective alone, but if necessary, other fertilizers, pesticides such as pesticides, acaricides, nematicides, It can be mixed with or used in combination with fungicides, antiviral agents, attractants, herbicides, plant growth regulators, synergists and the like.

The insecticide of the present invention can be used, for example, for controlling the following pests. However, the application of the insecticide of the present invention is not limited to these pests.

As the Hemiptera, for example, leafhopper (Nephotettix cincticeps), brown planthopper (Sogatella furcifera), brown planthopper (Nilap)
arvata lugens), Japanese brown planthopper (Laodelphax striat)
ellus), Rabbit bug (Riptortus clavatus),
Southern stink bug (Nezara viridula), Nashigumbai (Stephanitis nashi),
eurodes vaporariorum, cotton aphid (Aphis goss)
ypii), peach moth aphid (Myzus persicae), and moss aphid (Unaspis yanonensis).

[0177] As Lepidoptera, for example, Phyllonorycter ringoniella, Plutella xylostella, cotton moth (Promalactis i)
nonisema) and the apple snail (Adoxophyes ora)
na), Chahamaki (Homona magnanima), Mameshinguiga (Leguminivora glycinivorella), Kobumemeiga (C)
naphalocrocis medinalis, Chica suppe (Chilo suppe)
ressalis), Awanomeiga (Ostrinia furnacalis),
Armyworm (Mamestra brassicae), armyworm (Pseuda)
letiaseparata), Lotus armyworm (Spodoptera litur)
a), rice beetle (Parnaraguttata), cabbage butterfly (Pieris rapae crucivora), Heliothi (Heliothi)
s spp.), Tamanayaga (Agrotis ipsilon), Helicoverpa armigera, and the like.

Examples of Coleoptera include Coleoptera, Anomala cuprea, and Bean beetle (Popi
llia japonica), rice weevil (Echinocnemus squame)
us), rice weevil (Lissorhoptrus oryzophilu)
s), rice dung beetle (Oulema oryzae), beetle beetle (Anthrenus verbasci), coconut (Te
nebroides mauritanicus, weevil (Sitophilus)
zeamais), ladybird (Epilachna vigi)
ntioctopunctata), adzuki beetle (Callosobruchus)
chinensis), pine beetle (Monochamus alte)
rnatus), turtle beetle (Aulacophora femoralis), diabrotica (Diabrotica spp.) and the like.

As the Hymenoptera, for example, a wasp (Athalia rosae ruficornis), a lurichu range (Arge similis) and the like.

As Diptera, for example, Culex pipiens fatigans and Shimaka (Aede)
s spp.), soybean flies (Asphondylia spp.),
Housefly (Delia platura), Housefly (Musca domesti)
ca viclna), sea fly (Dacus cucurbitae), rice leaf fly (Agromyza oryzae), and millet (Lucilia)
spp.).

As the order Aphaniptera, for example, a human flea (Pulex irritans), a cheops flea (Xe
nopsylla cheopis, dog flea (Ctenocephalides cani)
s) and so on.

As the Thysanoptera, for example, Thrips palmi (Scirtothrips dorsalis),
Thrips Thrips (Thrips tabaci), Thrips palmi (Thrips palmi), Rice Thrips (Stenchaeto)
thrips biformis).

Examples of the lice [Anoplura] include white lice (Pediculs humanus corporis) and white lice (Phthirius pubis).

Examples of the order Psocoptera include, for example, Tropium pulsatorium, and Liposcelis bostrychophilus.

Examples of Orthoptera include, for example, mushrooms (Gryllotalpa spp.) And tonosa locusts (Locusta mi
gratoria), Oxya yezoensis, German cockroach (Blattella germanica), Black cockroach (P
eriplaneta fuliginosa).

As termite pests, for example, termites (Reticulitermes speratus) and house termites (C
optotermes formosanus).

As spider mites, for example, spider mites (Te
tranychus urticae), Kanzawa spider mite (Tetranychusk)
anzawai), mandarin mites (Panonychus citri), apple spider mites (Panonychus ulmi), mandarin mites (Aculo)
ps pelekassi).

Examples of the plant parasitic nematodes include sweet potato nematodes (Meloidogyne incognita), nematodes (Pratylenchus spp.) And soybean cyst nematodes (Heterodera glycines).

As other pests, unpleasant animals, sanitary pests, and parasites, for example, a black mussel (Pomacea cana
liculata), slugs (Incilaria sp.), Gastropods such as African snail (Achatina fulica)
a), Dermatophagoides (Armadillidium spp.), Warbler beetles, Centipedes, etc., Isopoda, Trichodectes sp.
p. Louses such as Cimex spp. Lice such as bed bugs, bovine ticks (Boophilus microplus), and animal parasites such as Haemaphysalis longicornis, and Dermatophagoides.

[0190]

The production examples of the compound of the formula (I) according to the present invention will be described below with reference to Reference Production Examples 1 to 6 and Examples 1 to 13.

Reference Production Example 1 Production of 4- (2-propenyloxycarbonylamino) benzyl bromide a) Production of 4- (bromomethyl) phenyl isocyanate 2.67 g (20 mmol) of 4-tolyl isocyanate and 25 ml of carbon tetrachloride were placed in a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. And heated. At 40 ° C., 0.33 g (2 mmol) of 2,2′-azobis (isobutyronitrile) and 3.56 g (20 mmol) of N-bromosuccinimide at 70 ° C. were added in three portions.
The mixture was heated and stirred for 1.5 hours. Chloroform and cold water were added to the reaction mixture for extraction. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump to obtain 4.24 g of a crude product.

B) Preparation of 4- (2-propenyloxycarbonylamino) benzyl bromide The above obtained a) was obtained in a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. 4- (bromomethyl) phenyl isocyanate 4.
24 g (20 mmol) and 25 ml of N, N-dimethylformamide were added and cooled with ice water. After adding 3 drops of triethylamine and 1.74 g (30 mmol) of 2-propen-1-ol at 7 ° C.
Stir at room temperature for 3 hours. Toluene, tetrahydrofuran and water were added to the obtained reaction mixture and extracted. The organic layer was washed with water, then with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure using a vacuum pump.

Using 3.6 g of the obtained crude product as a developing solvent, a toluene-acetone mixed solution (solvent volume ratio: toluene: acetone =
Purification by chromatography on silica gel (trade name: silica gel 60H, manufactured by Merck Ltd.) using 100: 1) gave 3.05 g of the title compound as white crystals (yield: 56).
%). 101-103 ° C.

¹ H-NMR (δ ppm / CDCl ₃ ): 4.5 (2H, s),
4.7 (2H, d, J = 5.7Hz), 5.2-5.4 (2H, m), 5.9-6.1 (1H,
m), 6.8 (1H, s), 7.1-7.4 (4H, m).

Reference Production Example 2 Production of 4- [N- (2-propenyloxycarbonyl) -N-methylamino] benzyl bromide a) Production of N-methyl-4-tolylcarbamoyl chloride Diphosgene 1.13 in a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C.
g (5.7 mmol), 1.33 g (11 mmol) of N-methyl-4-toluidine and 10 ml of toluene were added dropwise at room temperature with stirring. After completion of the dropwise addition, the mixture was stirred at 80 ° C. for 2 hours. The solvent was distilled off from the reaction mixture under reduced pressure using a vacuum pump. The obtained crude product
2.0 g was washed with n-hexane to obtain 1.6 g of the title compound (yield
80%).

B) Preparation of N-methyl-4-bromomethylphenylcarbamoyl chloride The N obtained in the above a) was placed in a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. -Methyl-4-tolylcarbamoyl chloride 1.6g
(8.7 mmol) and 15 ml of carbon tetrachloride were added, and heated and stirred. 2,9'-azobis (isobutyronitrile) 0.29 at 70 ° C
g (1.7 mmol) and N-bromosuccinimide 1.55 g (8.7
mmol) was added in three portions and stirred at 75 ° C. for 3 hours. Chloroform and water were added to the reaction mixture for extraction, the chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. 2.3 g of the obtained crude product was purified by chromatography on silica gel (trade name: silica gel 60H, manufactured by Merck) using an n-hexane-toluene mixed solution (solvent volume ratio n-hexane: toluene = 2: 1) as a developing solvent. Thus, 2.1 g of the title compound was obtained (yield: 92%).

¹ H-NMR (δ ppm / CDCl ₃ ): 3.4 (3H, br.
s), 4.5 (2H, s), 7.2-7.5 (4H, m).

C) Production of 4- [N- (2-propenyloxycarbonyl) -N-methylamino] benzyl bromide In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. 0.32 g (8 mmol) of 60% oily sodium hydride and 10 m of tetrahydrofuran
l, and stirred at 6 ° C with 0.49 g of 2-propen-1-ol (8.4 g).
mmol) was added dropwise. After stirring at room temperature for 1 hour, 2.0 g (7.6 mmol) of N-methyl-4-bromomethylphenylcarbamoyl chloride obtained in the above b) was added at -7 ° C. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water, extracted with toluene, washed with saturated saline, the toluene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. 2.1 g of the obtained crude product was purified by silica gel (trade name: silica gel 60H, manufactured by Merck) using toluene as a developing solvent to obtain 1.7 g of the title compound (79% yield).

¹ H-NMR (δ ppm / CDCl ₃ ): 3.3 (3H, s),
4.5 (2H, s), 4.6 (2H, d, J = 5.5Hz), 5.1 to 5.3 (2
H, m), 5.8-6.0 (1H, m), 7.2-7.4 (4H, m).

Reference Production Example 3 Production of 4- (chloromethyl) phenyl isocyanate In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.69 g (10.6 mmol) of sodium azide and 3 ml of water were placed and cooled with ice water. 2.0 g of 4-chloromethylbenzoic acid chloride at 5 ° C
(10.6 mmol) and a mixed solution of 7 ml of tetrahydrofuran were added dropwise. After stirring at room temperature for 1 hour, the tetrahydrofuran layer was separated and dried over anhydrous sodium sulfate to obtain a solution of 4- (chloromethyl) benzoic azide in tetrahydrofuran.

In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 10 ml of toluene was charged and heated to 80 ° C. Keep 80 ℃ above
A solution of 4- (chloromethyl) benzoic azide in tetrahydrofuran was added dropwise. After stirring at 80 ° C. for 1 hour, it was confirmed that the generation of nitrogen had stopped, and the reaction was terminated. The solvent was distilled off from the reaction mixture under reduced pressure of a vacuum pump to obtain 1.59 g of the title compound (yield 90%).

Reference Production Example 4 Production of 4- (bromomethyl) phenylisothiocyanate 6.4 g (43 mmol) of 4-tolyl isothiocyanate and 50 ml of carbon tetrachloride were heated in a 200 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., and heated. 1.0 g (4.1 mmol) of benzoyl peroxide at 75 ° C
At 75 ° C. and 7.65 g of N-bromosuccinimide (43 m
mol) was added in three portions, and the mixture was further stirred under reflux for 1 hour. Chloroform and cold water were added to the reaction mixture for extraction. The chloroform layer was dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure of a vacuum pump to obtain 9.8 g of a crude product. The crude product was washed with n-hexane to give the title compound (8.0 g, pale yellow crystals, yield 82%). 94-99 ° C.

¹ H-NMR (δ ppm / CDCl ₃ ): 4.5 (2H, s),
7.2 to 7.4 (4H, m).

Reference Production Example 5 Production of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine a) Preparation of N-trimethylsilyl isonipecotate ethyl ester In a 11-neck four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 25.8 g (0.164 mol) of ethyl isonipecotate, diethyl ether 360 ml of ether and 17.4 g (0.172 mol) of triethylamine were added, the inside of the reaction system was replaced with nitrogen gas, and cooled with ice water. 10 ℃
Then, a mixed solution of 18.9 g (0.174 mol) of trimethylsilyl chloride and 25 ml of diethyl ether was added dropwise. After stirring at room temperature for 2 hours, the precipitated crystals were filtered, and the filtrate was concentrated under reduced pressure of a vacuum pump to obtain 34.2 g of a crude product. The crude product was distilled under reduced pressure (boiling point: 106 to 109 ° C./4 mmHg) to obtain 31.5 g of the title compound (yield: 84%).

B) Preparation of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine 4-Tris was placed in a 300 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. 0.5 g (2.3 mmol) of fluoromethoxybromobenzene, 2.5 ml of tetrahydrofuran, 1.4 g (57.6 mmol) of magnesium and 0.01 g of iodine were added, and the inside of the reaction system was replaced with nitrogen gas. After stirring at 64 ° C for 10 minutes, 50 ml of tetrahydrofuran was added, and at 64 ° C, a mixture of 5.3 g (23 mmol) of ethyl N-trimethylsilylisonipecotate, 12.9 g (53.4 mmol) of 4-trifluoromethoxybromobenzene and 50 ml of tetrahydrofuran was added. The solution was added dropwise. After stirring at reflux for 2 hours, the reaction mixture was cooled with ice water, poured into an ammonium chloride solution,
Extracted with ethyl acetate. After washing with saturated sodium bicarbonate and then with saturated saline, drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure of a vacuum pump gave 10.0 g of the title compound (100% yield). .

Reference Production Example 6 Production of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine hydrochloride In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 2.9 g (6.7 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, 10 ml of diethyl ether And n
-Hexane (10 ml) was added, and hydrochloric acid gas was introduced at room temperature with stirring for 30 minutes. The precipitated crystals of the obtained reaction mixture were filtered to obtain 2.0 g of the title compound (yield 63%). Melting point
217-221 ° C (decomposition).

¹ H-NMR (δ ppm / CD ₃ C OC D ₃ ): 1.6
(2H, d, J = 13.8Hz), 1.9 to 2.2 (2H, m), 3.0 to 3.2
(3H, m), 3.4-3.6 (2H, d, J = 12.6Hz), 7.2-7.8
(8H, m).

Example 1 Production of N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 1) In a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 3.0 g (7 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, 30 ml of chloroform and triethylamine 2.0 g (20 mmol) was added and stirred. 4- (2
1.89 g (7 mmol) of -propenyloxycarbonylamino) benzyl bromide was added, and the mixture was stirred at room temperature for 2 hours. The obtained reaction mixture was poured into cold water and extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. Using 4.4 g of the obtained crude product as a developing solvent, a mixed solution of toluene and acetone (solvent volume ratio: toluene: acetone = 5: 1) was used, and silica gel (manufactured by Merck: silica gel 60) was used.
H) Purification by chromatography gave 2.5 g of the title compound as white crystals (57% yield). Melting point 148-1
51 ° C.

¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 to 1.5 (4H,
m), 1.5-1.7 (1H, br.s), 1.9-2.1 (2H, m), 2.3
~ 2.5 (1H, m), 2.9 (2H, d, J = 11.4Hz), 3.5 (2H,
s), 4.7 (2H, d, J = 5.7Hz), 5.2 to 5.4 (2H, m), 5.
9-6.0 (1H, m), 6.6 (1H, s), 7.1-7.5 (12H,
m).

Example 2 Production of N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine N-oxide (Compound No. 2) N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) was placed in a 30 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. ) Hydroxymethyl] piperidine (0.8 g, 1.3 mmol) and chloroform (10 ml) were added and stirred. 0.32 g of m-chloroperbenzoic acid at 7 ° C under ice water cooling
(1.3 mmol), and the mixture was stirred at room temperature for 2 hours. The obtained reaction mixture was poured into a saturated sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. 0.8 g of the obtained crude product was purified by chromatography on silica gel (trade name: silica gel 60H, manufactured by Merck) using a chloroform-methanol mixed solution (solvent volume ratio: chloroform: methanol = 10: 1) as a developing solvent. 0.7 g of the target compound was obtained as white crystals (yield 84%). Mp 182-183 ° C.

¹ H-NMR (δ ppm / CDCl ₃ -CD ₃ OD): 1.2 to 1.4
(2H, m), 2.2-2.5 (3H, m), 3.0-3.2 (4H, m),
4.3 (2H, s), 4.7 (2H, d, J = 5.7Hz), 5.2 to 5.4 (2
H, m), 5.9 to 6.1 (1H, m), 7.0 to 7.6 (12H, m).

Example 3 Production of N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine hydrochloride (Compound No. 3) N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) was placed in a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. ) Hydroxymethyl] piperidine 0.8 g (1.3 mmol), diethyl ether 10 ml and n
-Hexane (10 ml) was added, and hydrochloric acid gas was introduced at room temperature with stirring for 20 minutes. After further stirring at room temperature for 1 hour, the reaction supernatant was decanted, 20 ml of n-hexane was added to the residue, and after stirring at room temperature for 30 minutes, the precipitated crystal was isolated by filtration and air-dried to give 0.6 g of the title compound as a pale yellow crystal. (Yield 71
%). 148-155 ° C (decomposition).

¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 to 1.7 (2H,
m), 2.1 to 3.6 (7H, m), 4.0 to 4.3 (2H, br.s), 4.6
(2H, d, J = 5.7Hz), 5.2 to 5.4 (2H, m), 5.8 to 6.0
(1H, m), 7.0-7.7 (12H, m), 11.3 (1H, br.s).

Example 4 Production of N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethylphenyl) hydroxymethyl] piperidine (Compound No. 12) 0.5 g (8 mmol) of 2-propen-1-ol, 10 ml of N, N-dimethylformamide and 2 drops of diisopropylethylamine are placed in a 100 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. The inside of the flask was replaced with nitrogen gas. After adding 0.7 g (4 mmol) of 4- (chloromethyl) phenyl isocyanate at 2 ° C. under ice cooling, the mixture was stirred at room temperature for 1 hour. Next, 4- [bis (4-trifluoromethylphenyl) is added to the reaction mixture at 5 ° C. under ice water cooling.
1.6 g (4 mmol) of [hydroxymethyl] piperidine and 1.5 g (12 mmol) of diisopropylethylamine were added, and the mixture was further stirred at room temperature for 3 hours. The obtained reaction mixture was poured into cold water, and ethyl acetate was added for extraction.

The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. 2.0 g of the obtained crude product was dissolved in toluene-
Acetone mixture (solvent volume ratio: toluene: acetone = 5:
Purification was performed by silica gel chromatography (trade name: silica gel 60H, manufactured by Merck) using 1) to obtain 1.7 g of the title compound as white crystals (yield: 71%). Melting point 16
8-170 ° C.

¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 to 1.5 (4H,
m), 1.5-1.7 (1H, br.s), 1.9-2.1 (2H, m), 2.4
~ 2.5 (1H, m), 2.9 (2H, d, J = 11.7Hz), 3.5 (2H,
s), 4.7 (2H, d), 5.2 to 5.4 (2H, m), 5.9 to 6.1 (1
H, m), 6.6 (1H, s), 7.2-7.7 (12H, m).

Example 5 N- [4- (2-propenylthiocarbonylamino) benzyl]-
Production of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 40) In a 50 ml four-necked flask equipped with a stirrer, reflux condenser and thermometer capable of measuring up to 100 ° C., 2-propene-1-
0.45 g (6 mmol) of thiol, 15 ml of tetrahydrofuran and 1 drop of triethylamine were added and cooled with cold water. 5
0.84 g of 4- (chloromethyl) phenyl isocyanate at ℃
(5 mmol) was added, followed by stirring at room temperature for 3 hours. next,
2.2 g (5 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine and 1.94 g (15 mmol) of diisopropylethylamine were added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hours. The obtained reaction mixture was poured into cold water, and ethyl acetate was added for extraction. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. The obtained crude product (3.2 g) was purified by silica gel (trade name: silica gel 60H, manufactured by Merck) using a toluene-acetone mixture (solvent volume ratio: toluene: acetone = 10: 1) as a developing solvent, and purified under the title. 1.5 g of the desired compound was obtained as a yellow oil (yield 47%).

¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 to 1.5 (4H,
m), 1.5-1.7 (1H, br.s), 1.9-2.1 (2H, m), 2.5
~ 2.7 (1H, m), 2.9 (2H, d, J = 11.5Hz), 3.5 (2H,
s), 3.6 (2H, d, J = 6.8Hz), 5.0 to 5.3 (2H, m), 5.
7 to 6.0 (1H, m), 7.0 (1H, s), 7.1 to 7.5 (12H,
m).

Example 6 N- [4- (1-methyl-2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 83)
Manufacturing of In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.43 g (6 mmol) of 3-buten-2-ol, 10 ml of N, N-dimethylformamide and 2 drops of triethylamine were placed. . After adding 0.5 g (3 mmol) of 4- (chloromethyl) phenyl isocyanate at room temperature, the mixture was stirred at room temperature for 1 hour. Next, 1.5 g (3.4 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, 15 ml of tetrahydrofuran and 1.16 g of diisopropylethylamine were added to the reaction mixture at room temperature.
(9 mmol) and further stirred at room temperature for 3 hours.

The obtained reaction mixture was poured into a saturated saline solution, and extracted with ethyl acetate. The organic layer was washed with water, washed twice with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. The obtained crude product (1.9 g) was purified by silica gel (trade name: silica gel 60H, manufactured by Merck) using a toluene-acetone mixture (solvent volume ratio: toluene: acetone = 5: 1) as a developing solvent, and purified under the title. 1.0 g of the target compound was obtained as yellow crystals (yield 52%). 77-80 ° C.

¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 (3H, d, J =
6.4Hz), 1.4 to 1.7 (4H, m), 1.9 to 2.0 (2H, m), 2.
2 to 2.3 (1H, m), 2.9 (2H, d, J = 11.7Hz), 3.5 (2
H, s), 5.1-5.4 (3H, m), 5.8-6.0 (1H, m), 6.6
(1H, s), 7.1-7.5 (12H, m).

Example 7 N- [4- (2,4-hexadienyloxycarbonylamino)
Production of benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 168) 0.6 g (6 mmol) of 2,4-hexadienol and 15 ml of N, N-dimethylformamide in a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C.
And 2 drops of triethylamine and cooled with ice. 10 ℃
0.67 g of 4- (chloromethyl) phenyl isocyanate
(4 mmol) was added, followed by stirring at room temperature for 3 hours. 4- [bis (4-trifluoromethoxyphenyl) in the reaction mixture
[Hydroxymethyl] piperidine (1.7 g, 4 mmol) and potassium carbonate (1.1 g, 8 mmol) were added.
Stirred for hours. The obtained reaction mixture was poured into cold water, and ethyl acetate was added for extraction. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. Using 2.5 g of the obtained crude product as a developing solvent, toluene
-Acetone mixture (solvent volume ratio toluene: acetone = 5:
Purification by chromatography on silica gel (trade name: silica gel 60H, manufactured by Merck) using 1) to obtain 1.7 g of the title compound as a pale yellow oil (yield: 65%).

¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 to 1.5 (4H,
m), 1.7 (3H, d, J = 6.8Hz), 1.9 to 2.0 (2H, m), 2.
3 to 2.5 (1H, m), 2.9 (2H, d, 11.4Hz), 3.4 (2H,
s), 4.6 (2H, d, J = 6.6Hz), 5.6 to 5.8 (2H, m), 6.
0 to 6.4 (2H, m), 6.7 (1H, s), 7.1 to 7.5 (12H,
m).

Example 8 N- [4- (2-cyclohexenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl)
Production of [Hydroxymethyl] piperidine (Compound No. 173) In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.6 g (6 mmol) of 2-cyclohexenol, 10 ml of N, N-dimethylformamide and 2 drops of pyridine are put and cooled with ice. did. After adding 0.67 g (4 mmol) of 4- (chloromethyl) phenyl isocyanate at 7 ° C., the mixture was stirred at room temperature for 1.5 hours. 1.7 g (4 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hours. The obtained reaction mixture was poured into cold water, and a mixture of diethyl ether and ethyl acetate was added for extraction. The organic layer was washed with a saturated sodium hydrogen carbonate solution, then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. 2.3 g of crude product obtained
Was purified by chromatography on silica gel (trade name: silica gel 60H, manufactured by Merck Ltd.) using a toluene-acetone mixture (solvent volume ratio: toluene: acetone = 5: 1) as a developing solvent, to give 1.6 g of the title compound as a pale yellow oil (62% yield). ¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 to 1.5
(4H, m), 1.6-2.1 (8H, m), 2.3-2.4 (1H, m),
2.9 (2H, d, J = 11.3Hz), 3.5 (2H, s), 5.2 to 5.3 (1
H, m), 5.7-5.8 (1H, m), 5.9-6.0 (1H, m), 6.6
(1H, s), 7.1-7.5 (12H, m).

Example 9 Production of N- [4- (2-propynyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 174) a) Production of 4- (2-propynyloxycarbonylamino) benzyl chloride 0.50 g of 4- (chloromethyl) phenyl isocyanate was placed in a 30 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. (3 mmol), 5 ml of chloroform and 2 drops of triethylamine were added and cooled with ice water. 0.18 g of 2-propyn-1-ol at 10 ° C (3.3mmo
After adding l), the mixture was stirred at room temperature for 2 hours. Chloroform and water were added to the obtained reaction mixture for extraction. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product was washed with diisopropyl ether to obtain 0.67 g of the title compound (yield: 100%).
121-122 ° C.

¹ H-NMR (δ ppm / CDCl ₃ ): 2.5 (1H, t, J =
2.4Hz), 4.6 (2H, s), 4.8 (2H, d, J = 2.4Hz), 6.
7 (1H, bs), 7.3 to 7.5 (4H, m).

B) Production of N- [4- (2-propynyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine Measured with a stirrer, reflux condenser and up to 100 ° C. 1.31 g (3 mmol) of [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, 10 ml of dimethyl sulfoxide, 1.16 g (9 mmol) of diisopropylethylamine and 4- (2-
0.67 g (3 mmol) of propynyloxycarbonylamino) benzyl chloride was added, and the mixture was stirred at room temperature for 5 hours. Ethyl acetate and water were added to the obtained reaction mixture for extraction. The organic layer was washed with water and then with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. Using the obtained crude product as a developing solvent, a mixed solution of toluene and acetone (solvent volume ratio: toluene: acetone = 5: 1), silica gel (trade name: silica gel 60H, manufactured by Merck)
Purify by chromatography to give the title compound, 0.
60 g was obtained as a light brown oil (yield 32%).

¹ H-NMR (δ ppm / CDCl ₃ ): 1.3 to 1.5 (4H,
m), 1.9 to 2.1 (2H, m), 2.3 to 2.4 (1H, m), 2.5 (1H
H, t, J = 2.5 Hz), 2.9 (2H, d, J = 11.6 Hz), 3.5 (2
H, s), 4.8 (2H, d, J = 2.5Hz), 6.7 (1H, s), 7.1
~ 7.5 (12H, m).

Example 10 N- [4- (2-butynyloxycarbonylamino) benzyl]-
Production of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 204) In a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C., 0.42 g (6 mmol) of 2-butyn-1-ol, 15 ml of N, N-dimethylformamide and 2 drops of triethylamine were placed. . After adding 0.5 g (3 mmol) of 4- (chloromethyl) phenyl isocyanate at room temperature, the mixture was stirred at room temperature for 1 hour. Next, 1.5 g (3.4 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine and 1.16 g (9 mmol) of diisopropylethylamine were added to the reaction mixture at room temperature, and the mixture was further stirred at room temperature for 3 hours. did. The obtained reaction mixture was poured into cold water, and ethyl acetate was added for extraction. Wash the organic layer with water,
After washing with a saturated saline solution, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. The obtained crude product 2.
0 g was purified by chromatography on silica gel (trade name: silica gel 60H, manufactured by Merck Ltd.) using a toluene-acetone mixture (solvent volume ratio: toluene: acetone = 5: 1) as a developing solvent to obtain 1.0 g of the title compound as yellow crystals (Yield 53%). 108-110 ° C.

¹ H-NMR (δ ppm / CDCl ₃ ): 1.4 to 1.5 (4H,
m), 1.9 (3H, t, J = 2.4Hz), 1.9-2.0 (2H, m),
2.3 to 2.5 (1H, m), 2.9 (2H, d, J = 11.9Hz), 3.5 (2
H, s), 4.7 (2H, q, J = 2.4Hz), 6.6 (1H, s), 7.1
~ 7.5 (12H, m).

Example 11 N- [4- (1-Methyl-2-propynyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 250)
Manufacturing of 0.42 g (5.97 mmol) of 3-butyn-2-ol and 0.50 g (2.99 mmol) of 4- (chloromethyl) phenyl isocyanate in a 30 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. ) And 4 drops of diisopropylethylamine, and the mixture was stirred at 60 ° C for 30 minutes.
Methyl-2-propynyloxycarbonylamino) benzyl chloride was obtained. Next, 1.30 g (2.99 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine in a 50 ml four-necked flask equipped with another stirring device, a reflux condenser and a thermometer capable of measuring up to 100 ° C.
10 ml of dimethyl sulfoxide and 0.58 g (4.48 mmol) of diisopropylethylamine were added, and the crude 4- (1-methyl-2-propynyloxycarbonylamino) benzyl chloride obtained above was added at room temperature, followed by stirring for 3 hours. The obtained reaction mixture was poured into cold water and extracted with a mixed solvent of toluene and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. Using the obtained crude product as a developing solvent, a mixed solvent of toluene and acetone (solvent volume ratio: toluene: acetone = 2: 1), silica gel (trade name: silica gel 60H, manufactured by Merck)
Purify by chromatography to give the title compound, 0.
89 g was obtained (yield 47%).

Example 12 N- [4- (3-butynyloxycarbonylamino) benzyl]-
Production of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (Compound No. 229) 0.42 g (5.97 mmol) of 3-butyn-1-ol and 0.50 g (2.99 mmol) of 4- (chloromethyl) phenyl isocyanate in a 50 ml four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. ) And 1 drop of diisopropylethylamine, and the mixture was stirred at 50 ° C. for 30 minutes. Next, 1.30 g (2.99 mm) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine was added to the reaction mixture.
ol), 10 ml of dimethyl sulfoxide and 0.77 g (5.97 mmol) of diisopropylethylamine were added, and the mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was poured into cold water and extracted twice with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure of a vacuum pump. 1.9 g of the obtained crude product was purified by silica gel (trade name: silica gel 60H, manufactured by Merck Ltd.) using a toluene-acetone mixture (solvent volume ratio: toluene: acetone = 2: 1) as a developing solvent, and purified under the title. 0.98 g of the target compound was obtained (yield: 52%). 142-145 ° C.

Example 13 N- [4- (N'-methyl-N '-(2-propenyloxycarbonyl) amino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine (compound Number 3
0) Manufacturing 1.35 g (3.1 mmol) of 4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, 10 ml of tetrahydrofuran and 50 ml of a four-necked flask equipped with a stirrer, a reflux condenser and a thermometer capable of measuring up to 100 ° C. 0.85 g (8.4 mmol) of triethylamine was added, and while stirring at room temperature, 0.8 g (2.8 mmol) of 4- [N- (2-propenyloxycarbonyl) -N-methylamino] benzyl bromide was added, followed by stirring at room temperature for 2 hours. . Toluene and water were added to the reaction mixture for extraction, and the toluene layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure using a vacuum pump. Using 1.8 g of the obtained crude product as a developing solvent, a mixture of toluene and acetone (solvent volume ratio: toluene: acetone = 5: 1)
Using silica gel (trade name: silica gel 60, manufactured by Merck)
H) Purification by chromatography gave 1.0 g of the title compound (56% yield). ¹ H-NMR (δ ppm / CDCl ₃ ):
1.4 to 1.5 (4H, m), 1.6 to 1.7 (1H, br.s), 1.9 to 2.1
(2H, m), 2.3 to 2.5 (1H, m), 2.9 (2H, d, J = 11.2H
z), 3.3 (3H, s), 3.5 (2H, s), 4.6 (2H, d, J = 5.
3Hz), 5.1-5.3 (2H, m), 5.9-6.0 (1H, m), 7.1
~ 7.5 (12H, m).

Table 2 shows the compounds obtained in the above Examples 1 to 13 and the compounds of the present invention produced in the same manner as in these Examples. The compound numbers in Table 2 are also referred to in Tables 3, 4 and 5.

Table 3 shows ¹ H-NMR spectrum data of the compound of the present invention. In measuring ¹ H-NMR spectrum data of each compound, tetramethylsilane (TM
S) was used, and CDCl ₃ was used as a solvent. However, the measurement of Compound No. 2, the compound was suspended in CDCl _3, further to the clear solution by the addition of CD ₃ OD few drops of ¹
It was subjected to measurement of H-NMR spectrum.

[0236] Formulation Examples Next, formulation examples of the compound of the general formula (I) according to the present invention will be shown. "Parts" in the preparation examples represent parts by weight.

The additives and proportions of the following formulation examples are not limited to these formulation examples, but can be varied over a wide range.

Formulation Example 1 Emulsion 10 parts of the compound of the present invention (Compound No. 1) was added to Solvesso 150
It was dissolved in 45 parts and 35 parts of N-methyl-2-pyrrolidone, and 10 parts of Solpol 3005X (manufactured by Toho Chemical Co., Ltd.) was added thereto.
The mixture was stirred and mixed to obtain a 10% emulsion.

Formulation Example 2 Wettable powder 20 parts of the compound of the present invention (Compound No. 12) were added to a mixture of 2 parts of sodium lauryl sulfate, 4 parts of sodium ligninsulfonate, 20 parts of white carbon and 54 parts of clay, and the juice was added. The mixture was stirred and mixed with a mixer to obtain a 20% wettable powder.

Formulation Example 3 Granules 5 parts of the compound of the present invention (Compound No. 83), 2 parts of sodium dodecylbenzenesulfonate, 2 parts of carboxymethylcellulose, 2 parts of sodium lauryl sulfate, bentonite
10 parts and 79 parts of clay were added and sufficiently stirred and mixed. An appropriate amount of water was added, the mixture was further stirred, granulated by a granulator, and dried by ventilation to obtain 5% granules.

Formulation Example 4 Dust 1 part of the compound of the present invention (Compound No. 174) is dissolved in 2 parts of soybean oil, 5 parts of white carbon, 0.3 parts of isopropyl acid phosphate (PAP) and 91.7 parts of clay are added, and the mixture is mixed with a juice mixer. The mixture was stirred and mixed to obtain a 1% powder.

Formulation Example 5 Flowable agent 20 parts of the compound of the present invention (Compound No. 204) was mixed with 20 parts of water containing 2 parts, 1 part and 0.2 parts of polyoxyethylene alkyl ether, sodium dialkyl sulfosuccinate and Proxel GXL, respectively. After wet pulverization using a dyno mill, propylene glycol and xanthan gum were mixed with 60 parts of water containing 8 parts and 0.32 parts, respectively, to obtain a 20% suspension in water.

Test Examples Next, test examples show that the compounds of the present invention are useful as active ingredients of insecticides.

Test Example 1 Insecticidal test against Spodoptera litura After adding acetone, xylene and solpol 700HD (manufactured by Toho Chemical Co.) to each of the compounds of the present invention, the compounds were suspended in ion-exchanged water to prepare a drug solution (100 ppm). did. Cabbage leaf pieces (diameter 8 cm) were immersed in this chemical solution and air-dried. Put the leaf pieces into a plastic cup covered with filter paper, release 10 third-instar larvae of Spodoptera litura, which are resistant to synthetic pyrethroids, organophosphates, carbamates and chitin synthesis inhibitors. do it,
It was left still in a constant temperature room at 25 ° C. Six days after the treatment, the mortality of Spodoptera litura was examined. Table 4 shows the test results.

Test Example 2 Insecticidal test against Japanese moth moth Acetone, xylene and solpol 700HD (manufactured by Toho Chemical Co., Ltd.) were added to each of the compounds of the present invention, and then suspended in ion-exchanged water to prepare a drug solution (100 ppm). did. Cabbage leaf pieces (diameter 8 cm) were immersed in this chemical solution and air-dried. Put the leaf pieces in a plastic Petri dish covered with filter paper, and use the synthetic pyrethroids, organophosphates, carbamates and chitin synthesis inhibitors that are resistant to Konaga 3
Ten young larvae were released, covered, and allowed to stand in a constant temperature room at 25 ° C. Six days after the treatment, the mortality of the diamondback moth was examined. Table 4 shows the test results.

Test Example 3 Insecticidal Test Against Chahamaki Acetone, xylene and a solution of Solpol 700HD (manufactured by Toho Chemical Co., Ltd.) were added to each of the compounds of the present invention, and then suspended in ion-exchanged water to prepare a drug solution (100 ppm). did. Tea leaves (5 sheets) were immersed in this chemical solution and air-dried. Put the leaves in a plastic Petri dish, release 10 third-instar larvae of Chahamaki, which are resistant to synthetic pyrethroids, organophosphates, carbamates and chitin synthesis inhibitors, cover, cover, and incubate at 25 ° C It was left still. Six days after the treatment, the mortality of Chahamaki was investigated. Table 4 shows the test results.
It was shown to.

Test Example 4 Comparative Test of Insecticidal Activity against Spodoptera litura (Comparative Compounds A and B described in US Pat. No. 5,556,966 and Japanese Patent Publication No. 9-505080)
And C were tested against insects of the cutworm, Spodoptera litura.

Acetone, xylene and sorbol 700HD were added to each of the compounds of the present invention and comparative compounds A, B and C.
After adding a solution (manufactured by Toho Chemical Co., Ltd.), the solution was suspended in ion-exchanged water to prepare a drug solution (10 ppm). Cabbage leaf pieces (diameter 8 cm) were immersed in this chemical solution and air-dried. Put the leaf pieces into a plastic cup covered with filter paper, release 10 third-instar larvae of Spodoptera litura, which are resistant to synthetic pyrethroids, organophosphates, carbamates and chitin synthesis inhibitors. Then, it was left still in a constant temperature room at 25 ° C. Three days after the treatment, the mortality of Spodoptera litura was examined. Table 5 shows the test results.

[0249]

[0250]

The novel piperidine derivative of the present invention has excellent insecticidal activity as shown in the above Test Examples.
Compared with the conventional piperidine compound, a remarkably excellent immediate insecticidal activity was observed at a lower dose.

[0251]

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hirotaka Furukawa 2385 Toda, Atsugi-shi, Kanagawa Hokuko Chemical Dormitory (72) Inventor Yasunori Sato 50-1, Suenaga, Takatsu-ku, Kawasaki-shi, Kanagawa 1 (72) Inventor Mayumi Hayashi 1-32-14-601, Morino, Machida-shi, Tokyo F-term (reference) 4C054 AA02 CC03 DD01 EE01 FF04 FF05 FF12 4H011 AC01 BA01 BB13 BB16 BC01 BC03 BC07 BC09 BC17 BC18 BC19 BC20 BC22 DA02 DA15 DA16 DC04 DC05 DC06 DC08 DH02 DH02DH DH14

Claims (12)

[Claims] 1. Formula (I) [In the formula, two R _{1 s} may be the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower haloalkyl group, a lower haloalkoxy group or a lower alkylsulfonyloxy group; ₂ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxyalkyl group or a lower alkylcarbonyl group, X represents an oxygen atom or a sulfur atom, Y represents an oxygen atom or a sulfur atom, and R ₃ is unsubstituted Or a lower alkenyl group or a lower alkynyl group having a substituent (the substituent is a hydroxy group, a halogen atom, a lower alkoxy group, a lower haloalkoxy group, a lower alkylthio group,
A lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower cycloalkyl group, a lower alkoxyalkoxy group, an amino group, a lower alkylamino group, a lower dialkylamino group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a trimethylsilyl group or a phenyl group is there)
Or a lower cycloalkenyl group]], its N-oxide or its salt. 2. In the general formula (I), two R _{1 s} may be the same or different and each represents a halogen atom, a lower haloalkyl group or a lower haloalkoxy group, R ₂ represents a hydrogen atom, and X represents Y represents an oxygen atom; R ₃ represents an unsubstituted or substituted lower alkenyl group or lower alkynyl group (the substituent is a halogen atom, a lower alkoxy group, a lower haloalkoxy group, a lower haloalkoxy group, A piperidine derivative according to claim 1, which is an alkylthio group, a lower alkoxyalkoxy group, a lower dialkylamino group or a lower alkoxycarbonyl group).
N-oxide or a salt thereof. 3. In the general formula (I), two R _{1 s} may be the same or different and each represents a halogen atom, a lower haloalkyl group or a lower haloalkoxy group, R ₂ represents a hydrogen atom, and X Represents an oxygen atom, Y represents an oxygen atom, and R ₃ is an unsubstituted lower alkenyl group or lower alkynyl group, the piperidine derivative according to claim 1,
-An oxide form or a salt thereof. 4. N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, an N-oxide thereof or a salt thereof. 2. The piperidine derivative according to 1. (5) N- [4- (2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethylphenyl) hydroxymethyl] piperidine, its N-oxide or a salt thereof. 2. The piperidine derivative according to 1. 6. N- [4- (1-methyl-2-propenyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, its N
The piperidine derivative according to claim 1, which is an oxide form or a salt thereof. 7. N- [4- (2-propynyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, an N-oxide thereof or a salt thereof. 2. The piperidine derivative according to 1. 8. The method according to claim 8, which is N- [4- (2-butynyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, an N-oxide thereof or a salt thereof. Item 4. The piperidine derivative according to Item 1. 9. N- [4- (1-methyl-2-propynyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, its N
The piperidine derivative according to claim 1, which is an oxide form or a salt thereof. (10) N- [4- (3-butynyloxycarbonylamino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, an N-oxide thereof or a salt thereof. Item 4. The piperidine derivative according to Item 1. 11. N- [4- (N'-methyl-N '-(2-propenyloxycarbonyl) amino) benzyl] -4- [bis (4-trifluoromethoxyphenyl) hydroxymethyl] piperidine, its N The piperidine derivative according to claim 1, which is an oxide form or a salt thereof. 12. An insecticide, acaricide or nematicide containing the piperidine derivative according to any one of claims 1 to 11, its N-oxide or a salt thereof as an active ingredient.