WO2019240033A1

WO2019240033A1 - Method for producing dicyclohexanedicarboxylic acid diester and method for producing dicyclohexanedicarboxylic acid

Info

Publication number: WO2019240033A1
Application number: PCT/JP2019/022717
Authority: WO
Inventors: 和宏綱; 基将 ▲高▼橋
Original assignee: 富士フイルム株式会社
Priority date: 2018-06-11
Filing date: 2019-06-07
Publication date: 2019-12-19
Also published as: JP7027541B2; CN112272661B; JPWO2019240033A1; CN112272661A

Abstract

The present invention addresses the problem of providing: a method for producing a dicyclohexanedicarboxylic acid diester, which is capable of suppressing the generation of stereoisomers as by-products, and which is capable of separating isomers by a simple operation; and a method for producing a dicyclohexanedicarboxylic acid. A method for producing a dicyclohexanedicarboxylic acid according to the present invention is a method for producing a dicyclohexanedicarboxylic acid diester, which comprises a step for obtaining a dicyclohexanedicarboxylic acid diester represented by formula (2) by causing a reaction of a compound represented by formula (1) in the presence of a nickel catalyst and a reducing agent.

Description

Method for producing dicyclohexane dicarboxylic acid diester and method for producing dicyclohexane dicarboxylic acid

The present invention relates to a method for producing dicyclohexane dicarboxylic acid diester and a method for producing dicyclohexane dicarboxylic acid.

Optical films such as optical compensation sheets and retardation films are used in various image display devices in order to eliminate image coloring and expand the viewing angle.
A stretched birefringent film has been used as the optical film, but in recent years, it has been proposed to use an optical film having an optically anisotropic layer made of a liquid crystalline compound instead of the stretched birefringent film.

The liquid crystalline compound used for forming such an optically anisotropic layer includes, for example, a hydroxy compound for forming a skeleton (hereinafter also referred to as “core portion”) located at the molecular center of the liquid crystalline compound, It is known to synthesize by utilizing an esterification reaction with a carboxylic acid compound for forming a side chain portion of a liquid crystal compound (see, for example, Patent Documents 1 to 4).

JP 2010-031223 A JP 2012-097078 A International Publication No. 2014/010325 JP 2016-081035 A

The present inventors use dicyclohexanedicarboxylic acid represented by the following formula (3) (hereinafter also abbreviated as “DCHDA”) as a carboxylic acid compound for forming the side chain portion of the liquid crystalline compound. I found out.

The inventors of the present invention have studied a method for synthesizing DCHDA. For example, JP2013-544281 (hereinafter abbreviated as “Current Method 1”) and Helvetica Chem. Act. The method described in “Current method 2”) is considered applicable.
However, in the methods described in the present method 1 and the present method 2, the present inventors have obtained many stereoisomers as a by-product in the step of obtaining dicyclohexanedicarboxylic acid diester which is a precursor of DCHDA. It was clarified that it is necessary to separate the isomers by a complicated operation before or after the production.

Therefore, the present invention provides a method for producing dicyclohexane dicarboxylic acid diester and a method for producing dicyclohexane dicarboxylic acid, which can suppress by-production of stereoisomers and can separate isomers by a simple operation. This is the issue.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have reacted a predetermined cyclohexane compound having a leaving group and an ester group (—COOR) in the presence of a nickel catalyst and a reducing agent (coupling reaction). It was found that by obtaining dicyclohexanedicarboxylic acid diester, the by-production of stereoisomers was suppressed, and the isomers could be separated by a simple operation, and the present invention was completed.
That is, it has been found that the above-described problem can be achieved by the following configuration.

[1] A compound represented by the following formula (1) is reacted in the presence of a nickel catalyst and a reducing agent to obtain a dicyclohexane dicarboxylic acid diester represented by the following formula (2). Method for producing acid diester.

Here, in the formulas (1) and (2), R is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, or a carbon number which may have a substituent. A cyclic alkyl group having 3 to 8 carbon atoms, a linear or branched alkenyl group having 1 to 6 carbon atoms which may have a substituent, and a cyclic alkenyl group having 3 to 8 carbon atoms which may have a substituent Represents a group, an alkynyl group having 1 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent; ), X represents a leaving group.

[2] The process for producing dicyclohexanedicarboxylic acid diester according to [1], wherein R in the formulas (1) and (2) represents a linear or branched alkyl group having 1 to 6 carbon atoms.
[3] The process for producing dicyclohexanedicarboxylic acid diester according to [1], wherein R in the formulas (1) and (2) represents a methyl group, an ethyl group, a t-butyl group, or a trityl group.
[4] Production of dicyclohexanedicarboxylic acid diester according to any one of [1] to [3], wherein the reducing agent is at least one selected from the group consisting of a cobalt compound, magnesium, zinc, and manganese. Method.
[5] X in the formula (1) represents at least one selected from the group consisting of a halogen atom, an alkylthio group, an alkylsulfonyloxy group, and an arylsulfonyloxy group. The manufacturing method of the dicyclohexane dicarboxylic acid diester in any one.
[6] In any one of [1] to [5], X in the formula (1) represents at least one selected from the group consisting of a bromine atom, a methanesulfonyloxy group, and a toluenesulfonyloxy group. The manufacturing method of dicyclohexane dicarboxylic acid diester of description.
[7] The process for producing dicyclohexanedicarboxylic acid diester according to any one of [1] to [6], wherein X in formula (1) represents a halogen atom, and the reducing agent is zinc.
[8] In the formula (1), X represents a methanesulfonyloxy group or a toluenesulfonyloxy group, and the reducing agent is a combination of a cobalt compound and manganese. The manufacturing method of the dicyclohexane dicarboxylic acid diester in any one.
[9] The nickel catalyst is a catalyst prepared from a nickel compound and a ligand compound,
The method for producing dicyclohexanedicarboxylic acid diester according to any one of [1] to [8], wherein the ligand compound is 2,2′-bipyridine.

[10] A step of reacting a compound represented by the following formula (1) in the presence of a nickel catalyst and a reducing agent to obtain a dicyclohexanedicarboxylic acid diester represented by the following formula (2);
Hydrolyzing dicyclohexanedicarboxylic acid diester to form a salt, and then adding an acid to obtain dicyclohexanedicarboxylic acid represented by the following formula (3);
The manufacturing method of dicyclohexane dicarboxylic acid which has these.

ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of dicyclohexane dicarboxylic acid diester and the manufacturing method of dicyclohexane dicarboxylic acid which can suppress the by-product of a stereoisomer and can isolate | separate an isomer by simple operation are provided. be able to.

Hereinafter, the present invention will be described in detail.
The description of the constituent elements described below may be made based on typical embodiments of the present invention, but the present invention is not limited to such embodiments.
In this specification, a numerical range expressed using “to” means a range including numerical values described before and after “to” as a lower limit value and an upper limit value.

[Method for producing dicyclohexanedicarboxylic acid diester]
The method for producing dicyclohexanedicarboxylic acid diester of the present invention (hereinafter also abbreviated as “the method for producing diester of the present invention”) comprises a compound represented by the following formula (1) in the presence of a nickel catalyst and a reducing agent. It has the process (henceforth a "diesterification process") obtained by making it react and obtaining the dicyclohexane dicarboxylic acid diester represented by following formula (2).

As described above, in the method for producing a diester of the present invention, the compound represented by the above formula (1) is reacted in the presence of a nickel catalyst and a reducing agent, and the dicyclohexanedicarboxylic acid represented by the above formula (2). By obtaining the diester, the by-production of stereoisomers is suppressed, and the isomers can be separated by a simple operation.
Although this is not clear in detail, the present inventors presume as follows.
That is, after the leaving group in the above formula (1) is eliminated by the reducing agent, the carbon radical generated at the elimination site and the nickel atom of the nickel catalyst are bound to each other in an energetically advantageous direction (equatorial). Direction), the trans isomer was preferentially obtained, so that the trans isomer was also preferentially obtained in the subsequent coupling reaction. As a result, the isomers could be separated by a simple operation such as recrystallization. It is thought.
Below, the diesterification process which the manufacturing method of the diester of this invention has is explained in full detail.

[Diesterification process]
In the diesterification step of the diester production method of the present invention, the compound represented by the above formula (1) is reacted in the presence of a nickel catalyst and a reducing agent, and the dicyclohexanedicarboxylic acid represented by the above formula (2). In this step, an acid diester is obtained.

<Compound represented by Formula (1)>
The starting material used in the diesterification step is a compound represented by the following formula (1).

In the above formula (1), R is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, or a cyclic group having 3 to 8 carbon atoms which may have a substituent. It has an alkyl group, a linear or branched alkenyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkenyl group having 3 to 8 carbon atoms which may have a substituent, or a substituent. And an alkynyl group having 1 to 6 carbon atoms, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent.
In the above formula (1), X represents a leaving group.

Specific examples of the linear or branched alkyl group having 1 to 6 carbon atoms represented by R in the above formula (1) include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, and n-butyl. Group, isobutyl group, sec-butyl group, t-butyl group and the like.
Specific examples of the cyclic alkyl group having 3 to 8 carbon atoms represented by R include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

Specific examples of the linear or branched alkenyl group having 1 to 6 carbon atoms represented by R include, for example, vinyl group, 1-propenyl group, allyl group, isopropenyl group, 1-butenyl group, And 2-butenyl group.
Specific examples of the cyclic alkenyl group having 3 to 8 carbon atoms represented by R include a 2-cyclopenten-1-yl group and a 2-cyclohexen-1-yl group.

Specific examples of the alkynyl group having 1 to 6 carbon atoms include ethynyl group and propargyl group.
Specific examples of the aryl group include a phenyl group, a p-tolyl group, a naphthyl group, an m-chlorophenyl group, and an o-hexadecanoylaminophenyl group.
Specific examples of the heterocyclic group include monocyclic aromatic heterocyclic groups such as a furyl group, a pyrrolyl group, a thienyl group, a pyridinyl group, and a thiazolyl group; a benzothiazolyl group, a benzofuryl group, and a benzothienyl group. And polycyclic aromatic heterocyclic groups (including fused polycyclic aromatic heterocyclic groups); non-aromatic heterocyclic groups such as morpholinyl groups; and the like.

On the other hand, examples of the substituent that R in formula (1) may have include an alkyl group, an alkoxy group, and a halogen atom.
As the alkyl group, for example, a linear, branched or cyclic alkyl group having 1 to 18 carbon atoms is preferable, and an alkyl group having 1 to 8 carbon atoms (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group). N-butyl group, isobutyl group, sec-butyl group, t-butyl group, cyclohexyl group, etc.), more preferably an alkyl group having 1 to 4 carbon atoms, and a methyl group or an ethyl group. Is particularly preferred.
As the alkoxy group, for example, an alkoxy group having 1 to 18 carbon atoms is preferable, an alkoxy group having 1 to 8 carbon atoms (for example, a methoxy group, an ethoxy group, an n-butoxy group, a methoxyethoxy group, etc.) is more preferable. An alkoxy group having a number of 1 to 4 is more preferable, and a methoxy group or an ethoxy group is particularly preferable.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among them, a fluorine atom and a chlorine atom are preferable.

In the present invention, from the viewpoint of availability, R in the above formula (1) preferably represents a linear or branched alkyl group having 1 to 6 carbon atoms, and among them, a methyl group, an ethyl group , T-butyl group or trityl group is more preferable.

The leaving group represented by X in the above formula (1) is a group X1 directly bonded to the carbon atom constituting the cyclohexane ring, and is easily eliminated by taking in an electron pair of C—X1 bond. Represents a group capable of
Examples of the leaving group include a halogen atom, an alkylthio group, an alkylsulfonyloxy group, and an arylsulfonyloxy group.
Specific examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a bromine atom and an iodine atom are preferable, and availability and reaction (coupling) are preferred. From the viewpoint of (reactivity), it is more preferably a bromine atom.
Specific examples of the alkylthio group include a methylthio group and an ethylthio group.
Specific examples of the alkylsulfonyloxy group include a methanesulfonyloxy group, an ethanesulfonyloxy group, an n-propanesulfonyloxy group, and an n-butanesulfonyloxy group, and among them, a methanesulfonyloxy group. It is preferable.
Specific examples of the arylsulfonyloxy group include a toluenesulfonyloxy group, a 4-nitrophenylsulfonyloxy group, a 4-methoxyphenylsulfonyloxy group, a 2-nitrophenylsulfonyloxy group, a 3-chlorophenylsulfonyloxy group, and the like. Among them, a toluenesulfonyloxy group is preferable, and a p-toluenesulfonyloxy group is more preferable.
Among such leaving groups, at least one selected from the group consisting of a bromine atom, a methanesulfonyloxy group, and a toluenesulfonyloxy group is preferable.

<Nickel catalyst>
The nickel catalyst used in the diesterification step is not particularly limited, and examples thereof include those having a nickel atom valence of 0 to 2.
Specifically, as the nickel catalyst, for example,
Metal catalysts such as nickel (II) chloride;
[1,3-bis (diphenylphosphino) propane] nickel (II) dichloride, bis (triphenylphosphine) nickel (II) dichloride, [1,2-bis (diphenylphosphino) ethane] nickel (II) dichloride, [1,1′-bis (diphenylphosphino) ferrocene] nickel (II) dichloride, bis (1,5-cyclooctadiene) nickel (0), [1,3-bis (2,6-diisopropylphenyl) imidazole -2-ylidene] triphenylphosphine nickel (II) dichloride, bromo [(2,6-pyridinediyl) bis (3-methyl-1-imidazolyl-2-ylidene)] nickel bromide, bis (tricyclohexylphosphine) nickel ( II) Dichloride, bis (1,5-cyclooctadiene) di Neckel (0), chlorobis [dicyclohexyl (phenyl) phosphino] (o-tolyl) nickel (II), bis (dicyclohexylphenylphosphino) nickel (II) dichloride, bis (2,4-pentanedionato) nickel (II) Metal complex catalysts such as hydrates;
Etc.

The nickel catalyst is preferably a catalyst prepared from a nickel compound and a ligand compound (ligand) (for example, the above-described metal complex catalyst).
Here, examples of the nickel compound include nickel halide (eg, nickel fluoride, nickel chloride, nickel bromide, nickel iodide), nickel carboxylate (eg, nickel formate, nickel acetate, 2-ethyl). Nickel hexanoate, nickel cyclobutanoate, nickel oxalate, nickel stearate, nickel naphthenate, nickel citrate, etc.), nickel hypophosphite, nickel sulfate, nickel carbonate, nickel nitrate, nickel acetylacetonate, (dimethoxyethane) Examples thereof include nickel chloride, and among these, nickel halide is preferable.
Examples of the ligand compound include a nitrogen-containing bidentate ligand. Specific examples of the nitrogen-containing bidentate ligand include 2,2′-bipyridine and 1,10-phenanthroline. , Methylenebisoxazoline, N, N, N ′, N′-tetramethylethylenediamine and the like. Among them, 2,2′-bipyridine is preferable from the viewpoint of availability.

The amount of nickel catalyst used in the diesterification step is preferably 0.05 to 0.5 mol, preferably 0.1 to 0.5 mol, relative to 1 mol of the compound represented by the formula (1). The molar ratio is more preferably 0.1 to 0.2 mol.

<Reducing agent>
The reducing agent used in the diesterification step is not particularly limited, and specific examples thereof include cobalt compounds, magnesium, zinc, manganese, etc., and these may be used alone or in combination of two or more. May be.
Examples of the cobalt compound include a cobalt salt of an organic acid, a cobalt metal complex, and the like, and a cobalt salt of an organic acid is preferable. Specific examples of the cobalt salt of organic acid include, for example, cobalt naphthenate, cobalt stearate, cobalt neodecanoate, cobalt rosinate, cobalt versatate, cobalt tall oil, cobalt oleate, cobalt linoleate, and linolenic acid. Examples thereof include cobalt and cobalt palmitate.

Among these reducing agents, from the viewpoint of reaction yield, it is preferable to use zinc when X in the above formula (1) is a compound represented by a halogen atom.
From the same viewpoint, when X in the formula (1) is a compound represented by a methanesulfonyloxy group or a toluenesulfonyloxy group, it is preferable to use a combination of a cobalt compound and manganese. .

The amount of the reducing agent used in the diesterification step is preferably 1 to 5 mol and more preferably 1 to 2.5 mol with respect to 1 mol of the compound represented by the formula (1). The amount is preferably 1.3 to 1.7 mol.

<Solvent>
In the diesterification step, it is preferable to use a solvent.
Examples of the solvent include pyridines such as pyridine and methylpyridine; nitriles such as acetonitrile and propionitrile; amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone; and the like. You may use independently and may use 2 or more types together.
Of these, it is preferable to use a pyridine solvent and a nitrile solvent in combination.

The amount of the solvent used is preferably 1 to 10 times (ml / g), preferably 1 to 5 times (ml / g) of the compound represented by the formula (1). The amount is more preferably 1 to 3 times (ml / g).

<Reaction conditions>
Although the reaction conditions in the said diesterification process are not specifically limited, Since the nickel catalyst and reducing agent mentioned above are used, compared with the above-mentioned current method 1 etc., milder conditions can be employ | adopted.
For example, the reaction temperature is preferably 0 to 60 ° C., more preferably 5 to 50 ° C.
The reaction time is preferably 30 minutes to 10 hours, more preferably 4 to 8 hours.

In this invention, the dicyclohexane dicarboxylic acid diester represented by following formula (2) by which the by-product of the stereoisomer was suppressed by the diesterification process mentioned above can be obtained.
Thereby, dicyclohexane dicarboxylic acid diester represented by the following formula (2) can separate isomers by simple operations such as extraction, crystallization, distillation and column chromatography.
In addition, when using the dicyclohexane dicarboxylic acid diester represented by following formula (2) for the manufacturing method of the dicyclohexane dicarboxylic acid of this invention mentioned later, it uses for the process of obtaining dicyclohexane dicarboxylic acid, without performing separation operation. May be.

R in the above formula (2) is the same as that described as R in the above formula (1).
In the present invention, from the viewpoint of availability of the compound represented by the above formula (1), R in the above formula (2) represents a linear or branched alkyl group having 1 to 6 carbon atoms. Among them, it is preferable to represent a methyl group, an ethyl group, or a t-butyl group.

[Method for producing dicyclohexanedicarboxylic acid]
The method for producing dicyclohexanedicarboxylic acid according to the present invention (hereinafter also abbreviated as “the method for producing dicarboxylic acid according to the present invention”) is obtained by reacting a compound represented by the following formula (1) in the presence of a nickel catalyst and a reducing agent. A step of reacting to obtain a dicyclohexanedicarboxylic acid diester represented by the following formula (2) (diesterification step), and hydrolyzing the dicyclohexanedicarboxylic acid diester to form a salt; And a step of obtaining dicyclohexanedicarboxylic acid represented by (3) (hereinafter also abbreviated as “dicarboxylation step”).
Here, the said diesterification process in the manufacturing method of the dicarboxylic acid of this invention is the same as that demonstrated in the manufacturing method of the diester of this invention mentioned above, R in following formula (1) and (2), and X in the following formula (1) is the same as that described in the above-described method for producing a diester of the present invention.

[Dicarboxylation step]
In the dicarboxylation step of the method for producing dicarboxylic acid of the present invention, the dicyclohexanedicarboxylic acid diester represented by the above formula (2) is hydrolyzed to form a salt, and then an acid is added to the above formula (3). Is a step of obtaining dicyclohexanedicarboxylic acid represented by
The hydrolysis in the dicarboxylation step is preferably performed using a base in a solvent.

<Solvent>
Specific examples of the solvent suitably used in the hydrolysis include primary alcohols such as methanol and ethanol; secondary solvents such as 2-propanol (isopropanol), sec-butanol, cyclopentanol and cyclohexanol. Alcohols; tertiary alcohols such as 1-ethynyl-1-cyclopropanol, 1-adamantanol, tert-butanol and t-amyl alcohol; ethers such as tetrahydrofuran (THF) and 1,4-dioxane; hexane, heptane, benzene Hydrocarbons such as toluene, xylene and cumene; chlorinated solvents such as methylene chloride, chloroform and trichloroethylene; ketones such as acetone and 2-butanone; N, N-dimethylformamide and 1,3-dimethyl-2- Imidazolidinone, Jime Aprotic polar solvents such as chill sulfoxide and hexamethylphosphoric triamide; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and n-butyl acetate; and the like. You may use independently and may use 2 or more types together.
Among these, it is preferable to use a solvent containing alcohol.

<Base>
Specific examples of the base preferably used in the hydrolysis include, for example, inorganic Bronsted bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate; pyridine, triethylamine, And organic Bronsted bases such as dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine.
Among these, an inorganic Bronsted base is preferable, and from the viewpoint of availability and solubility, it is more preferably any of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

<Reaction conditions>
The reaction conditions for converting the dicyclohexanedicarboxylic acid diester represented by the above formula (2) into a salt are not particularly limited, and conventionally known hydrolysis reaction conditions can be appropriately employed.
For example, the reaction temperature is preferably −30 to 100 ° C., more preferably −20 to 50 ° C., and further preferably −10 to 40 ° C.
The reaction time is preferably 10 minutes to 24 hours, more preferably 20 minutes to 10 hours, and even more preferably 30 minutes to 8 hours.

<Acid>
Examples of the acid imparted to the salt of dicyclohexanedicarboxylic acid diester include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid or salts thereof; formic acid, acetic acid, propionic acid, Organic acids such as oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or salts thereof; lithium tetrafluoroborate, boron trifluoride, boron trichloride, triodor Lewis acids such as boron fluoride, aluminum trichloride, zinc chloride, zinc bromide, zinc iodide, tin tetrachloride, tin tetrabromide, tin dichloride, titanium tetrachloride, titanium tetrabromide, trimethyliodosilane; alumina, Oxides such as silica gel and titania; minerals such as montmorillonite; and the like may be used alone. It may be used in combination of two or more.

<Reaction conditions>
The reaction conditions for providing an acid to the salt of dicyclohexane dicarboxylic acid diester to produce dicyclohexane dicarboxylic acid represented by the above formula (3) are not particularly limited, and a conventionally known deprotection reaction using an acid is not limited. Reaction conditions can be employed as appropriate.
For example, the reaction temperature is preferably −30 to 100 ° C., more preferably −20 to 50 ° C., and further preferably −10 to 40 ° C.
The reaction time is preferably 10 minutes to 24 hours, more preferably 20 minutes to 10 hours, and even more preferably 30 minutes to 8 hours.

Hereinafter, the present invention will be described in more detail based on examples. The materials, amounts used, ratios, processing details, processing procedures, and the like shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the following examples.
In the following examples, “silica gel column chromatography” was performed using an intermediate pressure preparative column Smart FLASH EPCLC-W-Prep 2XY (Yamazen Co., Ltd.). The mixing ratio in the eluent represents the volume ratio. For example, “ethyl acetate / hexane = 1: 1 → ethyl acetate / hexane 4: 1” means that an eluent of 50 mass% ethyl acetate / 50 mass% hexane is finally added to 80 mass% ethyl acetate / 20 mass% hexane. It means that the eluent was changed.
The ¹ H-NMR (Nuclear Magnetic Resonance) spectrum was measured using Bruker AV400N (Bruker) using tetramethylsilane as an internal standard, and all δ values were shown in ppm.

[Example 1]

0.83 g of zinc, 165 mg of nickel chloride and 200 mg of 2,2′-bipyridine were stirred in 1.4 mL of pyridine for 15 minutes at 55 ° C., then cooled to below 30 ° C., and the black suspension was Obtained.
Next, with respect to the obtained suspension, 2.0 g of ethyl 4-bromo-cyclohexane-1-carboxylate obtained by the method described in the experimental section (Example 16) of US Pat. No. 6,143,774 was used. A solution prepared from 5.6 mL of acetonitrile was added.
Subsequently, after stirring for 6 hours at an internal temperature of 25 to 35 ° C., the resulting suspension was filtered through Celite. To the resulting solution were added 1M aqueous hydrochloric acid and ethyl acetate to remove the lower layer (aqueous layer), and then the upper layer (organic layer) was washed with saturated brine and further dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic layer was concentrated under reduced pressure by an evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1: 10 → ethyl acetate / hexane 1: 3) to obtain [1,1′-di (cyclohexane)]-in the above scheme. 1.08 g of ethyl 4,4′-dicarboxylate was obtained as a colorless amorphous (yield 82%). As a result of analysis by ¹ H-NMR, the trans / cis ratio was 5: 1. In addition, by repeating the separation by silica gel column chromatography, it was possible to separate the cis isomer and recover only the trans isomer.
The ¹ H-NMR of the product is shown below.
¹ H-NMR (CDCl ₃ ) δ value: 4.19-4.05 (4H, m), 2.23-2.13 (2H, m), 2.01-1.96 (4H, m), 1.81-1.77 (4H, m), 1.46-0.91 (16H, m)

[Example 2]

After dissolving 0.73 g of ethyl [1,1′-di (cyclohexane)]-4,4′-dicarboxylate synthesized in Example 1 in 1.5 mL of ethanol, 1.5 mL of 3N aqueous potassium hydroxide solution was added. Was added and heated to 80 ° C.
After confirming the completion of the reaction by TLC (Thin-Layer Chromatography), the reaction mixture was cooled to 30 ° C. or lower, and 5 mL of diluted hydrochloric acid was added. The resulting solid was filtered off, washed with distilled water, and air-dried for about 13 hours to obtain 0.41, g of [1,1′-di (cyclohexane)]-4,4′-dicarboxylic acid as a white solid. (74% yield). As a result of analysis by ¹ H-NMR, the trans / cis ratio was 100: 0.

[Example 3]

In the same manner as in Example 1, except that 1.0 g of methyl 4-bromo-cyclohexane-1-carboxylate was used instead of ethyl 4-bromo-cyclohexane-1-carboxylate, [1 , 1′-di (cyclohexane)]-4,4′-dicarboxylate (0.45 g) was obtained as colorless amorphous (yield 69%). As a result of analysis by ¹ H-NMR, the trans / cis ratio was 7: 1. In addition, by repeating the separation by silica gel column chromatography, it was possible to separate the cis form and recover only the trans form.
The ¹ H-NMR of the product is shown below.
¹ H-NMR (CDCl ₃ ) δ value: 3.66 (6H, s), 2.26-2.16 (2H, m), 2.01-1.96 (4H, m), 1.81- 1.77 (4H, m), 1.46-0.91 (10H, m)

[Example 4]

In the above scheme, the same procedure as in Example 1 was used, except that 1.2 g of 4-bromo-cyclohexane-1-carboxylate-t-butyl was used instead of ethyl 4-bromo-cyclohexane-1-carboxylate. Of [1,1′-di (cyclohexane)]-4,4′-dicarboxylic acid-tert-butyl was obtained as a colorless oil (yield 76%). As a result of analysis by ¹ H-NMR, the trans / cis ratio was 10: 1. In addition, by repeating the separation by silica gel column chromatography, it was possible to separate the cis form and recover only the trans form.
The ¹ H-NMR of the product is shown below.
¹ H-NMR (CDCl ₃ ) δ value: 2.12 to 2.04 (2H, m), 2.01-1.92 (4H, m), 1.82-1.70 (4H, m), 1.46-1.21 (24H, m), 1.12-0.88 (4H, m)

[Example 5]

576 mg of vitamin B12 (cyanocobalamin) as a cobalt compound, 701 mg of manganese, 165 mg of nickel chloride, and 200 mg of 2,2′-bipyridine were stirred in 1.4 mL of pyridine at 55 ° C. for 15 minutes, and then 30 ° C. Following cooling, a black suspension was obtained.
A solution prepared from 2.77 g of ethyl 4-methanesulfonyloxy-cyclohexane-1-carboxylate and 5.6 mL of acetonitrile was then added to the resulting suspension.
Subsequently, after stirring for 6 hours at an internal temperature of 25 to 35 ° C., the resulting suspension was filtered through Celite. To the resulting solution were added 1M aqueous hydrochloric acid and ethyl acetate to remove the lower layer (aqueous layer), and then the upper layer (organic layer) was washed with saturated brine and further dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic layer was concentrated under reduced pressure by an evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1: 10 → ethyl acetate / hexane 1: 3) to obtain [1,1′-di (cyclohexane)]-in the above scheme. 0.22 g of ethyl 4,4′-dicarboxylate was obtained as a colorless amorphous (yield 16%). As a result of analysis by ¹ H-NMR, the trans / cis ratio was 5: 1.

[Reference Example 1]

As shown in the above scheme, 125 g (0.462 mol) of dimethyl 4,4-biphenyldicarboxylate (S-1-a) was added to 1000 mL of acetic acid, and 12.5 g of palladium carbon catalyst (wet product) was added. The catalytic hydrogenation reaction was carried out in an autoclave at 130 ° C. and 2 MPa.
After completion of the reaction, the reaction mixture was cooled to room temperature (23 ° C.), and then the catalyst was removed by filtration.
Then, after acetic acid was distilled off under reduced pressure, ethyl acetate and an aqueous sodium hydrogen carbonate solution were added. Thereafter, the mixture was stirred and separated to remove the aqueous layer, and the organic layer was washed with 10% brine. Sodium sulfate was added to this solution for drying, and the solvent was concentrated to obtain dimethyl 4,4′-dicyclohexanedicarboxylate (S-1-b) (130 g).

Subsequently, in order to separate isomers, the following operation was performed.
First, dimethyl 4,4′-dicyclohexanedicarboxylate (130 g), potassium hydroxide pellets (manufactured by Aldrich, purity 90%) 86.3 g, cumene 1300 mL, and polyethylene glycol 2000 (manufactured by Tokyo Chemical Industry Co., Ltd.) 10 mL were mixed. Then, a Dean-Stark tube was attached and heated and stirred at 120 ° C. After the methanol was distilled off, the external temperature was set to 180 ° C., and the reflux was continued for 20 hours while the solvent was distilled off. The progress of the reaction was confirmed by NMR. After completion of the reaction, the reaction mixture was cooled, 1300 mL of ethanol was added to the reaction solution, and the precipitated potassium salt was collected by filtration.
Next, this potassium salt was dissolved in 1300 ml of water, concentrated hydrochloric acid was added under ice cooling until the pH of the system became 3, and the precipitated carboxylic acid was collected by filtration to recover a crude product.
The recovered crude product was suspended in 500 mL of acetone, stirred at 50 ° C. for 30 minutes, cooled to room temperature, and collected by filtration to obtain 93.9 g of a crystal of dicyclohexanedicarboxylic acid (S-1-c) (yield: 80 %)Obtained.

Claims

A compound represented by the following formula (1) is reacted in the presence of a nickel catalyst and a reducing agent to obtain a dicyclohexane dicarboxylic acid diester represented by the following formula (2). Production method.

Here, in the formulas (1) and (2), R is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, or a carbon which may have a substituent. A cyclic alkyl group having 3 to 8 carbon atoms, a linear or branched alkenyl group having 1 to 6 carbon atoms which may have a substituent, and a cyclic group having 3 to 8 carbon atoms which may have a substituent An alkenyl group, an optionally substituted alkynyl group having 1 to 6 carbon atoms, an optionally substituted aryl group, or an optionally substituted heterocyclic group; In (1), X represents a leaving group.
The method for producing dicyclohexanedicarboxylic acid diester according to claim 1, wherein R in the formulas (1) and (2) represents a linear or branched alkyl group having 1 to 6 carbon atoms.
The method for producing dicyclohexanedicarboxylic acid diester according to claim 1, wherein R in the formulas (1) and (2) represents a methyl group, an ethyl group, a t-butyl group, or a trityl group.
The method for producing dicyclohexanedicarboxylic acid diester according to any one of claims 1 to 3, wherein the reducing agent is at least one selected from the group consisting of a cobalt compound, magnesium, zinc, and manganese.
The X in the formula (1) represents at least one selected from the group consisting of a halogen atom, an alkylthio group, an alkylsulfonyloxy group, and an arylsulfonyloxy group. The manufacturing method of dicyclohexane dicarboxylic acid diester as described in any one of.
X in the formula (1) represents at least one selected from the group consisting of a bromine atom, a methanesulfonyloxy group, and a toluenesulfonyloxy group, according to any one of claims 1 to 5. A method for producing dicyclohexanedicarboxylic acid diester.
The method for producing dicyclohexanedicarboxylic acid diester according to any one of claims 1 to 6, wherein X in the formula (1) represents a halogen atom, and the reducing agent is zinc.
X in the formula (1) represents a methanesulfonyloxy group or a toluenesulfonyloxy group, and the reducing agent is a combination of a cobalt compound and manganese. The manufacturing method of the dicyclohexane dicarboxylic acid diester of claim | item.
The nickel catalyst is a catalyst prepared from a nickel compound and a ligand compound;
The method for producing dicyclohexanedicarboxylic acid diester according to any one of claims 1 to 8, wherein the ligand compound is 2,2'-bipyridine.
A step of reacting a compound represented by the following formula (1) in the presence of a nickel catalyst and a reducing agent to obtain a dicyclohexanedicarboxylic acid diester represented by the following formula (2);
Hydrolyzing the dicyclohexanedicarboxylic acid diester to form a salt, and then adding an acid to obtain dicyclohexanedicarboxylic acid represented by the following formula (3);
The manufacturing method of dicyclohexane dicarboxylic acid which has these.

Here, in the formulas (1) and (2), R is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, or a carbon which may have a substituent. A cyclic alkyl group having 3 to 8 carbon atoms, a linear or branched alkenyl group having 1 to 6 carbon atoms which may have a substituent, and a cyclic group having 3 to 8 carbon atoms which may have a substituent An alkenyl group, an optionally substituted alkynyl group having 1 to 6 carbon atoms, an optionally substituted aryl group, or an optionally substituted heterocyclic group; In (1), X represents a leaving group.