WO1999046233A1 - Benzyl alcohol derivatives - Google Patents

Abstract

Benzyl alcohol derivatives represented by general formula (I) and a process for producing the same; wherein R1 represents cyano or -COOR2 (wherein R2 represents linear C¿1-5? alkyl); and a process for producing from the above benzyl alcohol derivatives intermediates which are useful in producing drugs such as sertraline useful as antidepressant.

Description

 Description Benzyl alcohol derivative Technical field

 The present invention relates to benzyl alcohol derivatives. More specifically, the present invention relates to a benzyl alcohol derivative and a method for producing the same, and a method for producing an intermediate useful for a medicine such as sertraline useful as an anti-drug from the benzyl alcohol derivative. Background art

 Sertraline is a compound useful as an antidepressant. Conventionally, as a method for producing a tetrahydronaphthalenone derivative which is an intermediate for producing sertraline, a method for producing a tetrahydronaphthalenone derivative using a substituted benzophenone and a succinic acid diester as starting materials (US Pat. No. 4,536,518) And a method for producing a tetrahydronaphthalenone derivative using succinic anhydride and 0-dichlorobenzene (US Pat. No. 4,777,288).

 However, the former method has a disadvantage that the total yield is necessarily low due to the large number of steps. In addition, the latter method requires an operation of isolating and purifying an intermediate produced during the production, and the production process is complicated. Therefore, it cannot be said that this method is industrially advantageous. An object of the present invention is to provide a method for efficiently producing an intermediate useful for medicines such as sertraline, which is useful as an antidepressant, and a benzyl alcohol derivative useful as a starting compound for the intermediate. .

These and other objects will be apparent from the description below. Disclosure of the invention

 According to the present invention,

 [1] General formula (I):

(In the formula, R ¹ represents a cyano group or a single COOR ² group, and R ² represents a linear alkyl group having 1 to 5 carbon atoms.)

A benzyl alcohol derivative represented by the following formula: [2] 3,4-dicyclobenzaldehyde and a general formula (II):

H

 H C = C (II)

R ¹

(Wherein, R ¹ is the same as described above)

Reacting with a vinyl compound represented by the general formula (111)

〔式中、 R¹ は前記と同じ〕

(Wherein, R ¹ is the same as described above)

A method for producing a benzyl alcohol derivative represented by the general formula (I), comprising reducing a ketone derivative represented by the following formula:

[3] A general formula (IV) comprising condensing a benzyl alcohol derivative represented by the general formula (I) with benzene in the presence of a Lewis acid:

(Wherein, R ¹ is the same as described above)

A method for producing a diphenylbutanoic acid derivative represented by

[4] a difurbutanoic acid derivative represented by the general formula (IV),

[5] Formula (V) comprising using a benzyl alcohol derivative represented by the general formula (I) as a starting compound:

A method for producing a tetrahydronaphthalenone derivative represented by: [6] A compound represented by the formula (XI) comprising reacting a tetrahydronaphthyllenone derivative represented by the formula (V) with 1 to 20 mol of methylamine per 1 mol of the tetrahydronaphthalenone derivative in an alcohol. ):

Method for the production of 4- (3,4-dichroic phenyl) -1-1-methylimino 1,2,3,4-tetrahydronaphthalene represented by

Is provided. BEST MODE FOR CARRYING OUT THE INVENTION

 Equation (V):

As a starting material for producing the tetrahydronaphthalenone derivative represented by the general formula (I):

(In the formula, R ¹ represents a cyano group or a single COOR ² group, and R ² represents a linear alkyl group having 1 to 5 carbon atoms.)

A benzyl alcohol derivative represented by the following formula is used.

—In the general formula (I), R ¹ is a cyano group or a COOR ² group, and R ² is a linear alkyl group having 1 to 5 carbon atoms. Specific examples of the linear alkyl group having 1 to 5 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and an n-pentyl group. Among them, a methyl group and an ethyl group are preferred.

で表される 4— (3， 4—ジクロロフエニル） — 4ーヒドロキシブチロニトリル は、 好適に使用しうるものである。 Representative examples of the benzyl alcohol derivative represented by the general formula (I) include 4- (3,4-dichlorophenyl) -14-hydroxybutyronitrile and 4- (3,4-dichlorophenyl) -14 Methyl 4-hydroxybutanoate, 4- (3,4-dichlorophenyl) -1-ethyl 4-hydroxybutanoate, 4- (3,4-dichlorophenyl) n-propyl 4-hydroxybutanoate, 4- (3,4- Dichloromouth phenyl) — n-butyl 4-hydroxybutanoate and the like. Among them, 4- (3,4-dichrophenyl) -1-hydroxybutyronitrile, 4- (3,4-dichlorophenyl) -14-methyl 4-hydroxybutanoate and 4- (3,4 —Dichlorophenyl) ethyl 4-hydroxybutanoate, especially of formula (VI):

4- (3,4-dichlorophenyl) -4-hydroxybutyronitrile represented by the following formula can be suitably used.

 The benzyl alcohol derivative represented by the general formula (I) is composed of 3,4-dichlorobenzaldehyde and the general formula (II):

H ₂ C = C \ (II)

R ¹

(Wherein, R ¹ is the same as described above)

With a vinyl compound represented by the general formula (I 11)

(Wherein, R ¹ is the same as described above)

Can be produced by reducing the ketone derivative represented by

-Representative examples of the vinyl compound represented by the general formula (II) include acrylonitrile, methyl acrylate, ethyl acrylate, n-propyl acrylate, and n-butyl acrylate. Among those vinyl compounds, acrylonitrile Methyl acrylate and ethyl acrylate, especially acrylonitrile, can be suitably used.

 The reaction between 3,4-dichlorobenzaldehyde and a vinyl compound is performed by mixing the vinyl compound at a ratio of about 0.7 to 1.0 mole of the vinyl compound per mole of 3,4-dichlorobenzaldehyde, The reaction can be carried out at a temperature of about 0 to 100 in the presence of a catalyst such as sodium cyanide or potassium cyanide. The amount of the catalyst to be used is not particularly limited, but is usually about 0.05 to 0.2 mol per 1 mol of 3,4-dichlorobenzaldehyde.

 In the reaction, for example, a polar solvent such as dimethylformamide, an organic solvent such as alcohols such as methanol, ethanol, and isopropanol, and an ester such as esters such as ethyl acetate can be used. The amount of the organic solvent may usually be about 100 to 500 parts by weight based on 100 parts by weight of 3,4-dichlorobenzaldehyde.

 The atmosphere at the time of the reaction is not particularly limited, and may be usually air or an inert gas such as nitrogen gas or argon gas. The reaction temperature is preferably about 20 to 8 (TC).

 The completion of the reaction can be confirmed, for example, by high-performance liquid chromatography, by the decrease or disappearance of the peak of unreacted 3,4-dichlorobenzaldehyde.

In order to deactivate a catalyst such as sodium cyanide or potassium cyanide, it is preferable to add an acid such as acetic acid or formic acid to the obtained reaction solution. The amount of the acid may be about 1.05 to about 20 moles per mole of sodium or potassium cyanide. Thereafter, for example, an organic solvent and an aqueous layer are separated by using an extraction solvent such as toluene and water, and a ketone derivative can be obtained from the obtained organic layer. The obtained ketone derivative may be purified, if necessary, for example, by recrystallization from isopropanol or the like. Next, the obtained ketone derivative is reduced to obtain a benzyl alcohol derivative represented by the general formula (I).

 The reduction of the ketone derivative can be performed, for example, by hydride reduction using sodium borohydride. The amount of sodium borohydride is not particularly limited, but is usually about 0.3 to 3 mol, preferably about 0.4 to 1 mol, per 1 mol of the ketone derivative.

 In addition, when the ketone derivative is reduced, boric acid is preferably added. When boric acid is added, the formation of reaction by-products can be suppressed. Although the amount of boric acid is not particularly limited, it is generally desirable that the amount is 0.1 to 0.5 mol, preferably 0.2 to 0.4 mol, per 1 mol of the ketone derivative.

 In addition, a solvent can be used for the reduction of the ketone derivative. Examples of such a solvent include lower alcohols such as methanol and water. These solvents can be used alone or in combination of two or more. Further, another organic solvent may be used in order to improve the solubility of the ketone derivative. The amount of the solvent is not particularly limited, but is preferably about 300 to 200 parts by weight based on 100 parts by weight of the ketone derivative from the viewpoint of reaction yield and economy. It is usually about 0 to 100 ° C., preferably about 0 to 50 ° C., and more preferably about 0 to 20 ° C. The reaction time is usually about 0.5 to 3 hours.

 The end point of the reaction can be confirmed by high performance liquid chromatography that the peak of the unreacted ketone derivative has decreased or disappeared.

 The product can be recovered by, for example, extracting the reaction solution with an organic solvent such as toluene or ethyl acetate, washing the extract with water, and concentrating the organic layer.

The benzyl alcohol derivative represented by the general formula (I) thus obtained is, as described above, an intermediate useful for medicines such as sertraline useful as an antidepressant. It can be suitably used as an intermediate for producing a tetrahydronaphthalenone derivative represented by the formula (V).

 The tetrahydronaphthalenone derivative represented by the formula (V) can be produced by using a benzyl alcohol derivative represented by the general formula (I) as a starting compound. For example, a benzyl alcohol derivative represented by the general formula (I) is converted to a general formula (IV):

(Wherein, R ¹ is the same as described above)

By producing a diphenylbutanoic acid derivative represented by the following formula, and then closing the diphenylbutanoic acid derivative, a tetrahydronaphthalenone derivative represented by the formula (V) can be obtained.

 As a method for producing the diphenylbutanoic acid derivative represented by the general formula (IV), for example, a method of condensing a benzyl alcohol derivative represented by the general formula (I) with benzene in the presence of a Lewis acid is used. Is raised.

 When the benzyl alcohol derivative is condensed with benzene, another solvent may not be used because benzene serves as a reaction solvent. The amount of benzene to be used is preferably at least 500 parts by weight per 100 parts by weight of the benzyl alcohol derivative from the viewpoint of improving the stirring property and the reaction yield, and from the viewpoint of economy, it is preferably at least 500 parts by weight. It is preferably not more than 100 parts by weight.

Examples of Lewis acids include aluminum chloride, titanium tetrachloride, tin tetrachloride, boron trifluoride, concentrated sulfuric acid, chlorosulfonic acid, and trifluoromethanesulfonic acid. Throw. The amount of the Lewis acid used is about 1 to 5 mol, preferably about 2 to 4 mol, per 1 mol of the benzyl alcohol derivative.

 The reaction temperature may usually be in the range of room temperature to the reflux temperature of benzene. The reaction time varies depending on the reaction temperature and the like, and cannot be unconditionally determined, but is usually about 1 to 5 hours.

 The end point of the reaction can be confirmed by high-performance liquid chromatography that the peak based on the unreacted benzyl alcohol derivative has decreased or disappeared.

 Thus, the dibenzylbutanoic acid derivative represented by the general formula (IV) is obtained by condensing the benzyl alcohol derivative represented by the general formula (I) with benzene.

The diphenylbutanoic acid derivative represented by the general formula (IV) can be suitably used as an intermediate for producing the tetrahydronaphthalenone derivative represented by the following (V). In particular, among the diphenylbutanoic acid derivatives represented by the general formula (IV), a compound represented by the formula (VI II) in which R ¹ is a cyano group:

4- (3-, 4-dichlorophenyl) -4-phenylphenylonitrile represented by the following formula (1) can be suitably used in the present invention.

Next, the tetrahydronaphthalenone derivative represented by the formula (V) is obtained by reacting the diphenylbutanoic acid derivative represented by the general formula (IV) with a chlorinating agent, for example, after hydrolysis, and closing the ring. That is, 4— (3,4-dichloromouth phenyl) 1-1,2 1,3,4-Tetrahydro-11-naphthalenone is obtained. As described above, the tetrahydronaphthalenone derivative represented by the formula (V) is a compound useful as an intermediate of sertraline known as an antidepressant.

 Further, as another method for producing a tetrahydronaphthalenone derivative represented by the formula (V) from a benzyl alcohol derivative represented by the formula (I), a benzyl alcohol derivative represented by the formula (I) is used. Formula (VII) obtained by intramolecular cyclization

で表されるラクトン誘導体とベンゼンとを縮合させる方法があげられる。

A method of condensing a lactone derivative represented by the following formula with benzene.

 Lactone derivatives of formula (VII) are important intermediates for sertraline, a drug useful as an antidepressant.

 First, a benzyl alcohol derivative represented by the formula (VII) is obtained by intramolecular cyclization of a benzyl alcohol derivative represented by the general formula (I) by a conventional method.

By condensing the obtained lactone derivative and benzene according to a conventional method, a tetrahydronaphthalenone derivative represented by the formula (V) can be obtained. Also, as the benzyl alcohol derivative represented by the general formula (I), 4- (3,4-dichloromouth phenyl) —4-hydroxybutyronitrile represented by the formula (VI) wherein R ¹ is a cyano group: The 4- (3,4-dichlorophenyl) -14-hydroxybutyronitrile is condensed with benzene in the presence of a Lewis acid, and the obtained 4- (3,4) represented by the formula (VIII) is used. 4-Dichlorophenyl) 1-4-phenylbutyronitrile is hydrolyzed to give 4- (3,4-dichlorophenyl) -1-4-phenylbutane By cyclizing the acid, a tetrahydronaphthalenone derivative represented by the formula (V) can be produced.

 When condensing 4- (3,4-dichlorophenyl) -4-hydroxybutyronitrile with benzene, a solvent need not be used because benzene serves as a reaction solvent. Benzene is used in an amount of at least 500 parts by weight per 100 parts by weight of 4,1- (3,4-dichlorophenyl) -1-hydroxybutyronitrile from the viewpoint of improving the stirring property and the reaction yield. And from the viewpoint of economy, it is preferably not more than 2000 parts by weight.

 Examples of the Lewis acid include aluminum chloride, titanium tetrachloride, tin tetrachloride, boron trifluoride, concentrated sulfuric acid, chlorosulfonic acid, and trifluoromethanesulfonic acid. The amount of the Lewis acid used is about 1 to 5 mol, preferably about 2 to 4 mol, per 1 mol of 4- (3,4-dichloromouth phenyl) -4-hydroxybutyronitrile.

 4- (3,4-dichlorophenyl) 4-hydroxybutyronitrile can be condensed with benzene in the presence of 4- (3,4-dichlorophenyl) — 4-hydroxybutyro- yl directly in the presence of a Lewis acid. Examples include a method of reacting nitrile with benzene.

 The reaction temperature may usually be in the range of room temperature to the reflux temperature of benzene. In addition, the time required for the reaction varies depending on the reaction temperature and the like, and cannot be unconditionally determined, but is usually about 1 to 5 hours.

 The end point of the reaction can be confirmed by high-performance liquid chromatography that the peak based on unreacted 4- (3,4-dichlorophenyl) -14-hydroxybutyronitrile has decreased or disappeared.

Thus, by condensing 4-hydroxy (3,4-dichlorophenyl) -14-hydroxybutyronitrile with benzene, 4- (3,4-dichlorophenyl) -14 represented by the formula (VI II) is obtained. —Furnibutyronitrile is obtained. Next, the obtained 4- (3,4-dichloromouth phenyl) -141-phenylbutyronitrile is hydrolyzed.

 Examples of alkalis that can be used for hydrolyzing 4- (3,4-dichlorophenyl) -1-4-butyronitrile include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. And so on. The alkali can be usually used by dissolving it in a solvent. Examples of the solvent include monohydric alcohols such as methanol and ethanol, polyhydric alcohols such as ethylene glycol, propylene glycol and diethylene glycol, water, and mixed solvents thereof. Among them, polyhydric alcohols are preferably used because they are excellent in solubility of 4- (3,4-dichlorophenyl) -4-phenylbutyronitrile and alkali and promote hydrolysis. It is possible.

 Usually, the temperature at the time of hydrolysis is preferably about 50 to 200 ° C. The reaction time varies depending on the reaction conditions and the like, and thus cannot be unconditionally determined.

 Formula (IX) obtained by hydrolyzing 4- (3,4-dichloromethyl) phenyl 4-butyronitrile:

で表される 4一 ( 3 , 4ージクロ口フエニル） — 4一フエニルブタン酸を次に閉 環させるが、 かかる閉環の前には、 4一 （3， 4ージクロ口フエニル） 一 4ーフ ェニルブタン酸を式 （X) ：

で表される酸クロライドとすることができる。

The 4- (3-, 4-dichloro-butenyl) acid is then ring-closed, but prior to such ring-closure, the 4- (3-, 4-dichloro-but-phenyl) -1-phenylbutanoic acid is represented by To the formula (X):

The acid chloride represented by

 When chlorinating 4- (3-, 4-dichlorophenyl) -1-4-butanoic acid to an acid chloride, a chlorinating agent can be used.

 The chlorinating agent is not particularly restricted but includes, for example, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and the like. Among them, phenyl chloride is preferred because hydrogen chloride gas and sulfur dioxide gas generated after the reaction can be easily removed from the reaction system, and excess thionyl chloride can be easily removed. It can be used for

 Usually, the amount of the chlorinating agent used is preferably about 1.0 to 1.5 mol per 1 mol of 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid.

 When 4- (3,4-dichlorophenyl) -1-phenylbutanoic acid is used as the acid chloride, the 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid is suspended or dissolved in a solvent. This can be done later by adding a chlorinating agent to it.

 As the solvent, a solvent which is inert to the chlorinating agent and the generated acid chloride, for example, benzene, methylene chloride, dichloroethane, etc., having a monochrome mouth can be used. Among them, monochrome benzene can be preferably used because the risk of environmental pollution is low.

The amount of the solvent used is not particularly limited, but is usually about 200 to 500 parts by weight based on 100 parts by weight of 4- (3,4-dichlorophenyl) -14-phenylbutanoic acid. Preferably.

 Dimethylformamide (DMF) may be added to the suspension or solution of 4- (3,4-dichlorophenyl) -14-phenylbutanoic acid in order to promote the chromatization reaction.

 The reaction temperature may be usually in the range of normal temperature to 100.

 The end point of the reaction is, for example, conversion of the generated acid chloride to an amide, etc., and peaks based on unreacted 4- (3,4-dichlorophenyl) -14-phenylbutanoic acid are reduced or eliminated by high performance liquid chromatography. You can confirm by doing.

 Next, the ring closure of the 4- (3,4-dichlorophenyl) -4-phenylbutanoic acid represented by the formula (IX) or the acid chloride represented by the formula (X) results in the formation of the compound represented by the formula (V). The represented tetrahydronaphthalenone derivative can be obtained.

 The ring closure of the 4- (3,4-dichlorophenyl) —4-phenylbutanoic acid of the formula (IX) or the acid chloride of the formula (X) can be carried out by the Friedel-Crafts reaction in the presence of a Lewis acid. it can.

 As the Lewis acid, aluminum chloride is preferable. When aluminum chloride is used as the Lewis acid, the amount of the aluminum chloride used is represented by the formula (IX).

4- (3,4-dichlorophenyl) —1- to 2-mol, preferably 1.1 to 1.5 mol, per mol of 4-phenylbutanoic acid or the acid chloride represented by the formula (X). desirable.

Examples of the reaction solvent include solvents generally used in the Friedel-Crafts reaction, for example, dichloromethane, 1,2-dichloroethane, monochrome benzene, nitrobenzene, and the like. The reaction temperature may be usually from room temperature to about 100 ° C. The reaction time varies depending on the reaction conditions and the like, and thus cannot be determined unconditionally. However, it is usually preferably 1 to 5 hours. To isolate the product, hydrolyze the reaction solution, extract with an organic solvent such as toluene, and wash with water. After that, the reaction can be carried out by concentrating, adding methanol or the like, if necessary, crystallizing, and filtering.

 Thus, the tetrahydronaphthalenone derivative represented by the formula (V) can be obtained efficiently.

 Further, according to the present invention, in an alcohol, a tetrahydronaphthalenone derivative represented by the formula (V) is reacted with 1 to 20 mol of methylamine per 1 mol of the tetrahydronaphthalenone derivative in the alcohol. By formula (XI):

4- (3,4-dichlorophenyl) -1-methylimino-1,2,3,4-tetrahydronaphthalene represented by the following formula: The 4- (3,4-dichlorophenol) -11-methylimino 1,2,3,4-tetrahydronaphthalene is a compound useful as an intermediate for producing an antidepressant.

 One major feature of the present invention is that alcohol is used as a solvent. By using this alcohol, the tetrahydronaphthalenone derivative can be easily reacted with methylamine without using a catalyst such as titanium tetrachloride which was required in the conventional method.

The alcohol is preferably a lower alcohol having 1 to 4 carbon atoms such as methanol, ethanol, propanol, butanol, and isopropanol. The amount of alcohol to be used is such that the stirring of the reaction mixture is facilitated with respect to 100 parts by weight of 4- (3,4-dichloromouth phenyl) -111-oxo-1,2,3,4-tetrahydronaphthalene, 50 parts by weight or more, preferably from the viewpoint of progressing uniformly Is preferably at least 100 parts by weight, and from the viewpoint of economy, it is preferably at most 200 parts by weight, more preferably at most 100 parts by weight. The alcohol may be used, if necessary, by mixing it with an organic solvent inert to methylamine such as toluene or xylene, or water.

 Methylamine is a compound that is readily available commercially. The amount of methylamine used is 1 mol or more, preferably 2 mol or more, from the viewpoint of sufficient reaction with the tetrahydronaphthalenone derivative per 1 mol of the tetrahydronaphthalenone derivative, and 20 mol from the viewpoint of economy. The reaction of the tetrahydronaphthalenone derivative with methylamine, which is preferably 10 mol or less, is carried out, for example, by mixing the tetrahydronaphthalenone derivative and an alcohol, and dissolving methylamine in the alcohol in the obtained mixture. This can be done by adding a solution.

The reaction temperature is not particularly limited, but is usually preferably about 0 to 100. The reaction pressure is preferably normal pressure to 1 S kgf Z cm ² , preferably normal pressure to 1 O kgi Z cm ² in order to suppress the volatilization of methylamine and allow the reaction to proceed promptly. . The atmosphere during the reaction may be air or an inert atmosphere such as nitrogen gas.

 The reaction time may be any time as long as the reaction is completed, and is usually about 1 to 5 hours. The completion of the reaction can be confirmed, for example, by confirming that the IR of the precipitated crystal matches that of the target substance and that there is almost no IR peak derived from the raw material in the concentrate of the reaction mother liquor.

After completion of the reaction, for example, the crystals obtained by operations such as filtration and concentration of the reaction mixture are washed with methanol or the like to give 4- (3,4-dichroic phenyl) 1 1 -methylimino 1 1 , 2,3,4- Crystals of tetrahydronaphthylene can be recovered. The thus obtained 4- (3,4-dichloromouth phenyl) -1-methylimino 1,2,3,4-tetrahydronaphthalene is, for example, cis- (1S) (4S) -4-1 (3,4 —Dimethyl mouth phenyl) 11-Methylamino-1,2,3,4-tetrahydronaphthalene, that is, one that can be suitably used as an intermediate for producing an antidepressant known as sertraline. Example 1

 A 20 Oml four flask equipped with a thermometer, reflux condenser and alkali trap was charged with 30 ml of dimethylformamide, 3.7.5 g of 3,4-dichlorobenzaldehyde (0.1 Omo 1) and After charging 3.98 g (75.0 mMol) of acrylonitrile, add 0.49 g (10. Ommo1) of sodium cyanide at 30 to 35 ° C and stir at the same temperature for 4 hours. did.

 Next, 0.66 g of acetic acid (1.Ommo 1) was added to the obtained reaction solution, and the mixture was further stirred for 5 minutes, and then 5 Oml of toluene and 5 Oml of water were added to the reaction solution. After sufficient stirring, the layers were separated and the toluene layer was separated.

 The aqueous layer was further extracted with 5 Oml of toluene, combined with the toluene layer obtained above, and washed with 5 Om1 of water.

 The obtained toluene layer was concentrated under reduced pressure using an evaporator, 6 Oml of isopropanol was added to the concentrated residue, and the temperature was raised to 75 ° C to dissolve the precipitated solid, and then cooled to room temperature. The precipitated crystals were separated by filtration.

 The obtained crystals were further recrystallized from 100 ml of isopropanol to obtain 12.35 g of 4- (3,4-dichloromouth phenyl) -14-ketobutyronitrile as yellow crystals (acrylonitrile) Yield: 72.2%].

 The obtained 4- (3,4-dichrophthylphenyl) -14-ketopyronitrile was identified by having the following physical properties.

Melting point: 110-1 c IR (KB r) v (cm " ¹ ): 30 95, 2252, 1688, 1585, 1395, 1290, 1206 Example 2

 In Example 1, the amount of 3,4-dichlorobenzaldehyde used was changed to 17 · 50 g (0.1 Omo 1), and instead of 3.98 g of acrylonitrile, methyl acrylate 6.46 was used. The reaction was carried out in the same manner as in Example 1 except that g (75 mmo 1) was used, and pale yellowish-white crystals of 4- (3-, 4-dichloromethylphenyl) -4-methyl ketobutinate 1 1. 70 g was obtained [yield based on methyl acrylate: 59.7%] The obtained methyl 4- (3,4-dichlorophenyl) -14-ketobutanoate had the following physical properties and should be identified. Was completed.

Melting point: 82

 I R (KB r) V (cm "): 3085, 3065, 2955, 1742, 1686, 1583, 1311 Example 3

 In a 300 ml four-necked flask equipped with a thermometer and a dropping funnel, 90 ml of methanol and 4- (3,4-dichloromouth phenyl) obtained in Example 1-4-ketopoptyronitrile 10 0 g (43.8 mmo 1) was charged, and 0.82 g (2.1.7 mmol) of sodium borohydride was added to 0.5 g of 0.5% aqueous sodium hydroxide solution and 0.50 g of water. The solution dissolved in the mixed solution of l was added dropwise over about 30 minutes.

After completion of the dropwise addition, the temperature of the solution was adjusted to 20 to 30 ° C., and the mixture was stirred for about 30 minutes. After the obtained reaction solution was concentrated under reduced pressure in an evaporator, 40 ml of ethyl acetate and 40 ml of water were added thereto, and the mixture was stirred and separated, and the ethyl acetate layer was further added with 40 ml of water. Washed. After concentrating the ethyl acetate layer, 8 Oml of heptane was added, and the mixture was crystallized, filtered and dried, and white crystals of 4- (3,4-dichloromouth phenyl) -14-hydroxybutyronitrile 9.4 g was obtained [yield: 93.2%].

 The obtained 4- (3,4-dichlorophenyl) -1-hydroxybutyronitrile was identified by having the following physical properties.

Melting point: 63-65 ° C

IR (KB r) v (cm " ¹ ): 34 67, 225 1, 1 4 6 8, 1 386, 1 328, 1 076

H ¹ー 丽 R (CDC 13) ά (P pm): 1.8-2.8 (m, 4 H), 4.7-5.0 (t, 1 H), 7.1-7.6 (m, 3 H) Example 4

 In a 300 ml four-necked flask equipped with a thermometer and a dropping funnel, 90 ml of ethyl acetate, 30 ml of methanol, and 4- (3,4-dichloromethane) obtained in Example 1 were added. 10.0 g (43.8 mmol) of ketobutyronitrile was charged, and 0.82 g (13.3 mmol) of boric acid was added thereto, followed by stirring at room temperature for 30 minutes. Thereafter, the solution was cooled to 10 ° C, and 0.82 g (21.7 mmol) of sodium borohydride was added to 0.50 g of a 0.5% aqueous sodium hydroxide solution and 0.5 g of water. A solution dissolved in 0 ml of the mixture was dropped over about 30 minutes. After dropping, stir the solution at a temperature of 10 to 15 for about 30 minutes. After the reaction, adjust the pH with 35% hydrochloric acid. Adjusted to ~ 8. Thereafter, 40 ml of water was added to this solution, and the mixture was stirred and separated, and the ethyl acetate layer was further washed with 40 ml of water. The ethyl acetate layer was concentrated under reduced pressure to obtain 9.6 g of oily 4- (3,4-dichlorophenyl) -4-hydroxybutyronitrile [Yield: 95.1% 0

The obtained 4- (3,4-dichlorophenyl) -14-hydroxybutyronitrile was identified by having the following physical properties. Melting point: 63-65

IR (neat) v (cm " ¹ ): 344 5, 2934, 224 9, 1 470, 1 394, 1 204, 1 1 32, 1 078, 1 030, 886, 6 69

H ^1-丽 R (CDC 13) <5 (ppm): 1.9-2.8 (m, 4 H), 4.7-4.9 (t, 1 H), 7.1-7.5 (m, 3 H) Example 5

 In Example 3, in place of 0.0 g of 4- (3,4-dichlorophenyl) -1-4-ketopylononitrile, 4- (3,4-dichlorophenyl) methyl 4-ketobutanoate 1 The reaction was carried out in the same manner as in Example 3 except that 1.4 g was used. After completion of the reaction, the obtained reaction solution was distilled off under reduced pressure using an evaporator, and then 40 ml of ethyl acetate and 40 ml of water were added thereto. After stirring, the mixture was separated, and the ethyl acetate layer was further added with 40 ml of water. And washed.

 Next, the obtained ethyl acetate layer was concentrated to give methyl 4- (3,4-dichlorophenyl) -14-hydroxybutanoate and the 5- (3,4-dichloromouth phenyl) -tetrahydro-2 which was closed. — 10.5 g of an oily mixture of furanone was obtained.

 The composition of the obtained oily mixture was confirmed by high performance liquid chromatography, and it was confirmed that methyl 4- (3,4-dichlorophenyl) -4-hydroxybutanoate and 5- (3,4-dichlorophenyl) -tetrahydro-2- The furanone ratio was 1: 1 (molar ratio).

 The resulting mixture of methyl 5- (3,4-dichlorophenyl) -1-tetrahydro-12-furanone and methyl 4- (3,4-dichlorophenyl) -14-hydroxybutanoate has the following physical properties. , Could be identified.

IR (neat) v (cm ^-1 ): 34 63, 295 1, 1 779, 1 733, 1 469, 1 2 1 5, 1 1 32, 1 029

2 l Example 6

 In a 30 Oml four-necked flask equipped with a thermometer and a dropping funnel, 90 ml of ethyl acetate, 30 ml of methanol and 4- (3,4-dichloromethane) obtained in Example 1 were added. Methyl 4-ketobutanoate (11.4 g, 43.7 mmol) was charged, and boric acid (0.82 g, 13.3 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Thereafter, the solution was cooled to 10 ° C, and 0.82 g (21.7 mmol) of sodium borohydride was added to 0.50 g of a 0.5% aqueous sodium hydroxide solution and 0.5 g of water. A solution dissolved in 0 ml of the mixture was dropped over about 30 minutes. After the completion of the dropwise addition, the temperature of the solution was stirred at 10 to 15 ° C for 30 minutes to carry out the reaction.After the completion of the reaction, the obtained reaction solution was adjusted to pH 7 to 8 with 35% hydrochloric acid. did . Thereafter, 40 ml of water was added to this solution, and the mixture was stirred and separated, and the ethyl acetate layer was further washed with 40 ml of water.

 Next, the ethyl acetate layer was concentrated under reduced pressure to give methyl 4- (3,4-dichlorophenyl) -14-hydroxybutanoate and the 5- (3,4-dichloromethylphenyl) -tetrahydro-closed form thereof. 11.0 g of an oily mixture of 2-furanone was obtained. The composition of the obtained oily mixture was confirmed by high-performance liquid chromatography, and it was confirmed that 4- (3-, 4-dichloromethylphenyl) -14-hydroxybutanoic acid was obtained. The ratio of methyl to 5- (3,4-dichloromethyl) -tetrahydro-12-furanone was 4: 1 (molar ratio).

 The resulting mixture of methyl 5- (3,4-dichlorophenyl) -tetrahydro-2-furanone and 4- (3,4-dichlorophenyl) -1-hydroxybutanoate has the following physical properties, Could be identified.

IR (neat) v (cm " ¹ ): 34 52, 2952, 1 775, 1 732,

1 4 6 9, 1 1 76, 1 0 30 Example 7

 In a 300 ml four-necked flask equipped with a thermometer and a dropping funnel, 90 ml of ethyl acetate, 90 ml of methanol and 4- (3,4-dichloromouth phenol) obtained in Example 1-4 11.4 g (43.7 mmol) of methyl ketobutanoate was charged and stirred at room temperature for 30 minutes. The solution was then cooled to 10 and 0.82 g (21.7 mmol) of sodium borohydride was added to 0.50 g of a 0.5% aqueous sodium hydroxide solution and 10 ml of water The solution dissolved in the mixture was dropped over about 30 minutes.

 After completion of the reaction, the reaction solution was distilled off under reduced pressure using an evaporator. To this, 50 ml of ethyl acetate and 5 Oml of water were added, and the mixture was stirred and separated. The ethyl acetate layer was further washed with 50 ml of water.

 Next, the ethyl acetate layer is concentrated to give methyl 4- (3,4-dichlorophenyl) -4-hydroxybutanoate and 5- (3,4-dichlorophenyl) -tetrahydro-2-furanone, an oil in which it is closed. 10.5 g of a mixture was obtained. The composition of the obtained oily mixture was confirmed by high performance liquid chromatography, and it was confirmed that methyl 4- (3,4-dichlorophenyl) -1,4-hydroxybutanoate and 5-1 (3,4-dichlorophenyl) were used. The ratio of 1-tetrahydro-2-furanone was 1: 1 (molar ratio).

 The resulting mixture of methyl 5- (3,4-dichloromouth) -tetrahydro-2-furanone and 4- (3,4-dichlorophenyl) -14-hydroxybutanoate has the following physical properties, Could be identified.

IR (neat) v (cm " ¹ ): 3463, 2951, 1779, 1733,

1 4 6 9, 1 2 1 5, 1 1 32, 1 029 Example 8 In a 5 Om 1 four-necked flask equipped with a reflux condenser and a thermometer, 3.0 g (1) of the 4- (3,4-dichroic phenyl) -14-hydroxybutyronitrile obtained in Example 3 was added. 3.Ommo 1), water 2 Oml and sodium hydroxide 1.6 g (4 Ommo 1) were charged, and the mixture was stirred under reflux at 90 to 100 for 2 hours, and 35% hydrochloric acid was added to the obtained reaction solution. 6.8 g (65.2 mm 01) was added dropwise at 50-60 over 10 minutes. After completion of the dropwise addition of hydrochloric acid, the internal temperature was further adjusted to 90 to 100 ° C, and the mixture was stirred for 2 hours.

 After completion of the reaction, 50 ml of toluene was added to the reaction solution, and the mixture was vigorously stirred, separated, and the toluene layer was washed with 3 Om1 of water. Thereafter, the toluene layer was concentrated under reduced pressure, n-hexane 4 Om 1 was added to the obtained oily substance, and the mixture was vigorously stirred to precipitate white crystals. The crystals were separated by filtration and dried to obtain 2.9 g of 5- (3,4-dichlorophenyl) -tetrahydro-2-furanone as white crystals [yield: 96.2%) o

 The obtained 5- (3,4-dichlorophenyl) -tetrahydro-1-furanone could be identified by having the following physical properties.

Melting point: 63-65

 I R (KB r): 1 756, 1 474, 1 2 1 5, 1 1 93, 1 1 50,

 1 029 Example 9

 5.2 1 g of a mixture of 4- (3,4-dichlorophenyl) methyl 4-hydroxybutanoate and 5- (3,4-dichlorophenyl) -tetrahydro-2-furanone obtained in Example 5 To the mixture was added 0.42 g (2.2 mmo 1) of p-toluenesulfonic acid monohydrate, and the mixture was reacted under reduced pressure at 60 to 70 ° C. for 1 hour while distilling off generated methanol.

After the reaction, add 50 ml of toluene and 30 ml of water to the reaction solution and stir After separation, the aqueous layer was removed and the toluene layer was washed again with 30 ml of water. After concentrating the obtained toluene layer in the same manner as in Example 8, n-hexane 70 m

1 was added to precipitate white crystals. The crystals were separated by filtration to obtain 4.65 g of 5- (3,4-dichlorophenyl) -tetrahydro-12-furanone.

 The resulting 5- (3,4-dichlorophenyl) monotetrahydro-2-furanone is

Having the following physical properties, it could be identified.

Melting point: 63-64 ° C

IR (KB r) v (cm " ¹ ): 176 1, 1 474, 1 215, 1 193, 1 150, 1 029 Example 10

 In a 100 ml four-necked flask equipped with a thermometer, 20 ml (225 mmo 1) of benzene and 5.13 g (38.5 mmo l) of aluminum chloride were charged, and stirred at room temperature. A solution prepared by dissolving 4.43 g (19.3 mmol) of 4- (3,4-dichlorophenyl) -4-hydroxybutyronitrile obtained in Step 3 in 20 ml of benzene (225 mmol) was added dropwise. .

 After completion of the dropwise addition, the mixture was stirred at room temperature for 2.5 hours, and the obtained reaction solution was poured into 30 g of ice, stirred, and extracted with toluene 2 Om1.

 The obtained toluene layer was further washed with water (2 Oml), concentrated under reduced pressure to remove toluene, and then subjected to silica gel column chromatography to obtain oily 4- (3,4-dichlorophenyl) -14-phenylbutyronitrile 3 .89 g were obtained [Yield: 69.6%) o

 The obtained 4- (3-, 4-dichrophenyl)-4-phenylbutyronitrile was identified by having the following physical properties.

IR (neat) v (cm— ¹ ): 3061, 3028, 2938, 2246, 1682, 1470, 1400, 1133, 1029 H ¹ Bandit R (CDC 13) 5 (ppm): 2.1-2.6 (m, 4 H), 3.9-4.2 (t, 1 H), 7.0-7.5 ( m, 8 H)

 The 4- (3,4-dichlorophenyl) -14-phenylbutyronitrile obtained in Example 10 was placed in a 10-Om 1 four-necked flask equipped with a reflux condenser and a thermometer. g (13.4 mmol), 0.58 g (32.2 mmol) of water and 1.67 g of ethylene glycol, and then 1.6 g (40 mm) of sodium hydroxide Was added.

 The reaction temperature of the obtained mixture was raised to 150 to 160 ° C, and the mixture was stirred at the same temperature for 3 hours.

 After the reaction was completed, 20 ml of water and 4.33 g (41.5 mmo 1) of 35% hydrochloric acid were added to the mixture, stirred, and extracted with 20 ml of ethyl acetate. The ethyl acetate layer obtained by extraction was washed with water (2 Oml), concentrated by an evaporator under reduced pressure, added with 15 ml of toluene and 7 ml of heptane, and allowed to stand for 1 hour. On standing overnight, white crystals precipitated. The obtained crystals were filtered and washed with toluene to give 3.47 g of crystals of 4- (3,4-dichlorophenyl) -1-phenylbutanoic acid [yield: 83.7%] ].

 The obtained 4- (3,4-dichrophenyl) -4-phenylbutanoic acid was identified by having the following physical properties.

Melting point: 122 to 123

IR (KB r) v (cm " ¹ ): 2950, 17 14, 1 468, 1 324, 1 264, 1 2 1 2, 1 030 Example 1 2

In a 10 Om 1 four-necked flask equipped with a reflux condenser and a thermometer, 1) 4- (3,4-dichlorophenyl)-4-phenylbutanoic acid obtained in 1) 3.47 g (11.2 mmol), 20 ml of benzene with mono-mouth as solvent and a few drops of dimethylformamide After the addition, 1.60 g (13.4 mmo 1) of thionyl chloride was added thereto, and the temperature was raised to 50 ° C.

 After stirring at the same temperature for 3 hours, the obtained reaction solution was concentrated under reduced pressure at an evaporator, and 10 ml of benzene with a monochrome mouth was added to the obtained concentrated residue, which was further concentrated. The obtained concentrated residue was dissolved in 20 ml of benzene having a monochrome mouth, 2.24 g (16.8 mmol) of aluminum chloride was added at room temperature with stirring, and the mixture was stirred at the same temperature for 1 hour.

 After completion of the reaction, the reaction solution was poured into 40 g of ice, and extracted with 40 ml of toluene. The obtained toluene layer was washed with 10 ml of a 3% hydrochloric acid aqueous solution, and then the toluene layer was concentrated to obtain white crystals, ie, 4- (3,4-dichloromouth phenol) — 1, 2, 3, 3. 3.02 g of 4-tetrahydro-1-naphthalenone was obtained [Yield: 92.4% o

 The obtained 4- (3,4-dichlorophenyl) -11,2,3,4-tetrahydro-11-naphthalenone was identified by having the following physical properties. Melting point: 100-100C

IR (KB r) v (cm " ¹ ): 2950, 1677, 1592, 1470, 1286, 1204, 1029 Example 13

Into a 100 ml four flask equipped with a reflux condenser, a thermometer and a dropping funnel, 19.2 g (246 mmo 1) of benzene and the 4 -— (3,4-dichloromethane) obtained in Example 5 were added. 4.61 g of an oily mixture of methyl 4-hydroxybutanoate and 5- (3,4-dichlorophenyl) -tetrahydro-2-furanone was charged, and then concentrated while stirring at 50 ° C. 64.4 g of sulfuric acid (6 57mmol) It was added dropwise over 20 minutes.

 5 (After stirring with TC for 3 hours, the reaction solution was poured into 200 g of ice and stirred for 30 minutes. 5 Oml of toluene was added to the reaction solution, and the mixture was stirred vigorously, allowed to stand, and separated. 30 mL of water, 30 mL of saturated aqueous sodium hydrogen carbonate and water

After successive washing with 30 ml, the toluene layer was concentrated.

 4 Oml of methanol was added to the obtained concentrated residue, and the mixture was allowed to stand overnight, whereby white crystals were precipitated. The precipitated crystals are separated by filtration, washed with 5 ml of methanol, dried and dried to obtain 41- (3,4-dichlorophenyl) -11,2,3,4-tetrahydro-1-naphthalenone 2.69 g I got

 The obtained 4- (3,4-dichlorophenyl) -1,1,2,3,4-tetrahydro-11-naphthalenone was identified by having the following physical properties. Melting point: 102 ~ 103

IR (KB r) v (cm " ¹ ): 295 6, 1 677, 15 92, 1 470, 1 286, 1203, 1 029 Example 14

 100 ml of four flasks equipped with a reflux condenser, a thermometer and a dropping funnel were charged with 4- (3,4 dichloromouth phenyl) -methyl 4-hydroxybutanoate obtained in Example 5 and 5- (3 Dissolve 4.6 g of an oily mixture of 4-tetrachloro-2-furanone in 19.2 g of benzene (246 mmo 1) and use 32.9 g of trifluoromethanesulfonic acid as an acid. 19 mmol) was added dropwise over 20 minutes.

5 (After stirring with TC for 3 hours, the reaction solution was poured into 200 g of ice and stirred for 30 minutes. 5 Oml of toluene was added to the reaction solution, and the mixture was stirred vigorously, allowed to stand, and separated. Then, the toluene layer was successively washed with 30 ml of water, 3 Oml of saturated aqueous sodium hydrogen carbonate and 3 Oml of water, and then the toluene layer was concentrated. To the obtained concentrated residue, 4 Om 1 of methanol was added, and the mixture was left overnight, whereby white crystals were precipitated. The precipitated crystals are separated by filtration, washed with 5 ml of methanol, dried and dried to give 4- (3,4-dichlorophenol) 1-1,2,3,4-tetrahydro-1-naphthalenone 4. 65 g were obtained.

 The obtained 4- (3,4-dichlorophenyl) 1-1,2,3,4-tetrahydro-11-naphthalenone was identified by having the following physical properties. Melting point: 102 ° C

IR (KB r) v (cm " ¹ ): 295 6, 168 1, 15 92, 1 470, 1 287, 1 203, 1 029 Example 15

In a 200 ml autoclave, 4- (3,4-dichroic phenyl) -11,2,3,4-tetrahydro-1-naphthalenone 5.0 g (17.2 mmol), 40% methyl After charging 13.3 g (1771 mmol) of the amine methanol solution and 30 ml of methanol, the slurry-like reaction mixture obtained at S kg fZcm ² 80 ° C. was stirred for 3 hours.

 After completion of the reaction, the reaction solution was filtered, and the crystals collected by filtration with 20 ml of methanol were washed to obtain yellow-white crystals. The mother liquor was concentrated to sufficiently precipitate crystals, and then the precipitated crystals were collected by filtration, washed with 1 Oml of methanol, and yellow-white crystals were collected. The total yield of the obtained yellow-white crystals was 4.6 g, and the yield was 41-1,3,4-dichloromethane-1,1,2,3,4-tetrahydro-1-naphthene. On the other hand, it was 88%.

 It was confirmed by the following physical properties that the obtained yellow-white crystals were 4- (3,4-dichloromouth phenyl) -1-methylimino-1,2,3,4-tetrahydronaphthalene.

Melting point: 14.5-14.6.2 ° C IR (KB r) v (cm " ¹ ): 2933, 1 626, 1 594, 1 469,

 1402, 1031, 831, 764, 716Example 16

The same physical properties as the yellow-white crystals obtained in Example 15 in the same manner as in Example 15 except that the reaction pressure was S kg fZcm ² and the reaction temperature was 30 ° C in Example 15. Yellow-white crystals having the formula: 4- (3,4-dichlorophenyl) 1-11-methylimino 1,2,3,4-tetrahydronaphthalene 4.8 (4- (3,4-dichlorophenyl) -1- Yield based on 1,2,3,4-tetrahydro-1-naphthalenone: 92%). Example 17

 A yellow-white color having the same physical properties as the yellow-white crystal obtained in Example 15 in the same manner as in Example 15 except that the reaction pressure and the reaction temperature in Example 15 were changed to normal pressure and 30, respectively. 4.8 g of the crystals, ie 4- (3,4-dichlorophenyl) 1-1-methylimino 1,1,2,3,4-tetrahydronaphthalene were obtained (4-1 (3,4-dichlorophenyl) 1-1) , 2,3,4-tetrahydro-1-naphthalenone yield: 92%). Example 18

Example 15 was repeated except that 2.7 g (34.7 mmol) of a 40% methanol solution of methylamine was used, the reaction pressure was 2 kgf / cm ² , and the reaction temperature was 30 ° C. A yellow-white crystal having the same physical properties as the yellow-white crystal obtained in Example 15 in the same manner as in Example 15, that is, 4- (3,4-dichlorophenyl) -1-methylimino 1,2,3 4.2 g of, 4-tetrahydronaphthalene was obtained (4- (3,4 diphenyl phenyl) -1-1,2,3,4-tetrahydro-11-naphthalenone) (Yield: 80%). From the above results, it is understood that the benzyl alcohol derivative of the present invention can be easily produced by 3,4-dichlorobenzaldehyde.

 Further, it is found that the tetrahydronaphthalenone derivative represented by the formula (V) can be easily produced by condensing the benzyl alcohol derivative with benzene and further closing the ring.

 Further, according to the method of the present invention, even without using titanium tetrachloride conventionally used, it is possible to obtain 4- (3,4-dichloromethylphenyl) 1-1-methylimino 1,1,2,3,4 from a tetrahydronaphthylenone derivative. It can be seen that 4-tetrahydronaphthalene can be easily and industrially produced at a high yield. Industrial applicability

 According to the present invention, a tetrahydronaphthalenone derivative which is an intermediate useful for medicines such as sertraline useful as an antidepressant can be efficiently produced. Further, according to the present invention, a benzyl alcohol derivative useful as a production intermediate of the tetrahydronaphthalenone derivative can be produced efficiently and industrially advantageously. Furthermore, according to the present invention, 41- (3,4-dichlorophenyl) -11-methylimino-1,2,3,4-tetrahydronaphthalene can be easily and industrially advantageously produced from a tetrahydronaphthalenone derivative. .

Claims

The scope of the claims 1. General formula (I):

[In the formula, R ¹ represents a cyano group or —C〇OR ² group, and R ² represents a straight-chain alkyl group having 15 carbon atoms.] A benzyl all derivative represented by the formula: 2. The benzyl alcohol derivative according to claim ¹ , wherein R ¹ is a cyano group. 3. 3,4-Dichloro mouth benzaldehyde and general formula (II):

[In the formula, R ¹ represents a cyano group or —COOR ² group, and R ² represents a linear alkyl group having 15 carbon atoms.] Reacting with a vinyl compound represented by the following general formula (III):

(Wherein, R ¹ is the same as described above) General formula (I) comprising reducing a ketone derivative represented by

(Wherein, R ¹ is the same as described above) Of benzyl alcohol derivatives represented by 4. General formula (I)

(In the formula, R ¹ represents a cyano group or ^two C00R groups, and R ² represents a linear alkyl group having 1 to 5 carbon atoms.) General formula (IV) comprising condensing a benzyl alcohol derivative represented by the following formula with benzene in the presence of a Lewis acid:

(Wherein, R ¹ is the same as described above) Of diphenylbutenoic acid derivative represented by formula 5. General formula (IV):

[In the formula, R ¹ represents a cyano group or —COOR ² group, and R ² represents a linear alkyl group having 1 to 5 carbon atoms.] A difurbuic acid derivative represented by the formula: 6. General formula (I):

(In the formula, R ¹ represents a cyano group or a single COOR ² group, and R ² represents a linear alkyl group having 1 to 5 carbon atoms.) Formula (V) comprising using a benzyl alcohol derivative represented by the following formula as a starting compound:  0 (V) , C1  Manufacturing method of tetrahydronaphthalenone derivative represented by CI. 7. The benzyl alcohol derivative represented by the general formula (I) is converted into 3,4-dichlorobenzaldehyde by the general formula (II): H H ₉ C = C (II) R ¹ (Wherein, R ¹ is the same as described above) With a vinyl compound represented by the general formula (III)

(Wherein, R ¹ is the same as described above) 7. The method for producing a tetrahydronaphthalenone derivative according to claim 6, which is produced by reducing a ketone derivative represented by the formula: 8. The benzyl alcohol derivative represented by the general formula (I) is condensed with benzene in the presence of a Lewis acid, and the obtained general formula (IV):

(Wherein, R ¹ is the same as described above) 8. The process for producing a tetrahydronaphthalenone derivative according to claim 6, wherein the diphenylbutanoic acid derivative represented by the formula is closed. 9. Intramolecular cyclization of a benzyl alcohol derivative represented by the general formula (I) to obtain a formula (VII):

8. The method for producing a tetrahydronaphthalenone derivative according to claim 6, wherein the lactone derivative represented by the formula is condensed with benzene. 1 0. — Forty-one (3,4-dichlorophenyl) —4-hydroxybutyronitrile is used as the benzyl alcohol derivative represented by the general formula (I). —Hydroxybutyronitrile is condensed with benzene in the presence of a Lewis acid, and the resulting 4- (3,4-dichlorophenyl) -14-phenylphenylonitrile is hydrolyzed to give the resulting 4- (3, The process for producing a tetrahydronaphthalenone derivative according to claim 6 or 7, wherein ring closure of 4-dichlorophenyl) -4 monophenylbutanoic acid is performed. 11. The tetrahydronaphthalenone derivative according to claim 10, wherein the 1.4- (3,4-dichloromouth phenyl) -14-phenylbutyronitrile is hydrolyzed in a polyhydric alcohol using an alkali metal hydroxide. Manufacturing method. 10. The tetrahydronaphthalenone derivative according to claim 10, wherein after reacting 12.4- (3,4-dichlorophenyl) -14-phenylbutanoic acid with thionyl chloride in monochlorobenzene, the ring is closed with anhydrous aluminum chloride. Manufacturing method. 1 3.4- (3,4-dichlorophenyl) 1-4-phenylbutanoic acid 10. The production of the tetrahydronaphthalenone derivative according to claim 10, wherein the ring is closed after the addition. 14. Equation (V)

A reaction of a tetrahydronaphthalenone derivative represented by the following formula with 1 to 20 moles of methylamine per mole of the tetrahydronaphthalenone derivative in an alcohol is represented by the formula (XI):

A method for producing 4- (3,4-dichloromouth phenyl) -1-1-methylimino-1,2,3,4-tetrahydronaphthalene represented by