JP6459703B2 - Method for producing cyclohexanedicarboxylic acid monoester compound - Google Patents

Description

  The present invention relates to a method for industrially advantageously producing a cyclohexanedicarboxylic acid monoester compound that is useful as an intermediate for producing a polymerizable compound for obtaining an optical film, with high yield and high purity at low cost.

  Conventionally, the following formula (I)

（I）

(I)

(Wherein, A represents a hydrogen atom, etc., R represents a hydrogen atom or the like, R ^X represents a hydrogen atom or the like independently, n is an integer of 1-20.) The polymerizable compound represented by the (Hereinafter, also referred to as “polymerizable compound (I)”) is known as a polymerizable compound capable of producing an optical film capable of uniform polarization conversion in a wide wavelength range (international publication). No. 2014/010325).
The polymerizable compound (I) can be produced by the following steps.

(In the formula, A, R, R ^X , and n represent the same meaning as described above. L represents a leaving group such as a hydroxyl group, a halogen atom, an alkylsulfonyloxy group, and an arylsulfonyloxy group.)
That is, by reacting the aldehyde compound represented by the formula (II) with the carboxylic acid or carboxylic acid derivative represented by the formula (2a), a compound represented by the formula (III) is obtained, and then, The target polymerizable compound (I) can be obtained by reacting with a hydrazine derivative represented by the formula (IV).
Moreover, the compound (compound (2)) whose L is a hydroxyl group among the compounds shown by Formula (2a) which are the manufacturing intermediates used for the said manufacturing method can be manufactured according to the following processes, for example. Furthermore, compounds in which L is other than a hydroxyl group can be derived from the compound (2).

(In the formula, A and n represent the same meaning as described above. R ^b represents an alkyl group such as a methyl group or an aryl group which may have a substituent such as a p-methylphenyl group.)
That is, first, in the presence of a base such as triethylamine, 1,4-cyclohexanedicarboxylic acid represented by formula (4) is reacted with sulfonyl chloride to obtain a reaction mixture containing a mixed acid anhydride.
Subsequently, a compound (2) can be obtained by adding the compound represented by the formula (1) (compound (1)) and a base such as triethylamine to the obtained reaction mixture and further performing a reaction. Yes (Patent Document 1).
However, this production method includes the following formula (3):

（３）

(3)

(In the formula, A and n represent the same meaning as described above.) Since the compound (compound (3)) represented by the formula is by-produced, column purification or the like for separating the compound (3) is required. There was a problem in producing the compound (2) on an industrial production scale.
Moreover, although the method of manufacturing a compound (2) using a protecting group is disclosed, it cannot be said that it is an industrially advantageous manufacturing method in terms of cost (patent document 2).

International Publication No. 2014/126113 International Publication No. 2011/068138

  The present invention has been made under such circumstances, and a production intermediate (compound (2)) useful for industrially producing the polymerizable compound (I) is produced at low cost. It is an object of the present invention to provide a method for producing with high yield and high purity.

  The present inventors have intensively studied to solve the above problems. As a result, 1,4-cyclohexanedicarboxylic acid was reacted with an acid halide to obtain a mixed acid anhydride, and the resulting mixed acid anhydride was reacted with compound (1) to obtain compound (2). And the compound (3) is obtained, the crude crystals of the resulting reaction mixture are dissolved in an alcohol solvent, and the compound (3), which is an insoluble substance, is collected by filtration to obtain the target compound (2). The present inventors have found that it can be obtained with high yield and high purity, and have completed the present invention.

Thus, according to the present invention, a method for producing the cyclohexanecarboxylic acid monoester compound (compound (2)) of (1) to (4) is provided.
(1) A step of obtaining a mixed acid anhydride by reacting 1,4-cyclohexanedicarboxylic acid with an acid halide in the presence of a base (A),
To the mixed acid anhydride obtained in step (A), in the presence of a base, the following formula (1)

（１）

(1)

(In the formula, A represents a hydrogen atom, a methyl group or a chlorine atom, and n represents an integer of 1 to 20). By reacting with a hydroxy compound represented by the following formula (2)

（２）

(2)

(Wherein, A and n represent the same meaning as described above), and the following formula (3)

（３）

(3)

(Wherein A and n represent the same meaning as described above) (B) to obtain a reaction mixture containing the cyclohexanecarboxylic acid diester compound represented by:
A crude crystal is obtained from the reaction mixture obtained in the step (B), the obtained crude crystal is dissolved in an alcohol solvent, and the insoluble matter is filtered to obtain a cyclohexanecarboxylic acid diester compound represented by the formula (3). Having a step (C) of removing,
A method for producing a cyclohexanecarboxylic acid monoester compound represented by the formula (2).

(2) The acid halide is represented by the formula: R ^a SO ₂ —X (R ^a is an alkyl group having 1 to 20 carbon atoms, a haloalkyl group having 1 to 20 carbon atoms, or an unsubstituted or substituted carbon group. The production method according to (1), wherein the sulfonic acid halide is represented by 1 to 20 aryl groups, and X represents a halogen atom.
(3) The production method according to (1) or (2), wherein the alcohol solvent is methanol.
(4) The manufacturing method in any one of (1)-(3) whose A represents a hydrogen atom and n is 6 in said Formula (1)-(3).

  According to the production method of the present invention, it is possible to produce the compound (2), which is a production intermediate of the polymerizable compound (I), which is a production raw material of the optical film, at low cost with high yield and high purity. it can.

Hereinafter, the present invention will be described in detail.
The manufacturing method of this invention is a manufacturing method of the compound (2) which has the following process (A)-process (C).
Step (A): 1,4-cyclohexanedicarboxylic acid is reacted with an acid halide in the presence of a base to obtain a mixed acid anhydride Step (B): Mixed acid anhydride obtained in Step (A) In the presence of a base, by reacting the hydroxy compound represented by the formula (1), the cyclohexanecarboxylic acid monoester compound (compound (2)) represented by the formula (2) and the formula (3) Step (C) for obtaining a reaction mixture containing the cyclohexanecarboxylic acid diester compound (compound (3)) represented by formula: (C): Crude crystals are obtained from the reaction mixture obtained in step (B), and the obtained crude crystals are converted into an alcohol solvent. Removing compound (3) by dissolving insoluble matter and filtering insoluble matter

In the above formula, A represents a hydrogen atom, a methyl group or a chlorine atom, preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.
n represents an integer of 1 to 20, preferably an integer of 2 to 10, and more preferably 6.

  The compound (2) obtained by the production method of the present invention is useful as a production intermediate for the polymerizable compound (I).

(Process (A))
In the production method of the present invention, step (A) is a step of obtaining a mixed acid anhydride by reacting 1,4-cyclohexanedicarboxylic acid (4) with an acid halide in the presence of a base.

  1,4-cyclohexanedicarboxylic acid may be a trans isomer, a cis isomer, or an isomer mixture, but is preferably a trans isomer from the viewpoint of obtaining a desired target product.

Examples of the acid halide to be used include a sulfonic acid halide represented by the formula: R ^a SO ₂ —X and a carboxylic acid halide represented by the formula: R ^a CO—X. Here, X represents a halogen atom such as a chlorine atom or a bromine atom. R ^a represents an alkyl group having 1 to 20 carbon atoms, a haloalkyl group having 1 to 20 carbon atoms, or an unsubstituted or substituted aryl group having 1 to 20 carbon atoms.
Examples of the alkyl group having 1 to 20 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, n-hexyl group, n-octyl group, An n-decyl group is mentioned.
Examples of the unsubstituted or substituted aryl group having 1 to 20 carbon atoms include phenyl group, 4-methylphenyl group, 2-chlorophenyl group, 3-methoxyphenyl group, 1-naphthyl group, 2-naphthyl group and the like. It is done.

  Specific examples of the sulfonic acid halide include methanesulfonyl chloride, ethanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, paratoluenesulfonyl chloride, methanesulfonyl fluoride, methanesulfonyl bromide, ethanesulfonyl bromide, benzenesulfonyl bromide, methanesulfonyl. Examples include iodide and benzenesulfonyl iodide.

  Specific examples of the carboxylic acid halide include acetyl chloride, propionic acid chloride, benzoyl chloride, acetyl bromide, and propionic acid bromide.

Among these, the sulfonic acid halide represented by the formula: R ^a SO ₂ —X is used as the acid halide from the viewpoints of obtaining the target product with good yield, availability, production cost, and the like. It is more preferable to use a sulfonic acid chloride represented by the formula: R ^a SO ₂ —Cl, and it is more preferable to use methanesulfonyl chloride or paratoluenesulfonyl chloride.
The usage-amount of an acid halide is 0.1-0.7 times mole normally with respect to 1, 4- cyclohexane dicarboxylic acid.

The reaction is carried out in the presence of a base.
Examples of the base used include organic bases such as triethylamine, diisopropylethylamine, phenyldimethylamine, pyridine, picoline, lutidine, 4- (dimethylamino) pyridine; sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate And inorganic bases such as potassium carbonate. These can be used alone or in combination of two or more.
Among these, an organic base is preferable, a tertiary amine such as triethylamine or diisopropylethylamine is more preferable, and triethylamine is particularly preferable from the viewpoint of obtaining the target product with good yield.
The usage-amount of a base is 0.1-0.7 equivalent normally with respect to 1 equivalent of 1, 4- cyclohexane dicarboxylic acid.

The reaction is preferably carried out in an organic solvent.
Examples of the organic solvent to be used include ethers such as diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1,4-dioxane and cyclopentyl methyl ether; esters such as ethyl acetate, propyl acetate and methyl propionate; N Amides such as N, dimethylformamide, N-methylpyrrolidone and hexamethylphosphoric triamide; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic carbons such as n-pentane, n-hexane and n-octane Hydrogen; alicyclic hydrocarbons such as cyclopentane and cyclohexane; and the like.
These solvents can be used alone or in combination of two or more.
Among these, ethers are preferable and THF is more preferable because the target product can be obtained with good yield.

  Although the usage-amount of a solvent is not specifically limited, Although it can determine suitably considering the kind of compound to be used, reaction scale, etc., it is 1-20 g normally with respect to 1-g of 1, 4- cyclohexane dicarboxylic acid.

The reaction temperature is usually −10 ° C. to + 40 ° C., preferably −5 ° C. to + 15 ° C. Although depending on the reaction scale and the like, the reaction time is usually from several minutes to several tens of hours, preferably from several tens of minutes to several hours.
The completion of the reaction can be confirmed by thin layer chromatography, gas chromatography or the like.
As described above, a reaction mixture containing a mixed acid anhydride is obtained. Although the mixed acid anhydride can be isolated, the reaction mixture is usually subjected to the next step (B) without isolation.

(Process (B))
Step (B) is a step of obtaining a reaction mixture containing Compound (2) and Compound (3) by reacting Compound (1) with the mixed acid anhydride obtained in Step (A) in the presence of a base. It is.
Compound (1) can be produced by a conventionally known method (International Publication No. 2014/010325, etc.). Moreover, a commercial item can also be used as it is.
The usage-amount of a compound (1) is 0.1-1 times mole normally with respect to the used 1, 4- cyclohexane dicarboxylic acid, Preferably, it is 0.4-0.6 times mole.

Examples of the base to be used include the same ones as exemplified in the step (A).
Among these, triethylamine, 4- (dimethylamino) pyridine, and a mixture thereof are preferable.
The usage-amount of a base is 1-3 times mole normally with respect to the used compound (1), Preferably it is 1-1.5 times mole.
The reaction can be carried out by adding compound (1) and a base to the reaction mixture obtained in step (A) and stirring.

The reaction temperature is usually −10 ° C. to + 40 ° C., preferably 0 ° C. to 30 ° C., more preferably 5 to 15 ° C.
The reaction time is usually from several minutes to several hours, although depending on the reaction scale and the like.
Thereby, the reaction mixture containing the target compound (2) and the by-product compound (3) is obtained.

(Process (C))
Step (C) is a step of removing compound (3) by obtaining crude crystals from the reaction mixture obtained in step (B), dissolving the obtained crude crystals in an alcohol solvent, and filtering insoluble matter. It is.

As a method for obtaining crude crystals from the reaction mixture obtained in step (B), for example, water is added to the reaction mixture obtained in step (B) and heated under normal pressure, or the organic solvent is distilled under reduced pressure. And a method of precipitating crude crystals by allowing the concentrated liquid to be allowed to cool or cool.
The amount of water to be added is not particularly limited as long as crude crystals can be precipitated, and is usually 300 to 3000 g, preferably 500 to 1500 g, based on 100 g of the compound (1) used.
Crude crystals can be obtained by filtering and drying the resulting precipitate.
When the organic solvent is distilled off by heating, a polymerization inhibitor such as 2,6-di-tert-butyl-p-cresol is added to the solution in an amount of about 0.01-fold mol with respect to the compound (1). It may be added.

The alcohol solvent added to the obtained crude crystals may be any one that can easily dissolve the compound (2) and hardly dissolve the compound (3). By using such a solvent, the compound (3) which is an insoluble substance in the crude crystal can be removed, and the compound (2) can be isolated.
Examples of the alcohol solvent used include aliphatic alcohols having 1 to 6 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, n-pentanol, n-hexanol; And alicyclic alcohols having 3 to 10 carbon atoms such as tanol, cyclohexanol, cycloheptanol and the like. Among these, alcohols having 1 to 3 carbon atoms are preferable, and methanol is particularly preferable from the viewpoint of obtaining the target product with higher yield and an economical viewpoint.

  The addition amount of the alcohol solvent is usually 100 to 3000 g, preferably 500 to 1500 g based on 100 g of the compound (1) used, although it depends on the type of alcohol used, the compound (2), the reaction scale, and the like.

After the alcohol solvent is added, the alcohol solution is preferably stirred in order to quickly dissolve the compound (2). The stirring temperature is usually 0 to 40 ° C., preferably 10 to 35 ° C., and the stirring time is usually several minutes to several hours, preferably several minutes to 1 hour.
If the stirring is performed at an excessively high temperature or for a long time, the compound (3) is dissolved in an alcohol solvent, and the purity of the compound (2) to be isolated later may be lowered. On the other hand, if the temperature is too low or the stirring time is short, the compound (2) cannot be completely dissolved and the yield of the compound (2) may be reduced.
After stirring, the compound (3) remaining as an insoluble substance can be removed by filtration.
Thereby, a filtrate containing the compound (2) at a high concentration can be obtained.

By recrystallizing the compound (2) from the alcohol solution of the compound (2) obtained in the step (C), high-purity crystals of the compound (2) can be obtained.
The recrystallization method is not particularly limited. For example, water is added to the alcohol solution to precipitate crystals, heated and dissolved at 45 to 60 ° C., and then cooled to −20 to 0 ° C. to precipitate the crystals of compound (2). Can do.
The amount of water used depends on the type of compound (1), but is usually 10 to 1000 g, preferably 20 to 500 g, based on 100 g of the alcohol used.
When adding water and heating, a polymerization inhibitor such as 2,6-di-tert-butyl-p-cresol is further added to the solution in an amount of about 0.001 times mol to the compound (1) used. May be.

By filtering the solution in which the crystals are precipitated, the crystals of the compound (2) can be obtained with high purity.
The purity of the obtained compound (2) is usually 80% or more.
The yield of the compound (2) obtained is usually 40% or more.
According to the present invention, compound (2), which is a production intermediate of polymerizable compound (I), can be produced advantageously industrially advantageously at a low cost and in a high yield with a high purity.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited by the following examples.

Example 1 Production of Compound 1

（１ａ）

(1a)

In a nitrogen stream, 130.28 g (756.65 mmol) of trans-1,4-cyclohexanedicarboxylic acid and 750 g of tetrahydrofuran (THF) were added to a three-necked reactor equipped with a thermometer. Next, the reactor was immersed in an ice bath to adjust the internal temperature of the reaction solution to 5 ° C., and 45.50 g (397.21 mmol) of methanesulfonyl chloride was added to the reaction solution. Furthermore, 42.11 g (416.15 mmol) of triethylamine was added dropwise over 30 minutes while maintaining the internal temperature of the reaction solution at 15 ° C. or lower. After completion of the dropwise addition, the whole volume was further stirred at 5 ° C. for 1 hour.
To the resulting reaction solution, 100.00 g (378.33 mmol) of 4- (6-acryloyloxy-hex-1-yloxy) phenol (manufactured by DKSH) and 4.62 g of 4- (dimethylamino) pyridine (37 .82 mmol) was added. Thereto, 42.11 g (416.15 mmol) of triethylamine was added dropwise over 30 minutes while maintaining the internal temperature of the reaction solution at 15 ° C. or lower, and the whole was stirred at 25 ° C. for another 2 hours.

  After completion of the reaction, the reaction solution was cooled to 15 ° C., and 0.83 g (3.77 mmol) of 2,6-di-tert-butyl-p-cresol (BHT) and 800 g of distilled water were added. The resulting solution was concentrated under normal pressure until the internal temperature of the solution reached 75 ° C., whereby THF was distilled off. Thereafter, the concentrated liquid was cooled to 60 ° C., 20.0 g of a filter aid (LocaHelp 4209, manufactured by Mitsui Kinzoku Mining Co., Ltd.) was added, and further cooled to 5 ° C. The precipitate was collected by filtration, and the filtrate was vacuum dried to obtain crude crystals.

The obtained crude crystals were added to 1080 g of methanol, and the mixture was stirred at 25 ° C. for 30 minutes, and then the insoluble components were filtered. The filtrate was subjected to 0.08 g (0 of 2,6-di-tert-butyl-p-cresol (BHT)). .36 mmol) and 519 g of distilled water were added. Next, the solution was heated to 55 ° C. and then cooled to −5 ° C. for recrystallization. The obtained crystals were collected by filtration, and the filtrate was vacuum-dried to obtain 79.16 g of Compound 1 as a white solid (yield = 50%).
The structure of the target product was identified by ¹ H-NMR.

¹ H-NMR (500 MHz, DMSO-d6, TMS, δ ppm) = 12.12 (s, 1H), 6.99 (d, 2H, J = 9.0 Hz), 6.92 (d, 2H, J = 9.0 Hz), 6.32 (dd, 1 H, J = 1.5 Hz, 175 Hz), 6.17 (dd, 1 H, J = 10.0 Hz, 17.5 Hz), 5.93 (dd, 1 H, J = 1.5 Hz, 10.0 Hz), 4.11 (t, 2H, J = 6.5 Hz), 3.94 (t, 2H, J = 6.5 Hz), 2.48-2.56 (m, 1H), 2.18-2.26 (m, 1H), 2.04-2.10 (m, 2H), 1.93-2.00 (m, 2H), 1.59-1.75 ( m, 4H), 1.35 to 1.52 (m, 8H)

Claims (4)

Step (A) of obtaining a mixed acid anhydride by reacting 1,4-cyclohexanedicarboxylic acid with an acid halide in the presence of a base,
To the mixed acid anhydride obtained in step (A), in the presence of a base, the following formula (1)

(In the formula, A represents a hydrogen atom, a methyl group or a chlorine atom, and n represents an integer of 1 to 20). By reacting with a hydroxy compound represented by the following formula (2)

(Wherein, A and n represent the same meaning as described above), and the following formula (3)

(Wherein A and n represent the same meaning as described above) (B) to obtain a reaction mixture containing the cyclohexanecarboxylic acid diester compound represented by:
A crude crystal is obtained from the reaction mixture obtained in the step (B), the obtained crude crystal is dissolved in an alcohol solvent, and the insoluble matter is filtered to obtain a cyclohexanecarboxylic acid diester compound represented by the formula (3). Removing (C) ,
The alcohol solvent is an alcohol having 1 to 3 carbon atoms;
A method for producing a cyclohexanecarboxylic acid monoester compound represented by the formula (2). The acid halide is represented by the formula: R ^a SO ₂ —X (R ^a is an alkyl group having 1 to 20 carbon atoms, a haloalkyl group having 1 to 20 carbon atoms, or an unsubstituted or substituted carbon group having 1 to 20 carbon atoms. The production method according to claim 1, which is a sulfonic acid halide represented by the following formula:   The production method according to claim 1, wherein the alcohol solvent is methanol.   The manufacturing method in any one of Claims 1-3 whose A represents a hydrogen atom and n is 6 in said Formula (1)-(3).