JP2009242357A - Method for producing dicyclohexane derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing dicyclohexane derivative which can give a trans isomer preferentially. <P>SOLUTION: The method for producing a dicyclohexane derivative is characterized in that the hydrogenation reaction of a compound expressed by general formula (I) is carried out in the presence of a palladium catalyst at 2 MPa or less hydrogen pressure, to thereby produce a dicyclohexane derivative expressed by the general formula (II) containing a trans isomer preferentially. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a dicyclohexane derivative. More specifically, the present invention relates to a method for producing a dicyclohexane derivative capable of preferentially obtaining a trans isomer by hydrogenating a biphenyl derivative in a solution.

The trans form of the dicyclohexane derivative is a compound expected as a raw material for liquid crystal compounds for display, pharmaceutical intermediates and the like.
When a dicyclohexane derivative is to be obtained from a biphenyl derivative, a hydrogenation reaction of the benzene ring is usually performed using a metal catalyst. However, the hydrogenation to the benzene ring is performed in a cis form of cyclohexane except when a substituent has a hydroxyl group. It is common to provide a ring (Non-patent Document 1).
On the other hand, when it has -COOH, -COOR, and a phenyl group as a substituent of a cyclohexane ring like patent documents 1-3, it is known that it can isomerize to a trans body after hydrogenation. .
JP-A-10-237015 JP-A-10-298144 JP 2004-256490 A J. Prakt. Chem./ Chem.-Ztg., 334 (1992), 625-629

従って、シクロヘキサン環の置換基がアルキル基等の場合に、トランス体を優先的に与える水素化反応が求められている。
本発明の目的は、トランス体を優先的に得ることができるジシクロヘキサン誘導体を与える製造方法を提供することである。 However, when the substituent on the cyclohexane ring is an alkyl group or the like, isomerization to the trans isomer is extremely difficult. For example, in the case of the following 4′-ethyl-dicyclohexyl-4-carboxylic acid, the B ring can be isomerized to the trans isomer by the method described in the above patent document, but the isomerization of the A ring to the trans isomer is extremely difficult. It is.

Accordingly, there is a need for a hydrogenation reaction that preferentially gives a trans isomer when the substituent on the cyclohexane ring is an alkyl group or the like.
An object of the present invention is to provide a production method for providing a dicyclohexane derivative capable of preferentially obtaining a trans isomer.

The above problems have been achieved by the following means.
[1] Transformation of the cyclohexane derivative represented by the following general formula (II) is preferred by conducting the hydrogenation reaction of the compound represented by the following general formula (I) in the presence of a palladium catalyst at a hydrogen pressure of 2 MPa or less. A process for producing a dicyclohexane derivative, characterized in that it is obtained by a method.

[Wherein, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , and R ₁₀ each independently represent a hydrogen atom or a substituent. R ₃ represents —COOR ₁₁ or —CONR ₁₂ R ₁₃ . R ₁₁ , R ₁₂ , and R ₁₃ each independently represent a hydrogen atom or an alkyl group. R ₈ represents an alkyl group, a cycloalkyl group, or an alkoxy group. R ₁₄ represents an alkyl group, a cycloalkyl group, an alkoxy group, or —COR ₁₅ . R ₁₅ represents an alkyl group. ]
[2] The process for producing a dicyclohexane derivative according to [1], wherein 1 to 30% by mass of palladium is supported on a support, and the support is carbon or alumina.

  According to the method for producing a dicyclohexane derivative according to the present invention, high selectivity and yield can be obtained by hydrogenating a specific biphenyl derivative in the presence of a palladium catalyst at a low hydrogen pressure (2 MPa or less) in a specific solvent. The desired transdicyclohexane can be obtained.

Hereinafter, the manufacturing method of the dicyclohexane derivative based on this invention is demonstrated concretely.
[Compounds Represented by General Formula (I) / General Formula (II)]
R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , and R ₁₀ each independently represent a hydrogen atom or a substituent, preferably a hydrogen atom.
The following are mentioned as a substituent.
A cyano group, a nitro group, a carboxyl group, an alkoxy group (preferably a substituted or unsubstituted alkoxy group having 1 to 30 carbon atoms such as a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, and an n-octyloxy group. Group, 2-methoxyethoxy group), aryloxy group (preferably a substituted or unsubstituted aryloxy group having 6 to 30 carbon atoms, such as phenoxy group, 2-methylphenoxy group, 4-tert-butylphenoxy group, 3-nitrophenoxy group, 2-tetradecanoylaminophenoxy group), benzyl group, 4-methoxybenzyl group.
An alkyl group (preferably an alkyl group having 1 to 30 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, n-octyl group, 2-ethylhexyl group), a polymerizable group at the terminal An alkyl group having 1 to 30 carbon atoms (preferably having 1 to 30 carbon atoms), an alkyl group having a benzyl carbamate group (preferably having 9 to 30 carbon atoms), and an alkyl group having a t-butyl carbamate group at the terminal (Preferably having 6 to 30 carbon atoms), an alkyl group having a benzene ring at the end (preferably having 1 to 10 carbon atoms), an alkyl group having an ether linkage (preferably having an ether linkage having 1 to 30 carbon atoms). Alkyl group having, for example, 2-methoxybutyl group, 3-methoxybutyl group, 4-methoxybutyl group, 4-ethoxybutyl group), cycloalkyl (Preferably, a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, such as a cyclohexyl group, a cyclopentyl group, or 4-n-dodecylcyclohexyl group), a bicycloalkyl group (preferably a substituent having 5 to 30 carbon atoms) Or an unsubstituted bicycloalkyl group, that is, a monovalent group obtained by removing one hydrogen atom from a C 5-30 bicycloalkane, for example, bicyclo [1,2,2] heptan-2-yl, bicyclo [ 2,2,2] octane-3-yl))) and the like.

R ₃ represents —COOR ₁₁ or —CONR ₁₂ R ₁₃ . R ₁₁ , R ₁₂ , and R ₁₃ each independently represent a hydrogen atom or an alkyl group. When R ₁₁ , R ₁₂ , and R ₁₃ are alkyl groups, the carbon number is, for example, 1 to 30.
R ₃ is preferably —COOR ₁₁ and more preferably —COOH.

R ₈ represents an alkyl group, a cycloalkyl group, or an alkoxy group. These may be unsubstituted or may have a substituent. Examples of the substituent include the substituents exemplified in the description of R _{1 and the} like.
R ₈ is preferably an alkyl group having 1 to 30 carbon atoms and an alkoxy group having 1 to 30 carbon atoms, more preferably an alkyl group having 1 to 10 carbon atoms and an alkoxy group having 1 to 10 carbon atoms. .

R ₁₄ represents an alkyl group, a cycloalkyl group, an alkoxy group, or —COR ₁₅ . R ₁₅ represents an alkyl group. These may be unsubstituted or may have a substituent. Examples of the substituent include the substituents exemplified in the description of R _{1 and the} like. When R ₁₅ is an alkyl group, the carbon number is, for example, 1 to 30.

[catalyst]
The hydrogenation reaction according to the present invention uses a palladium catalyst. The palladium catalyst is obtained by supporting a palladium component as a catalytic metal active component on a carrier. Examples of the carrier include carbon, alumina, silica alumina, zirconium oxide, titanium oxide, activated clay, and the like. Carbon and alumina are particularly preferable. Specific examples of the palladium compound that forms the palladium catalyst include metal palladium, palladium oxide, palladium hydroxide, and the like.
The amount of the palladium component supported on the carrier is preferably 1 to 30% by mass, more preferably 5 to 30% by mass, and particularly preferably 10 to 30% by mass as the amount of metallic palladium.
The amount of the palladium catalyst used is preferably 0.5 to 30 parts by mass, more preferably 1 to 20 parts by mass with respect to 100 parts by mass of the starting biphenyl derivative.

[Hydrogen pressure]
The hydrogen pressure at the time of hydrogenation is 2 MPa or less, more preferably 0.1 to 1 MPa, and still more preferably 0.1 to 0.5 MPa.

[solvent]
Hydrogenation of the biphenyl derivative is carried out in a solvent. Examples of the solvent include aliphatic saturated alcohols having 1 to 12 carbon atoms, hexane, water, ethyl acetate, carboxylic acids having 1 to 5 carbon atoms, and the like. In particular, acetic acid and water are preferable.

[Hydrogenation of biphenyl derivatives]
In a preferred embodiment of the method for producing a dicyclohexane derivative according to the present invention, the biphenyl derivative is hydrogenated in a solvent (preferably water or acetic acid) in the presence of the palladium catalyst. Hydrogenation is preferably performed by replacing the interior of the system with an inert gas such as nitrogen gas or argon gas and then replacing with hydrogen. The reaction temperature is preferably 80 to 230 ° C. Since the reaction time is monitored by proton NMR measurement or GC measurement, the reaction time is not particularly limited. Usually, it is about several tens of minutes to 30 hours.
Separation and recovery of the trans form from the cyclohexane derivative can be performed by a method using a column (for example, column chromatography using silica gel) or a recrystallization method.
In this specification, “obtained preferentially in the trans isomer” means that the trans isomer ratio of the cyclohexane ring is 51% or more, more preferably 70% or more.

Example 1
[Preparation of 4′-ethyl-dicyclohexyl-4-carboxylic acid]
An autoclave with an internal volume of 50 ml was charged with 0.50 g (2.2 mmol) of 4′-ethyl-biphenyl-4-carboxylic acid and 2 ml of acetic acid, and 10% palladium / carbon (50% wet product manufactured by Kawaken Fine Chemical Co., Ltd.) as a palladium catalyst. 100 mg of was added.
After the completion of the above preparation, the operation of increasing the pressure in the autoclave to 0.5 MPa with nitrogen and then depressurizing was repeated a total of three times to perform nitrogen replacement in the system. Next, the inside of the system is replaced with hydrogen by the same operation as the above nitrogen substitution with hydrogen, and then the temperature in the system is increased, and when the temperature reaches 125 ° C., the hydrogen pressure in the system is adjusted to 0.4 MPa, The theoretical amount of hydrogen required for hydrogenation was supplied.
After the hydrogenation reaction was carried out at 125 ° C. for 16 hours, the reaction solution in the system was cooled to room temperature, and the catalyst was removed by filtration from the reaction solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain 0.52 g (> 99%) of 4′-ethyl-dicyclohexyl-4-carboxylic acid as a target product. As a result of analysis by gas chromatography, the cis / trans ratio of cyclohexane ring A was 18/82. (The cyclohexane ring B can be isomerized as described above.)

(Example 2)
[Preparation of 4′-propyl-dicyclohexyl-4-carboxylic acid]
An autoclave with an internal volume of 50 ml was charged with 0.50 g (2.1 mmol) of 4′-propyl-biphenyl-4-carboxylic acid and 2 ml of distilled water, and 10% palladium / carbon (50% wet product manufactured by Kawaken Fine Chemical Co., Ltd.) as a palladium catalyst. ) Was added 100 mg.
After the completion of the above preparation, the operation of increasing the pressure in the autoclave to 0.5 MPa with nitrogen and then depressurizing was repeated a total of three times to perform nitrogen replacement in the system. Next, the inside of the system is replaced with hydrogen by the same operation as the above nitrogen substitution with hydrogen, and then the temperature in the system is increased, and when the temperature reaches 125 ° C., the hydrogen pressure in the system is adjusted to 0.4 MPa, The theoretical amount of hydrogen required for hydrogenation was supplied.
After the hydrogenation reaction was carried out at 125 ° C. for 16 hours, the reaction solution in the system was cooled to room temperature, and the catalyst was removed by filtration from the reaction solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain 0.52 g (> 99%) of 4′-propyl-dicyclohexyl-4-carboxylic acid as a target product. As a result of analysis by gas chromatography, the cis / trans ratio of cyclohexane ring C was 17/83. (The cyclohexane ring D can be isomerized as described above.)

(Example 3-1)
[Preparation of 4′-acetyl-biphenyl-4-carboxylic acid]

2 g of biphenyl was dissolved in 10 ml of orthodichlorobenzene, and 4.5 g of aluminum chloride and 2.14 ml of diethylcarbamoyl chloride were added, followed by stirring at 100 ° C. for 4 hours. The reaction solution was cooled to 30 ° C., and 1.01 ml of acetyl chloride was added dropwise (internal temperature of 40 ° C. or less). After stirring at 40 ° C. for 1 hour, the reaction solution was cooled to room temperature and added dropwise to 20 ml of ice-cold water. After extraction with ethyl acetate and washing with saturated brine, the organic layer was concentrated under reduced pressure and purified by column chromatography to obtain 3.5 g of 2.
23.5 g was dissolved in 32 ml of 12N hydrochloric acid and stirred at 130 ° C. for 24 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and washed with water. 1 L of methanol was added to the obtained crystals, washed by boiling, brought to room temperature, filtered and dried to obtain 2.8 g of 4′-acetyl-biphenyl-4-carboxylic acid 3.

¹ H-NMR (solvent: dimethyl-d6 sulfoxide, standard: tetramethylsilane) δ (ppm):
2.61 (3H, s)
7.80-7.90 (4H, m)
8.00-8.10 (4H, m)

(Example 3-2)
[Preparation of 4′-ethyl-dicyclohexyl-4-carboxylic acid]
A 50 ml autoclave was charged with 0.50 g (2.1 mmol) of 4′-acetyl-biphenyl-4-carboxylic acid and 2 ml of acetic acid, and 10% palladium / carbon (50% wet product manufactured by Kawaken Fine Chemical Co., Ltd.) as a palladium catalyst. 100 mg of was added.
After the completion of the above preparation, the operation of increasing the pressure in the autoclave to 0.5 MPa with nitrogen and then depressurizing was repeated a total of three times to perform nitrogen replacement in the system. Next, the inside of the system is replaced with hydrogen by the same operation as the above nitrogen substitution with hydrogen, and then the temperature in the system is increased, and when the temperature reaches 125 ° C., the hydrogen pressure in the system is adjusted to 0.4 MPa, The theoretical amount of hydrogen required for hydrogenation was supplied.
The hydrogenation reaction was carried out at 85 ° C. for 5 hours and then at 125 ° C. for 16 hours. Thereafter, the reaction solution in the system was cooled to room temperature, and the catalyst was removed by filtration from the reaction solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain 0.52 g (> 99%) of 4′-ethyl-dicyclohexyl-4-carboxylic acid as a target product. As a result of analysis by gas chromatography, the cis / trans ratio of cyclohexane ring A was 20/80. (The cyclohexane ring B can be isomerized as described above.)

Example 4
[Preparation of 4′-ethyl-dicyclohexyl-4-carboxylic acid ethyl ester]
An autoclave with an internal volume of 50 ml was charged with 0.50 g (1.9 mmol) of 4'-ethyl-biphenyl-4-carboxylic acid ethyl ester and 2 ml of acetic acid, and 10% palladium / carbon (50% wet by Kawaken Fine Chemical Co., Ltd.) as a palladium catalyst. 100 mg) was added.
After the completion of the above preparation, the operation of increasing the pressure in the autoclave to 0.5 MPa with nitrogen and then depressurizing was repeated a total of three times to perform nitrogen replacement in the system. Next, the inside of the system is replaced with hydrogen by the same operation as the above nitrogen substitution with hydrogen, and then the temperature in the system is increased, and when the temperature reaches 125 ° C., the hydrogen pressure in the system is adjusted to 0.4 MPa, The theoretical amount of hydrogen required for hydrogenation was supplied.
After the hydrogenation reaction was performed at 160 ° C. for 8 hours, the reaction solution in the system was cooled to room temperature, and the catalyst was removed by filtration from the reaction solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain 0.52 g (> 99%) of 4′-ethyl-dicyclohexyl-4-carboxylic acid ethyl ester as a target product. As a result of analysis by gas chromatography, the cis / trans ratio of cyclohexane ring E was 24/76. (The cyclohexane ring F can be isomerized as described above.)

(Comparative Example 1)
[Preparation of 4′-ethyl-dicyclohexyl-4-carboxylic acid]
An autoclave with an internal volume of 50 ml was charged with 0.50 g (2.2 mmol) of 4′-ethyl-biphenyl-4-carboxylic acid and 2 ml of acetic acid, and 10% palladium / carbon (50% wet product manufactured by Kawaken Fine Chemical Co., Ltd.) was used as a catalyst. 100 mg was added.
After the completion of the above preparation, the operation of increasing the pressure in the autoclave to 0.5 MPa with nitrogen and then depressurizing was repeated a total of three times to perform nitrogen replacement in the system. Next, the inside of the system is replaced with hydrogen by the same operation as the above-described nitrogen substitution, and then the temperature in the system is increased, and when the temperature reaches 160 ° C., the hydrogen pressure in the system is adjusted to 5.5 MPa, The theoretical amount of hydrogen required for hydrogenation was supplied.
After performing the hydrogenation reaction at 160 ° C. for 16 hours, the reaction solution in the system was cooled to room temperature, and the catalyst was removed by filtration from the reaction solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain 0.52 g (> 99%) of 4′-ethyl-dicyclohexyl-4-carboxylic acid as a target product. As a result of analysis by gas chromatography, the cis / trans ratio of cyclohexane ring A was 37/63.

(Comparative Example 2)
[Preparation of 4′-ethyl-dicyclohexyl-4-carboxylic acid]
A 50 ml autoclave was charged with 0.50 g (2.2 mmol) of 4′-ethyl-biphenyl-4-carboxylic acid and 2 ml of water, and 100 mg of 5% ruthenium / carbon (50% wet product manufactured by NECHEMCAT) was added as a catalyst. did.
After the completion of the above preparation, the operation of increasing the pressure in the autoclave to 0.5 MPa with nitrogen and then depressurizing was repeated a total of three times to perform nitrogen replacement in the system. Next, the inside of the system is replaced with hydrogen by the same operation as the above-described nitrogen substitution, and then the temperature in the system is increased, and when the temperature reaches 160 ° C., the hydrogen pressure in the system is adjusted to 5.5 MPa, The theoretical amount of hydrogen required for hydrogenation was supplied.
After performing the hydrogenation reaction at 160 ° C. for 16 hours, the reaction solution in the system was cooled to room temperature, and the catalyst was removed by filtration from the reaction solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain the desired product, 4′-ethyl-dicyclohexyl-4-carboxylic acid (90%). As a result of analysis by gas chromatography, the cis / trans ratio of cyclohexane ring A was 73/27.

  From these results, it is understood that a trans cyclohexane ring can be obtained with a high selectivity of 70% or more by the method of the present invention.

Claims (2)

The cyclohexane derivative represented by the following general formula (II) is preferentially obtained in the trans isomer by conducting a hydrogenation reaction of the compound represented by the following general formula (I) in the presence of a palladium catalyst at a hydrogen pressure of 2 MPa or less. A process for producing a dicyclohexane derivative.

[Wherein, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , and R ₁₀ each independently represent a hydrogen atom or a substituent. R ₃ represents —COOR ₁₁ or —CONR ₁₂ R ₁₃ . R ₁₁ , R ₁₂ , and R ₁₃ each independently represent a hydrogen atom or an alkyl group. R ₈ represents an alkyl group, a cycloalkyl group, or an alkoxy group. R ₁₄ represents an alkyl group, a cycloalkyl group, an alkoxy group, or —COR ₁₅ . R ₁₅ represents an alkyl group. ]   2. The method for producing a dicyclohexane derivative according to claim 1, wherein 1 to 30% by mass of palladium is supported on the support, and the support is carbon or alumina.