JPWO2007055197A1 - Process for producing 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile and intermediates thereof - Google Patents

Abstract

A piperidine derivative represented by the general formula ## STR1 ## wherein Y1 and Y2 are the same or different and each represents a hydroxyl group, a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group, or a salt thereof is intermediate. The production method to form a 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile, which is important as a pharmaceutical production intermediate, is safe in a high yield. It is useful as a method for producing easily.

Description

  The present invention relates to a process for producing 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile and intermediates thereof.

4- (3- (4- (3- (4- (amino (imino) methyl) phenoxy) propyl) -1-piperidinyl) propoxy) benzamidine (hereinafter referred to as T-2307) exhibits strong antifungal activity. And is useful as an antifungal agent (Non-patent Document 1).
WO03 / 074476 (Patent Document 1) describes a method for producing a T-2307 related compound. However, this production method has disadvantages such as (1) a large number of steps, (2) use of harmful reagents and solvents, (3) inconvenient reaction operation, and (4) use of expensive raw materials. Have.
WO 2006/003881 (Patent Document 2) describes a method for producing T-2307. However, this production method has many steps and complicated reaction operations.
There is no known simple manufacturing method of T-2307 that is safe for the human body, has a low environmental impact, and can be mass-produced using inexpensive raw materials.

International Publication No. 03/074476 Pamphlet International Publication No. 2006/003881 Pamphlet 44th Interscience Conference Abstracts (44th ICAAC abstracts), In Vitro and In Vivo Antifungal Activity of T-23207: a Novel Arylamidine. 2004, p. 209

  There is a strong demand for a simple production method of T-2307 that is safe for the human body, has a low environmental impact, and can be mass-produced using inexpensive raw materials.

「式中、Ｙ^１およびＹ^２は、同一または異なって、ヒドロキシル基、ハロゲン原子、アルカンスルホニルオキシ基またはアリールスルホニルオキシ基を示す。」で表されるピペリジン誘導体またはその塩が、４−（３−（４−（３−（４−シアノフェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンゾニトリルまたはその塩の有用な製造中間体であることを見出した。すなわち、本発明者らは、式［１ａ］

の化合物またはその塩を塩基の存在下、一般式［２］

「式中、Ｘは、ハロゲン原子を示す。」で表されるベンゾニトリル誘導体と反応させるか、または、一般式［１ｂ］

「式中、Ｙ^１ａおよびＹ^２ａは、同一または異なって、ハロゲン原子、アルカンスルホニルオキシ基またはアリールスルホニルオキシ基を示す。」で表されるピペリジン誘導体またはその塩を塩基の存在下、触媒の存在下または不存在下、４−ヒドロキシベンゾニトリルと反応させることにより、４−（３−（４−（３−（４−シアノフェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンゾニトリルまたはその塩が容易に製造できることを見出し、本発明を完成させた。Under such circumstances, as a result of intensive studies, the present inventors have found that 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile is T- It was found to be an important production intermediate in the production of 2307. Furthermore, the general formula [1]

In the formula, Y ¹ and Y ² are the same or different and each represents a hydroxyl group, a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group. It was found to be a useful intermediate for the preparation of-(4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile or its salts. That is, the inventors have the formula [1a]

Or a salt thereof in the presence of a base of the general formula [2]

The compound is reacted with a benzonitrile derivative represented by “wherein X represents a halogen atom” or represented by the general formula [1b].

In the formula, Y ^1a and Y ^2a are the same or different and each represents a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group. A piperidine derivative represented by the formula: 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile or a salt thereof is easily reacted with 4-hydroxybenzonitrile under or in the absence of Thus, the present invention was completed.

  According to the production method of the present invention, 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile which is important as a pharmaceutical production intermediate can be conveniently and industrially produced. Can be manufactured on a scale. In this production method, (1) the number of steps is small and the yield is high (2) no harmful reagents and solvents are used, (3) the reaction operation is simple, and (4) raw materials are inexpensive. , Etc. In other words, the production method of the present invention is 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1- It is useful as a simple method for producing piperidinyl) propoxy) benzonitrile.

Hereinafter, the present invention will be described in detail.
In the present specification, unless otherwise specified, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkanesulfonyloxy group is, for example, methanesulfonyloxy, trifluoromethanesulfonyloxy and ethanesulfonyloxy A C _1-6 alkanesulfonyloxy group optionally substituted by a halogen atom such as; an arylsulfonyloxy group means, for example, a benzenesulfonyloxy group and a toluenesulfonyloxy group.
Examples of the leaving group include a halogen atom, an alkanesulfonyloxy group, and an arylsulfonyloxy group.

In the piperidine derivative represented by the general formula [1] or a salt thereof, preferable compounds include the following compounds.
A compound in which Y ¹ and Y ² are the same and is a hydroxyl group or a halogen atom is preferred, and a compound in which Y ¹ and Y ² are a hydroxyl group is more preferred.
In the piperidine derivative represented by the general formula [1], preferred salts include p-toluenesulfonate and hydrochloride.

で表される化合物またはその塩を塩基の存在下、一般式［２］

「式中、Ｘは、前記と同様の意味を有する。」で表されるベンゾニトリル誘導体と反応させる方法が好ましく、Ｘがフッ素原子である一般式［２］の化合物を用いる方法がさらに好ましい。In the present invention, as a preferable production method, the following methods may be mentioned.
In a process for producing 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile or a salt thereof, the compound represented by the formula [1a]

Or a salt thereof in the presence of a base in the general formula [2]

A method of reacting with a benzonitrile derivative represented by “wherein X has the same meaning as described above” is preferred, and a method using a compound of the general formula [2] wherein X is a fluorine atom is more preferred.

  Next, the manufacturing method of this invention is demonstrated.

「式中、Ｘは、前記と同様の意味を有する。」[Production Method 1]

“Wherein X has the same meaning as described above.”

  As the compound of the general formula [2], for example, 4-fluorobenzonitrile and 4-chlorobenzonitrile are commercially available.

The compound of the formula [3] or a salt thereof can be produced by reacting the compound of the formula [1a] or a salt thereof with the compound of the general formula [2] in the presence of a base.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether. Ethers such as; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; and acetonitrile Nitriles such as these may be used, and these may be used as a mixture. Preferred solvents include aromatic hydrocarbons and sulfoxides, more preferably toluene and dimethyl sulfoxide, and even more preferably a mixed solvent of toluene and dimethyl sulfoxide.
The amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [1a]. is there.

  Examples of the base used in this reaction include triethylamine, N, N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). ) And organic bases such as pyridine; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate And inorganic bases such as sodium hydride and potassium hydride. Preferred bases include potassium tert-butoxide and sodium tert-butoxide. The usage-amount of a base should just be 2 times mole or more with respect to the compound of Formula [1a], Preferably, it is 2-3 times mole.

The usage-amount of the compound of General formula [2] should just be 2 times mole or more with respect to the compound of Formula [1a], Preferably, it is 2-3 times mole.
This reaction may be carried out at −20 to 120 ° C., preferably at −15 to 40 ° C. for 1 minute to 24 hours.

「式中、Ｙ^１ａおよびＹ^２ａは、前記と同様の意味を有する。」[Production Method 2]

“Wherein Y ^1a and Y ^2a have the same meaning as described above.”

The compound of the formula [3] or a salt thereof is produced by reacting the compound of the general formula [1b] or a salt thereof with the compound of the formula [4] in the presence of a base in the presence or absence of a catalyst. Can do.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane Halogenated hydrocarbons such as methylene chloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl Amides such as -2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; nitriles such as acetonitrile; and water It is may be used in these mixed. Preferable solvents include amides, and N, N-dimethylacetamide is more preferable.
Although the usage-amount of a solvent is not specifically limited, Preferably, it is 1-50 times amount (v / w) with respect to the compound of general formula [1b], More preferably, 1-15 times amount (v / w) It is.

  Examples of the base used in this reaction include triethylamine, N, N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). ) And organic bases such as pyridine; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate And inorganic bases such as sodium hydride and potassium hydride. Preferred bases include potassium carbonate and sodium carbonate. The usage-amount of a base should just be 2 times mole or more with respect to the compound of general formula [1b], Preferably, it is 2-3 times mole.

  Examples of the catalyst that is optionally used in this reaction include potassium iodide and sodium iodide. A preferred catalyst includes potassium iodide. The catalyst may be used in an amount of 0.01 to 10 times mol, preferably 0.1 to 1 times mol, of the compound of the general formula [1b].

The usage-amount of the compound of Formula [4] should just be 2 times mole or more with respect to the compound of General formula [1b], Preferably, it is 2-3 times mole.
This reaction may be carried out at 0 to 150 ° C., preferably 60 to 120 ° C. for 1 minute to 24 hours.

  Next, a method for producing the compound of the general formula [1] which is the compound of the present invention or a salt thereof will be described. The compound of the general formula [1] or a salt thereof is produced by a combination of methods known per se, and can be produced, for example, by the production method shown below.

「式中、Ｌ^１は、脱離基を示す。」[Production method A]

“Wherein L ¹ represents a leaving group.”

(A-1)
As the compound of the general formula [7], for example, 3-chloro-1-propanol is commercially available.

  The compound of the formula [6] can be produced by reacting the compound of the formula [5] with the compound of the general formula [7].

The solvent that is optionally used in this reaction is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic carbonization such as hexane and cyclohexane Hydrogens; halogenated hydrocarbons such as methylene chloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; N, N-dimethylformamide, N, N-dimethylacetamide and 1 Amides such as methyl-2-pyrrolidone; esters such as ethyl acetate; ketones such as acetone and 2-butanone; nitriles such as acetonitrile; and water These may be used as a mixture. Preferred solvents include water and toluene.
Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-50 times amount (v / w) with respect to the compound of Formula [5], More preferably, it is 1-15 times amount (v / w). is there.

The usage-amount of the compound of General formula [7] should just be 1 time mole or more with respect to the compound of Formula [5], Preferably, it is 1-2 times mole.
This reaction may be carried out at 0 to 200 ° C., preferably 70 to 120 ° C. for 1 minute to 24 hours.

  The compound of the formula [6] may be used in the next reaction as it is without being isolated.

(A-2)
The compound of the formula [1a] can be produced by subjecting the compound of the formula [6] to a reduction reaction.
Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.

When the compound of formula [6] is subjected to a catalytic hydrogenation reaction, the solvent used is not particularly limited as long as it does not affect the reaction. For example, methanol, ethanol, 2-propanol and 2-methyl Alcohols such as 2-propanol; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; benzene Aromatic hydrocarbons such as toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether; S; ketones such as acetone and 2-butanone; esters such as ethyl acetate; carboxylic acids such as acetic acid; such as well water and the like, may be used which are mixed. Preferred solvents include water and toluene.
The amount of the solvent used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) the amount of the compound of formula [6]. is there.

Examples of the metal catalyst include palladium catalysts such as palladium-carbon, palladium oxide, palladium hydroxide and palladium black, nickel catalysts such as Raney nickel, platinum oxide and the like. The amount may be 0.001 to 1 times (w / w), preferably 0.01 to 0.5 times (w / w).
Examples of the reducing agent other than hydrogen include formic acid; formate salts such as sodium formate, ammonium formate, and triethylammonium formate; cyclohexene, cyclohexadiene, and the like. The amount used is 6 relative to the compound of formula [6]. ˜100 times mole, preferably 6 to 10 times mole.
The hydrogen pressure may be 1 to 30 atmospheres, preferably 1 to 10 atmospheres.
This reaction may be carried out at 0 to 200 ° C., preferably 50 to 100 ° C. for 1 minute to 24 hours.

  The compound of the formula [1a] or a salt thereof may be used as it is in the next reaction without isolation.

「式中、Ｌ^１は、前記と同様の意味を有する。」[Production method B]

“Wherein L ¹ has the same meaning as described above.”

(B-1)
The compound of the formula [8] or a salt thereof can be produced by subjecting the compound of the formula [5] to a reduction reaction.
This reaction may be performed according to production method A-2.
The compound of the formula [8] or a salt thereof may be used as it is in the next reaction without isolation.

(B-2)
The compound of the formula [1a] or a salt thereof can be produced by reacting the compound of the formula [8] or a salt thereof with a compound of the general formula [7] in the presence or absence of a base.

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; N, N-dimethylformamide, N Amides such as N, dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; and nitriles such as acetonitrile. May be used. Preferable solvents include amides, and N, N-dimethylacetamide is more preferable.
Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-50 times amount (v / w) with respect to the compound of Formula [8], More preferably, it is 1-15 times amount (v / w). is there.

  Bases optionally used in this reaction include, for example, triethylamine, N, N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine and 1,8-diazabicyclo [5.4.0] undec-7-ene. Organic bases such as (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate And inorganic bases such as sodium hydride and potassium hydride. Preferred bases include potassium carbonate and sodium carbonate. The usage-amount of a base should just be 1 time mole or more with respect to the compound of Formula [8], Preferably, it is 1-3 times mole.

The usage-amount of the compound of General formula [7] should just be 1 time mole or more with respect to the compound of Formula [8], Preferably, it is 1-2 times mole.
This reaction may be carried out at 0 to 200 ° C., preferably 30 to 120 ° C. for 1 minute to 24 hours.

  The compound of the formula [1a] or a salt thereof may be used as it is in the next reaction without isolation.

「式中、Ｌ^２は、脱離基を；Ｙ^１ａおよびＹ^２ａは、前記と同様の意味を有する。」[Production Method C]

“Wherein L ² represents a leaving group; Y ^1a and Y ^2a have the same meaning as described above.”

(C-1)
As the compound of general formula [9], for example, 1-bromo-3-chloropropane and the like are commercially available.

  The compound of the general formula [1c] can be produced by reacting the compound of the formula [8] or a salt thereof with the compound of the general formula [9] in the presence or absence of a base.

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane Halogenated hydrocarbons such as methylene chloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl Amides such as -2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate; ketones such as acetone and 2-butanone; and acetonitrile Include such as nitriles, it may be used as a mixture. Preferred solvents include esters, and ethyl acetate is more preferred.
Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-50 times amount (v / w) with respect to the compound of Formula [8], More preferably, it is 1-15 times amount (v / w). is there.

  Bases optionally used in this reaction include, for example, triethylamine, N, N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine and 1,8-diazabicyclo [5.4.0] undec-7-ene. Organic bases such as (DBU); metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate And inorganic bases such as sodium hydride and potassium hydride. Preferred bases include potassium carbonate and sodium carbonate. The usage-amount of a base should just be 1 time mole or more with respect to the compound of Formula [8], Preferably, it is 1-3 times mole.

The usage-amount of the compound of General formula [9] should just be 1 time mole or more with respect to the compound of Formula [8], Preferably, it is 1-2 times mole.
This reaction may be carried out at 0 to 200 ° C., preferably 30 to 120 ° C. for 1 minute to 24 hours.

  The compound of the general formula [1c] or a salt thereof may be used as it is in the next reaction without isolation.

(C-2)
The compound of the general formula [1b] or a salt thereof can be produced by converting the hydroxyl group of the compound of the general formula [1c] or a salt thereof into a leaving group.
When the leaving group is an alkanesulfonyloxy group or an arylsulfonyloxy group, the compound of the general formula [1c] or a salt thereof is added in the presence or absence of a base, for example, an alkanesulfonyl chloride such as methanesulfonyl chloride or What is necessary is just to make it react with aryl sulfonyl chlorides, such as p-toluenesulfonic acid chloride.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone. Amides; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether Nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and heteroaromatics such as pyridine. These may be used as a mixture.

The amount of alkanesulfonyl chloride and arylsulfonyl chloride used may be 2 to 10 times mol, preferably 2 to 3 times mol, of the compound of general formula [1c].
Bases optionally used in this reaction include, for example, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide; sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate Inorganic bases such as potassium carbonate, sodium hydride and potassium hydride; and organic bases such as triethylamine, N, N-diisopropylethylamine and pyridine. The amount of the base used may be 1 to 10 times mol, preferably 1 to 3 times mol, of the compound of the general formula [1c].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C., for 1 minute to 48 hours.

When the leaving group is a halogen atom, the compound of the general formula [1c] can be reacted with a reagent such as thionyl chloride, thionyl bromide, boron tribromide and carbon tetrabromide-triphenylphosphine. Good. The usage-amount of a reagent should just be 1-10 times mole with respect to the compound of general formula [1c], Preferably it may be 1-3 times mole.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone. Amides; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether Nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and heteroaromatics such as pyridine. These may be used as a mixture.
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C., for 1 minute to 48 hours.

  The compound of the general formula [1b] or a salt thereof may be used as it is in the next reaction without isolation.

「式中、Ｙ^１ｂおよびＹ^２ｂは、同一であり、ハロゲン原子、アルカンスルホニルオキシ基またはアリールスルホニルオキシ基を示す。」[Production Method D]

“ ^Wherein Y ^1b and Y ^2b are the same and represent a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group.”

The compound of the general formula [1d] or a salt thereof can be produced by converting the hydroxyl group of the compound of the general formula [1a] or a salt thereof into a leaving group.
This reaction may be performed according to the production method C-2.
The compound of the general formula [1d] or a salt thereof may be used as it is in the next reaction without isolation.

  In the above production method, the compound of the general formula [1] can also be used as a salt, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, Salts with organic carboxylic acids such as acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and methanesulfonic acid, benzenesulfonic acid, toluene And sulfonic acids such as sulfonic acid, mesitylene sulfonic acid, and naphthalene sulfonic acid.

  The thus obtained compound of the formula [1a] or a salt thereof and the compounds of the general formulas [1b], [1c] and [1d] or a salt thereof are known per se reactions such as condensation or hydrolysis. It can be derived to other compounds of the general formula [1] or salts thereof by attaching them to each other or by appropriately combining these reactions.

Next, although a reference example, an Example, and a manufacture example are given and this invention is demonstrated, this invention is not limited to these.
The mixing ratio in the eluent is a volume ratio. Unless otherwise specified, the carrier in silica gel column chromatography is Fuji Silysia Chemical Ltd., B.I. W. Silica gel, BW-127ZH.
In each example, each abbreviation has the following meaning.
Ms: Methanesulfonyl, Ts: p-toluenesulfonyl, PTS: p-toluenesulfonic acid, DMSO-d ₆ : heavy dimethyl sulfoxide

３−（ピペリジン−４−イル）プロパン−１−オ−ル5.00gをＮ,Ｎ−ジメチルアセトアミド25mLに溶解し、１−ブロモ−３−クロロプロパン5.77gおよび炭酸カリウム9.65gを加え、50℃で1時間撹拌した。反応液を冷却後、トルエンおよび水を加えた。有機層を分取し、水および飽和食塩水で順次洗浄後、減圧下で溶媒を留去し、黄色固体の３−（１−（３−クロロプロピル）ピペリジン−４−イル）プロパン−１−オ−ル5.21gを得た。
¹H-NMR(CDCl₃)δ値：1.15-2.15(13H,m),2.42-2.46(2H,m),2.80-3.00(2H,m),3.50-3.75(4H,m)Example 1

Dissolve 5.00 g of 3- (piperidin-4-yl) propan-1-ol in 25 mL of N, N-dimethylacetamide, add 5.77 g of 1-bromo-3-chloropropane and 9.65 g of potassium carbonate, and Stir for 1 hour. After cooling the reaction solution, toluene and water were added. The organic layer was separated, washed successively with water and saturated brine, and the solvent was evaporated under reduced pressure to give 3- (1- (3-chloropropyl) piperidin-4-yl) propan-1- 5.21 g of allol was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.15-2.15 (13H, m), 2.42-2.46 (2H, m), 2.80-3.00 (2H, m), 3.50-3.75 (4H, m)

３−（ピペリジン−４−イル）プロパン−１−オ−ル炭酸塩2.00gを酢酸エチル10mLに懸濁し、１−ブロモ−３−クロロプロパン3.4mLおよび炭酸カリウム4.77gを加え、40℃で6時間撹拌した。反応液を冷却後、水および塩酸を加えpH1.0とした。水層を分取し、20％水酸化ナトリウム水溶液およびトルエンを加え、pH10とした。有機層を分取し、トリエチルアミン2.40mLおよびメタンスルホニルクロリド1.16mLを加え、室温で30分間撹拌した。反応液に水および20％水酸化ナトリウム水溶液を加え、pH10とし、有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；クロロホルム：メタノ−ル＝５０：１）で精製し、淡黄色油状の３−（１−（３−クロロプロピル）ピペリジン−４−イル）プロピル＝メタンスルホナート2.21gを得た。
¹H-NMR(CDCl₃)δ値：1.15-1.40(5H,m),1.60-2.00(8H,m),2.44(2H,t,J=7.2Hz),2.84-2.92(2H,m),3.00(3H,s),3.58(2H,t,J=6.6Hz),4.21(2H,t,J=6.6Hz)Example 2

2.00 g of 3- (piperidin-4-yl) propane-1-ol carbonate is suspended in 10 mL of ethyl acetate, 3.4 mL of 1-bromo-3-chloropropane and 4.77 g of potassium carbonate are added, and the mixture is heated at 40 ° C. for 6 hours. Stir. After cooling the reaction solution, water and hydrochloric acid were added to adjust the pH to 1.0. The aqueous layer was separated, and 20% aqueous sodium hydroxide solution and toluene were added to adjust the pH to 10. The organic layer was separated, 2.40 mL of triethylamine and 1.16 mL of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 30 minutes. Water and a 20% aqueous sodium hydroxide solution were added to the reaction solution to adjust the pH to 10, the organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 50: 1) to give 3- (1- (3-chloropropyl) piperidin-4-yl) propyl as a pale yellow oil. = 2.21 g of methanesulfonate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.15-1.40 (5H, m), 1.60-2.00 (8H, m), 2.44 (2H, t, J = 7.2Hz), 2.84-2.92 (2H, m), 3.00 (3H, s), 3.58 (2H, t, J = 6.6Hz), 4.21 (2H, t, J = 6.6Hz)

３−（ピペリジン−４−イル）プロパン−１−オ−ル炭酸塩2.00gを酢酸エチル10mLに懸濁し、１−ブロモ−３−クロロプロパン2.3mLおよび炭酸カリウム3.18gを加え、50℃で5時間撹拌した。反応液を冷却後、水および塩酸を加え、pH1.0とした。水層を分取し、20％水酸化ナトリウム水溶液およびトルエンを加え、pH10とした。有機層を分取し、トリエチルアミン2.40mLおよびｐ−トルエンスルホニルクロリド2.85gを加え、60℃で4時間撹拌した。反応液に水および20％水酸化ナトリウム水溶液を加え、pH10とし、有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；酢酸エチル）で精製し、淡黄色油状の３−（１−（３−クロロプロピル）ピペリジン−４−イル）プロピル＝４−メチルベンゼンスルホナート2.00gを得た。
¹H-NMR(CDCl₃)δ値：1.05-1.30(5H,m),1.50-2.00(8H,m),2.43(2H,t,J=7.2Hz),2.45(3H,s),2.80-2.88(2H,m),3.57(2H,t,J=6.6Hz),4.01(2H,t,J=6.6Hz),7.35(2H,d,J=8.4Hz),7.79(2H,d,J=8.4Hz)Example 3

2.00 g of 3- (piperidin-4-yl) propane-1-ol carbonate is suspended in 10 mL of ethyl acetate, 2.3 mL of 1-bromo-3-chloropropane and 3.18 g of potassium carbonate are added, and the mixture is stirred at 50 ° C. for 5 hours. Stir. After cooling the reaction solution, water and hydrochloric acid were added to adjust the pH to 1.0. The aqueous layer was separated, and 20% aqueous sodium hydroxide solution and toluene were added to adjust the pH to 10. The organic layer was separated, 2.40 mL of triethylamine and 2.85 g of p-toluenesulfonyl chloride were added, and the mixture was stirred at 60 ° C. for 4 hours. Water and a 20% aqueous sodium hydroxide solution were added to the reaction solution to adjust the pH to 10, the organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 3- (1- (3-chloropropyl) piperidin-4-yl) propyl 4-methylbenzenesulfonate as a pale yellow oil. 2.00 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.05-1.30 (5H, m), 1.50-2.00 (8H, m), 2.43 (2H, t, J = 7.2Hz), 2.45 (3H, s), 2.80- 2.88 (2H, m), 3.57 (2H, t, J = 6.6Hz), 4.01 (2H, t, J = 6.6Hz), 7.35 (2H, d, J = 8.4Hz), 7.79 (2H, d, J = 8.4Hz)

３−（ピペリジン−４−イル）プロパン−１−オ−ル0.50gをアセトン5mLに溶解し、１−ブロモ−３−クロロプロパン0.60gおよび炭酸カリウム0.48gを加え、室温で1時間30分間、ついで40℃で2時間撹拌した。反応液にトルエンおよび水を加え、有機層を分取し、水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をトルエン5mLに溶解し、塩化チオニル0.51mLを加え、70℃で5分間撹拌した。反応液の溶媒を減圧下で留去した。得られた残留物にトルエンを加え、固形物をろ取し、淡黄色固体の１，４−ビス（３−クロロプロピル）ピペリジン塩酸塩0.66gを得た。
¹H-NMR(CDCl₃)δ値：1.45-1.60(3H,m),1.75-1.95(4H,m),2.00-2.15(2H,m),2.40-2.55(2H,m),2.60-2.75(2H,m),3.05-3.15(2H,m),3.53(2H,t,J=6.5Hz),3.55-3.65(2H,m),3.68(2H,t,J=5.9Hz),12.45(1H,s)Example 4

Dissolve 0.50 g of 3- (piperidin-4-yl) propan-1-ol in 5 mL of acetone, add 0.60 g of 1-bromo-3-chloropropane and 0.48 g of potassium carbonate, and then at room temperature for 1 hour and 30 minutes, Stir at 40 ° C. for 2 hours. Toluene and water were added to the reaction solution, the organic layer was separated, washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 5 mL of toluene, 0.51 mL of thionyl chloride was added, and the mixture was stirred at 70 ° C. for 5 minutes. The solvent of the reaction solution was distilled off under reduced pressure. Toluene was added to the resulting residue, and the solid was collected by filtration to obtain 0.66 g of 1,4-bis (3-chloropropyl) piperidine hydrochloride as a pale yellow solid.
¹ H-NMR (CDCl ₃ ) δ value: 1.45-1.60 (3H, m), 1.75-1.95 (4H, m), 2.00-2.15 (2H, m), 2.40-2.55 (2H, m), 2.60-2.75 (2H, m), 3.05-3.15 (2H, m), 3.53 (2H, t, J = 6.5Hz), 3.55-3.65 (2H, m), 3.68 (2H, t, J = 5.9Hz), 12.45 ( 1H, s)

３−（ピペリジン−４−イル）プロパン−１−オ−ル1.00gをＮ,Ｎ−ジメチルアセトアミド5mLに溶解し、トリエチルアミン1mLおよび３−クロロ−１−プロパノ−ル0.66gを加え、100℃で2時間30分間撹拌した。反応液を冷却後、室温で塩化チオニル1.5mLを加え、同温度で30分間撹拌した。反応液に酢酸エチル、炭酸水素ナトリウム水溶液および20％水酸化ナトリウム水溶液を加えた。有機層を分取し、希塩酸を加えた。水層を分取し、水酸化ナトリウムおよびトルエンを加えた。有機層を分取し、無水硫酸ナトリウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；クロロホルム：メタノール＝２０：１）で精製し、淡黄色油状の１，４−ビス（３−クロロプロピル）ピペリジン1.06gを得た。
¹H-NMR(CDCl₃)δ値：1.15-1.45(5H,m),1.60-2.00(8H,m),2.44(2H,t,J=7.2Hz),2.80-2.95(2H,m),3.52(2H,t,J=6.8Hz),3.58(2H,t,J=6.6Hz)Example 5

Dissolve 1.00 g of 3- (piperidin-4-yl) propan-1-ol in 5 mL of N, N-dimethylacetamide, add 1 mL of triethylamine and 0.66 g of 3-chloro-1-propanol, and Stir for 2 hours 30 minutes. After cooling the reaction solution, 1.5 mL of thionyl chloride was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate, aqueous sodium hydrogen carbonate solution and 20% aqueous sodium hydroxide solution were added to the reaction solution. The organic layer was separated and diluted hydrochloric acid was added. The aqueous layer was separated and sodium hydroxide and toluene were added. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 20: 1) to obtain 1.06 g of 1,4-bis (3-chloropropyl) piperidine as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ value: 1.15-1.45 (5H, m), 1.60-2.00 (8H, m), 2.44 (2H, t, J = 7.2Hz), 2.80-2.95 (2H, m), 3.52 (2H, t, J = 6.8Hz), 3.58 (2H, t, J = 6.6Hz)

（１） ３−（４−ピリジル）プロパン−１−オール150gを水150mLに溶解し、３−クロロ−１−プロパノ−ル109gを加え、還流下で3時間撹拌した。反応液を冷却後、10％パラジウム−炭素（50％Wet）15.0gを加え、水素加圧下（5kg/cm²）、75℃で7時間30分間撹拌した。反応液を冷却後、不溶物をろ去し、残渣を水140mLで洗浄した。ろ液と洗液を合わせ、水酸化ナトリウム48.1gを加え、室温まで冷却した。塩化メチレンを加え、有機層を分取し、常圧下で溶媒を留去した。得られた残留物を２−プロパノール1.20Lに溶解し、ｐ−トルエンスルホン酸１水和物208gを加えた。固形物をろ取し、白色固体の３−（４−（３−ヒドロキシプロピル）−１−ピペリジニル）−１−プロパノール ｐ−トルエンスルホン酸塩292gを得た。
¹H-NMR(D₂O)δ値：1.25-1.70(7H,m),1.90-2.10(4H,m),2.40(3H,s),2.85-3.00(2H,m),3.10-3.25(2H,m),3.50-3.65(4H,m),3.69(2H,t,J=6.1Hz),7.38(2H,d,J=8.0Hz),7.70(2H,d,J=8.0Hz)Example 6

(1) 3- (4-Pyridyl) propan-1-ol 150 g was dissolved in 150 mL of water, 109 g of 3-chloro-1-propanol was added, and the mixture was stirred under reflux for 3 hours. After cooling the reaction solution, 15.0 g of 10% palladium-carbon (50% Wet) was added, and the mixture was stirred at 75 ° C. for 7 hours 30 minutes under hydrogen pressure (5 kg / cm ² ). After cooling the reaction solution, the insoluble material was removed by filtration, and the residue was washed with 140 mL of water. The filtrate and washings were combined, 48.1 g of sodium hydroxide was added, and the mixture was cooled to room temperature. Methylene chloride was added, the organic layer was separated, and the solvent was distilled off under normal pressure. The obtained residue was dissolved in 1.20 L of 2-propanol, and 208 g of p-toluenesulfonic acid monohydrate was added. The solid was collected by filtration to obtain 292 g of 3- (4- (3-hydroxypropyl) -1-piperidinyl) -1-propanol p-toluenesulfonate as a white solid.
¹ H-NMR (D ₂ O) δ value: 1.25-1.70 (7H, m), 1.90-2.10 (4H, m), 2.40 (3H, s), 2.85-3.00 (2H, m), 3.10-3.25 ( 2H, m), 3.50-3.65 (4H, m), 3.69 (2H, t, J = 6.1Hz), 7.38 (2H, d, J = 8.0Hz), 7.70 (2H, d, J = 8.0Hz)

(2) 30 g of 3- (4-pyridyl) propan-1-ol and 21.7 g of 3-chloro-1-propanol were dissolved in 180 mL of toluene and stirred for 9 hours under reflux. After cooling the reaction solution, 30 mL of water and 3.0 g of 10% palladium-carbon (50% Wet) were added, and the mixture was stirred at 75 ° C. for 5 hours under hydrogen pressure (5 kg / cm ² ). After cooling the reaction solution, the insoluble material was removed by filtration, and the residue was washed with 30 mL of water. The filtrate and washings were combined, and 9.6 g of sodium hydroxide in 30 mL of water and 9.0 g of sodium chloride were added. The organic layer was separated at 45 ° C., and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 210 mL of 2-propanol, the insoluble material was removed by filtration, and the residue was washed with 30 mL of 2-propanol. The filtrate and the washing solution were combined, and 41.6 g of p-toluenesulfonic acid monohydrate was added. The solid was collected by filtration to obtain 62.4 g of 3- (4- (3-hydroxypropyl) -1-piperidinyl) -1-propanol p-toluenesulfonate as a white solid.
¹ H-NMR in D ₂ O was consistent with the value of Example 6 (1).

３−（ピペリジン−４−イル）プロパン−１−オ−ル65.0gを酢酸エチル325mLに懸濁し、１−ブロモ−３−クロロプロパン143gおよび炭酸カリウム125gを加え、50℃で3時間撹拌した。反応液を冷却後、水325mLおよび塩酸160mLを加えた。水層を分取し、20％水酸化ナトリウム水溶液75mLおよびトルエン325mLを加えた。有機層を分取し、水160mLで2回洗浄した。分取した有機層374gのうち、185gにトリエチルアミン33.8gおよびメタンスルホニルクロリド33.2gを加え、室温で1時間撹拌した。反応液に水160mLおよび20％水酸化ナトリウム水溶液25mLを加えた。分取した有機層208gのうち、32.5gにＮ,Ｎ−ジメチルアセトアミド25mL、４−シアノフェノール8.31g、炭酸カリウム10.6gおよびヨウ化カリウム0.58gを加え、100℃で5時間撹拌した。反応液を冷却後、水100mLを加え、固形物をろ取し、淡黄色固体の４−（３−（４−（３−（４−シアノフェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンゾニトリル8.70gを得た。
¹H-NMR(CDCl₃)δ値：1.20-1.45(5H,m),1.65-2.05(8H,m),2.48(2H,t,J=7.3Hz),2.88-2.98(2H,m),3.99(2H,t,J=6.5Hz),4.06(2H,t,J=6.3Hz),6.89-6.97(4H,m),7.53-7.60(4H,m)Example 7

65.0 g of 3- (piperidin-4-yl) propan-1-ol was suspended in 325 mL of ethyl acetate, 143 g of 1-bromo-3-chloropropane and 125 g of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 3 hours. After cooling the reaction solution, 325 mL of water and 160 mL of hydrochloric acid were added. The aqueous layer was separated, and 75 mL of 20% aqueous sodium hydroxide solution and 325 mL of toluene were added. The organic layer was separated and washed twice with 160 mL of water. From 374 g of the separated organic layer, 33.8 g of triethylamine and 33.2 g of methanesulfonyl chloride were added to 185 g, followed by stirring at room temperature for 1 hour. To the reaction solution, 160 mL of water and 25 mL of 20% aqueous sodium hydroxide solution were added. From 208 g of the separated organic layer, 25 mL of N, N-dimethylacetamide, 8.31 g of 4-cyanophenol, 10.6 g of potassium carbonate and 0.58 g of potassium iodide were added to 32.5 g, and the mixture was stirred at 100 ° C. for 5 hours. After cooling the reaction solution, 100 mL of water was added, the solid was collected by filtration, and 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile was collected as a pale yellow solid. 8.70 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.20-1.45 (5H, m), 1.65-2.05 (8H, m), 2.48 (2H, t, J = 7.3 Hz), 2.88-2.98 (2H, m), 3.99 (2H, t, J = 6.5Hz), 4.06 (2H, t, J = 6.3Hz), 6.89-6.97 (4H, m), 7.53-7.60 (4H, m)

３−（ピペリジン−４−イル）プロパン−１−オ−ル65.0gを酢酸エチル325mLに懸濁し、１−ブロモ−３−クロロプロパン143gおよび炭酸カリウム125gを加え、50℃で3時間撹拌した。反応液を冷却後、水325mLおよび塩酸160mLを加えた。水層を分取し、20％水酸化ナトリウム水溶液75mLおよびトルエン325mLを加えた。有機層を分取し、水160mLで2回洗浄した。分取した有機層374gのうち、185gにトリエチルアミン33.8gおよびｐ−トルエンスルホニルクロリド55.3gを加え、60℃で4時間撹拌した。反応液を冷却後、水160mLおよび20％水酸化ナトリウム水溶液25mLを加えた。分取した有機層215gのうち、33.6gにＮ,Ｎ−ジメチルアセトアミド25mL、４−シアノフェノール8.31g、炭酸カリウム10.6gおよびヨウ化カリウム0.58gを加え、100℃で5時間撹拌した。反応液を冷却後、水100mLを加え、固形物をろ取し、淡黄色固体の４−（３−（４−（３−（４−シアノフェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンゾニトリル7.09gを得た。
CDCl₃中における¹H-NMRは、実施例７の値と一致した。Example 8

65.0 g of 3- (piperidin-4-yl) propan-1-ol was suspended in 325 mL of ethyl acetate, 143 g of 1-bromo-3-chloropropane and 125 g of potassium carbonate were added, and the mixture was stirred at 50 ° C. for 3 hours. After cooling the reaction solution, 325 mL of water and 160 mL of hydrochloric acid were added. The aqueous layer was separated, and 75 mL of 20% aqueous sodium hydroxide solution and 325 mL of toluene were added. The organic layer was separated and washed twice with 160 mL of water. From 374 g of the separated organic layer, 33.8 g of triethylamine and 55.3 g of p-toluenesulfonyl chloride were added to 185 g, and the mixture was stirred at 60 ° C. for 4 hours. After cooling the reaction solution, 160 mL of water and 25 mL of 20% aqueous sodium hydroxide solution were added. From 215 g of the separated organic layer, 25 mL of N, N-dimethylacetamide, 8.31 g of 4-cyanophenol, 10.6 g of potassium carbonate and 0.58 g of potassium iodide were added to 33.6 g, and the mixture was stirred at 100 ° C. for 5 hours. After cooling the reaction solution, 100 mL of water was added, the solid was collected by filtration, and 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile was collected as a pale yellow solid. 7.09 g was obtained.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 7.

１，４−ビス（３−クロロプロピル）ピペリジン塩酸塩4.00gおよび４−シアノフェノール3.48gをＮ,Ｎ−ジメチルアセトアミド24mLに溶解し、炭酸カリウム6.05gおよびヨウ化カリウム0.24gを加え、100℃で2時間撹拌した。反応液を冷却後、炭酸カリウム1.01gを加え、100℃で1時間撹拌した。反応液を冷却後、水50mLを加え、固形物をろ取し、淡褐色固体の４−（３−（４−（３−（４−シアノフェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンゾニトリル5.18gを得た。
CDCl₃中における¹H-NMRは、実施例７の値と一致した。Example 9

Dissolve 4.00 g of 1,4-bis (3-chloropropyl) piperidine hydrochloride and 3.48 g of 4-cyanophenol in 24 mL of N, N-dimethylacetamide, add 6.05 g of potassium carbonate and 0.24 g of potassium iodide, and add 100 ° C. For 2 hours. After cooling the reaction solution, 1.01 g of potassium carbonate was added and stirred at 100 ° C. for 1 hour. After cooling the reaction solution, 50 mL of water was added, the solid was collected by filtration, and a light brown solid of 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile. 5.18 g was obtained.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 7.

（１） ３−（４−（３−ヒドロキシプロピル）−１−ピペリジニル）−１−プロパノール ｐ−トルエンスルホン酸塩8.00gをジメチルスルホキシド40mLに溶解し、カリウムｔｅｒｔ−ブトキシド7.5gを加えた後、50〜57℃で40分間撹拌した。反応液を冷却後、23〜26℃で４−フルオロベンゾニトリル5.4gのジメチルスルホキシド8mL溶液を滴下し、同温度で2時間撹拌した。反応液を冷却後、酢酸0.6mLを加え、90〜94℃で水48mLを滴下した後、20℃まで冷却した。ついで、同温度で炭酸カリウム1.5gの水8mL溶液を加え、固形物をろ取し、淡黄色固体の４−（３−（４−（３−（４−シアノフェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンゾニトリル7.26gを得た。
CDCl₃中における¹H-NMRは、実施例７の値と一致した。Example 10

(1) After dissolving 8.00 g of 3- (4- (3-hydroxypropyl) -1-piperidinyl) -1-propanol p-toluenesulfonate in 40 mL of dimethyl sulfoxide and adding 7.5 g of potassium tert-butoxide, Stir at 50-57 ° C. for 40 minutes. After cooling the reaction solution, a solution of 5.4 g of 4-fluorobenzonitrile in dimethyl sulfoxide (8 mL) was added dropwise at 23 to 26 ° C., and the mixture was stirred at the same temperature for 2 hours. After cooling the reaction solution, 0.6 mL of acetic acid was added, 48 mL of water was added dropwise at 90 to 94 ° C., and then cooled to 20 ° C. Then, a solution of 1.5 g of potassium carbonate in 8 mL of water was added at the same temperature, and the solid was collected by filtration to give 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl as a pale yellow solid. ) Propoxy) benzonitrile 7.26g was obtained.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 7.

(2) 326 g of potassium tert-butoxide was suspended in 1.75 L of toluene and 700 mL of dimethyl sulfoxide, and 350 g of 3- (4- (3-hydroxypropyl) -1-piperidinyl) -1-propanol p-toluenesulfonate was added. Then, it stirred at 50-60 degreeC for 30 minutes. After cooling the reaction solution, a solution of 238 g of 4-fluorobenzonitrile in 350 mL of toluene was added dropwise at 0 to 15 ° C., and the temperature was raised to 25 ° C., followed by stirring at the same temperature for 1 hour. 175 mL of an aqueous solution of 28.1 g of acetic acid and 875 mL of water were added to the reaction solution. The mixture was stirred for 30 minutes under reflux, and then cooled to 20 ° C. Then, a solution of 64.8 g of potassium carbonate in 350 mL of water was added at the same temperature, and the solid was collected by filtration to give 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl as a pale yellow solid. ) Propoxy) benzonitrile (328 g) was obtained.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 10 (1).

４−（３−（４−（３−（４−シアノフェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンゾニトリル1.15gのエタノール20mL懸濁液に、氷冷下、塩化水素を導入した後、室温で24時間攪拌した。減圧下で溶媒を留去し、得られた残留物をエタノール20mLに溶解した。ついで、酢酸アンモニウム1.54gを加え、3時間45分間加熱還流した。反応混合物を室温まで冷却し、水を加えた後、減圧下でエタノールを留去した。得られた残留物にクロロホルムを加え、5.0mol/L水酸化ナトリウム水溶液を加え、pH12.5に調整した。固形物をろ取し、白色固体の４−（３−（４−（３−（４−（アミノ（イミノ）メチル）フェノキシ）プロピル）−１−ピペリジニル）プロポキシ）ベンズアミジン1.13gを得た。
¹H-NMR(DMSO-d₆)δ値：1.00-1.40(5H,m),1.60-1.80(4H,m),1.80-1.95(4H,m),2.35-2.45(2H,m),2.80-2.90(2H,m),3.98(2H,t,J=6.5Hz),4.03(2H,t,J=6.3Hz),6.30-7.20(4H,broad),6.85-7.00(4H,m),7.65-7.80(4H,m)Production Example 1

4- (3- (4- (3- (4-Cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile (1.15 g) in ethanol (20 mL) was introduced with hydrogen chloride under ice-cooling, and then at room temperature. For 24 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 20 mL of ethanol. Next, 1.54 g of ammonium acetate was added, and the mixture was heated to reflux for 3 hours and 45 minutes. The reaction mixture was cooled to room temperature, water was added, and ethanol was distilled off under reduced pressure. Chloroform was added to the obtained residue, and a 5.0 mol / L aqueous sodium hydroxide solution was added to adjust the pH to 12.5. The solid was collected by filtration to obtain 1.13 g of 4- (3- (4- (3- (4- (amino (imino) methyl) phenoxy) propyl) -1-piperidinyl) propoxy) benzamidine as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.00-1.40 (5H, m), 1.60-1.80 (4H, m), 1.80-1.95 (4H, m), 2.35-2.45 (2H, m), 2.80 -2.90 (2H, m), 3.98 (2H, t, J = 6.5Hz), 4.03 (2H, t, J = 6.3Hz), 6.30-7.20 (4H, broad), 6.85-7.00 (4H, m), 7.65-7.80 (4H, m)

  The method for producing 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile according to the present invention has the following advantages: (1) The number of steps is small and the yield is high. It is useful as an industrial production method because it has features such as (2) no use of harmful reagents and solvents, (3) simple reaction operation, and (4) inexpensive raw materials.

Claims (6)

General formula

A piperidine derivative represented by “in the formula, Y ¹ and Y ² are the same or different and each represent a hydroxyl group, a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group” or a salt thereof. The piperidine derivative or a salt thereof according to claim 1, wherein Y ¹ and Y ² are the same and are a hydroxyl group or a halogen atom. The piperidine derivative or a salt thereof according to claim 1 or ^{2, wherein} Y ¹ and Y ² are hydroxyl groups. formula

Or a salt thereof in the presence of a base in the general formula

4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-), which is reacted with a benzonitrile derivative represented by “wherein X represents a halogen atom”. A method for producing piperidinyl) propoxy) benzonitrile or a salt thereof. General formula

In the formula, Y ^1a and Y ^2a are the same or different and each represents a halogen atom, an alkanesulfonyloxy group or an arylsulfonyloxy group. A piperidine derivative represented by the formula: 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile or a salt thereof, characterized by reacting with 4-hydroxybenzonitrile under or in the absence Manufacturing method. The process for producing 4- (3- (4- (3- (4-cyanophenoxy) propyl) -1-piperidinyl) propoxy) benzonitrile or a salt thereof according to claim 4, wherein X is a fluorine atom.