WO2017209458A1 - Novel method for preparing 4'-hydroxy-4-biphenylcarboxylic acid - Google Patents

Abstract

The present invention relates to a novel method for preparing 4'-hydroxy-4-biphenylcarboxylic acid, which is prepared through a hydrolysis reaction from a compound of R1-COO-Ph-Ph-CO-CR-Y. In the formula: R¹ is a C_1-6 alkyl, cycloalkyl or aryl group; Ph is phenyl; R is hydrogen or an alkyl group; Y is >N⁺-(X^-); X is a leaving group selected from chloride, bromide, iodide, methanesulfonate, benzenesulfonate and toluenesulfonate; and >N⁺- is a quaternary amine salt, which is an amine salt comprising three identical or different alkyl groups or aromatic hydrocarbons or a cyclic aromatic amine salt such as pyridine.

Description

New preparation method of 4'-hydroxy-4-biphenylcarboxylic acid

The present invention relates to a novel process for preparing 4'-hydroxy-4-biphenylcarboxylic acid, and more particularly to 4'-hydroxy-4- ratio useful as a liquid crystal, a liquid crystal polymer, and a high heat dissipation high heat resistant resin material. It relates to an industrially useful process for preparing phenylcarboxylic acid from 4-phenylphenol.

The existing techniques for 4'-hydroxy-4-biphenylcarboxylic acid useful as liquid crystal, liquid crystal polymer, and high heat dissipation and high heat resistant resin material can be classified.

As shown in [Chemical Scheme 1], two differently substituted benzene derivatives are coupled to a Suzuki coupling reaction to a target compound. Methods for synthesizing 4'-hydroxy-4-biphenylcarboxylic acid are known from JP 2009298727, RCS Advances, 2014, 4 (6), 2984, Organic & Bimolecular Chemistry 2014, 12 (25), 4511 and the like.

[Chemical Scheme 1]

However, such Suzuki coupling reactions require the use of expensive boronic acid compounds or expensive palladium catalysts, and thus are not industrially feasible.

Alternatively, methods for synthesizing 4'-hydroxy-4-biphenylcarboxylic acid from a 4-phenylphenol derivative in which a hydroxy group is protected with a protecting group through carboxylation and deprotection are known.

In Huaxue Shiji 2007, 29 (4), 239, the hydroxy group is protected with a benzyl group and carboxylated as shown in [Chemical Reaction Formula 2] below, and then debenzylated to give the desired compound 4'-hydroxy-4-biphenylcarboxyl. Methods of synthesizing acids are known.

[Chemical Scheme 2]

In this method, the hydroxy group of phenylphenol is protected with acetyl group, then acetylated, deacetylated, and then protected with benzyl, and then hypochlorous acid is reacted and carboxylated under alkaline conditions, followed by deprotection of the protecting group benzyl by hydrogen reaction under palladium catalyst. It is reported that the target compound 4'-hydroxy-4-biphenyl carboxylic acid was synthesized.

This process consists of complex multistage reactions such as multistage protection-deprotection, as well as the use of a large amount of hypochlorite salts and commercially dangerous hydrogen reactions required for deprotection of benzyl protecting groups. It is evaluated as a process that lacks much economic feasibility.

Huaxue Shiji 2005, 13 (6), 614 has a method similar to that of [Chemical Scheme 2]. As shown in [Chemical Reaction Formula 3], the hydroxy group of phenylphenol is first protected with a methyl group, and then the hypochlorite salt is reacted under alkaline conditions to be carboxylated. It is reported that the target compound 4'-hydroxy-4-biphenylcarboxylic acid is obtained as a step of deprotecting the methyl group.

[Chemical Scheme 3]

However, this method also uses a large amount of hypochlorite salt, and in order to deprotect the methyl protecting group, it is evaluated as a process lacking in economical efficiency in terms of manufacturing cost such as acetic acid as a solvent and high temperature reaction using expensive bromic acid. do.

Apart from these, Japanese Patent No. 04243851 uses phosgene derivatives to protect two 4-phenylphenol hydroxy groups and to carboxylate them using oxalyl chloride to target compound 4'-hydroxy-4. In the method of synthesizing biphenyl carboxylic acid and Japanese Patent No. 63119440, the phosgene derivative N, N-dimethyl chloroformamide is obtained as shown in the following [Chemical Reaction Scheme 4] by reacting with 4-phenylphenol and hydrolysis. Methods of synthesizing the desired compound 4'-hydroxy-4-biphenylcarboxylic acid are known.

[Chemical Scheme 4]

However, these methods require the use of industrially difficult phosgene derivatives or expensive oxalyl chlorides, and they are economically poor in terms of purification due to impurities such as isomers produced by the use of highly reactive raw materials. .

In addition, International Patent Publication No. 2004/76397 discloses a target compound 4'-hydroxy-4-biphenylcarboxylic acid by reacting formic acid with biphenyl and palladium di (trifluoroacetate) for 48 hours. However, it is difficult to commercialize due to the use of expensive catalysts and high purification costs due to the generation of various by-products. In European Patent 240362, 4'-hydroxy-4-biphenyl is used by utilizing the following bisphenol derivatives. Although it was introduced that the carboxylic acid can be synthesized, the cost of preparing the bisphenol derivative of Chemical Formula 6, which is a raw material, is a large commercial burden in the preparation of the target compound 4'-hydroxy-4-biphenylcarboxylic acid.

[Formula 6]

Therefore, as the electronics industry develops, new 4'-hydroxy-4-biphenylcarboxyl which is easy to mass-produce and economical in the liquid crystal, liquid crystal polymer, and high heat dissipation high heat-resistance resin material industries requiring various and efficient physical materials. Development of acid production processes is required.

On the other hand, an object of the present invention is to provide a novel method of producing 4'-hydroxy-4-biphenylcarboxylic acid having a simple process and high productivity.

The novel process for preparing 4'-hydroxy-4-biphenylcarboxylic acid of formula (1) of the present invention is characterized in that it is prepared through a hydrolysis reaction from a compound of formula (2).

[Formula 1]

[Formula 2]

In Chemical Formula 2,

R ¹ is an alkyl, cycloalkyl, or aryl group having 1 to 6 carbon atoms,

R is hydrogen or an alkyl group,

X is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, benzenesulfonate, toluenesulfonate,

Quaternary amine salts are amine salts consisting of three identical or different alkyl groups or aromatic hydrocarbons, or cyclized aromatic amine salts such as pyridine.

Here, the hydrolysis refers to a reaction for heating if necessary in an alkaline aqueous solution or a mixed solution of an alkaline aqueous solution and an organic solvent, and the alkali used is NaOH, KOH, CsOH, Na ₂ CO ₃ , K ₂ CO ₃ , Cs Alkali salts such as ₂ CO ₃ .

The alkali is used in the amount of 2 to 5 equivalents, preferably 2 to 3 equivalents based on the compound of formula (2).

The hydrolysis reaction temperature is 20-100 degreeC, Preferably it is 60-100 degreeC.

The compound of Formula 2 is prepared through the reaction of a compound of Formula 3 with a tertiary amine.

[Formula 3]

In Chemical Formula 3,

R ¹ is an alkyl, cycloalkyl or aryl group having 1 to 6 carbon atoms,

R is hydrogen or an alkyl group,

X is a leaving group such as chlorine, bromine, iodine, methanesulfonate, benzenesulfonate, toluenesulfonate.

As a tertiary amine reacted with the compound of Formula 3, tertiary amines consisting of three identical or different alkyl groups or aromatic hydrocarbons; There are cyclized aromatic amines such as pyridine.

Reaction temperature is 20-150 degreeC, especially 80-120 degreeC is efficient.

The compound of Formula 3 is prepared by a catalytic condensation reaction of a compound of Formula 4 with a compound of Formula 5.

[Formula 4]

[Formula 5]

In the above formula,

R ¹ is an alkyl, cycloalkyl or aryl group having 1 to 6 carbon atoms,

R is hydrogen or an alkyl group,

X is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, benzenesulfonate, toluenesulfonate.

As a catalyst used for the condensation reaction, AlCl ₃ , FeCl ₃ , ZnCl ₂ ; Lewis acids such as organic sulfonate metal salts, such as metal salts of trifluoromethane sulfonate.

The manufacturing process of the present invention has the advantage of providing high manufacturing economics with the simplicity of the process.

In particular, the manufacturing process of the present invention has the advantage that the synthesis process is simple and the purification process is convenient to provide a process for economically manufacturing high purity products.

Hereinafter, the present specification will be described in more detail.

The present invention provides a novel process for preparing compound 4'-hydroxy-4-biphenylcarboxylic acid of formula (1).

[Formula 1]

The manufacturing process of the present invention can be represented by the chemical reaction path of the following Chemical Scheme 5.

[Chemical Scheme 5]

Reaction stage i

In Chemical Scheme 5, in the reaction step i, an acyl group is introduced to protect an alcohol group of 4-phenylphenol to obtain a compound of Chemical Formula 4. As the acylated compound, R is an alkyl group having 1 to 6 carbon atoms or an aryl group; X ₁ is chlorine, bromine, or acylated compound as acetic anhydride; Acid anhydrides such as propionic anhydride are used.

As the base used in the reaction step i, NaOH, Na ₂ CO ₃ , KOH, K ₂ CO ₃ , tertiary amines are used. As the reaction solvent used in the reaction step i, esters such as ethyl acetate; Ethers such as diisopropyl ether; Ketones such as acetone; Amides such as dimethyl formamide; Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide are used.

Reaction step ii

In reaction step ii, an acyl compound, such as Formula 5, substituted with a leaving group having a good 2-position to the compound of Formula 4 obtained through Reaction Step i under a Lewis catalyst to obtain a compound of Formula 3, wherein R is Hydrogen, an alkyl group having 1 to 6 carbon atoms; X is a good leaving group such as chlorine, bromine, iodine, methanesulfonate, toluenesulfonate, benzenesulfonate, and the compound of formula 5 is an acid chloride having such a leaving group.

The catalyst used in the reaction step ii may be Lewis acid such as AlCl ₃ , FeCl ₃ , ZnCl ₂ , an organic sulfonate metal salt, and the solvent used in the reaction step ii may include chlorinated hydrocarbons such as dichloromethane and dichloroethane; Nitro alkanes such as nitromethane are used.

Reaction step iii

In reaction step iii, tertiary amines used to synthesize compounds of formula 2 from compounds of formula 3 include tertiary amines composed of three alkyl groups, the same as or different from each other; Tertiary amines having one or more aryl groups; Tertiary amines which form a ring such as pyridine are used.

Solvents used in reaction step iii include tertiary amines such as pyridine used to form the compound of formula (2); Esters such as ethyl acetate; Ethers such as diisopropyl ether; Ketones such as acetone; Amides such as dimethyl formamide; Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide; Water or a mixed solvent of water and an organic solvent is used.

In reaction step iii, the reaction temperature is 20 to 150 ° C, particularly 80 to 120 ° C.

Reaction step iv

In the reaction step iv, which is a hydrolysis step, an alkaline aqueous solution; Hydrolysis using a mixed solution of an alkaline aqueous solution and an organic solvent, NaOH, Na ₂ CO ₃ , KOH, K ₂ CO ₃ , CsOH, Cs2CO ₃ and the like are used as the alkali used in the reaction step iv The alkali equivalent is 2 to 5 equivalents, in particular 2 to 3 equivalents.

The organic solvent used in the reaction step iv by mixing with the aqueous alkali solution is alcohols such as methyl alcohol; Amides such as dimethylformamide; Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide; Ketones such as 2-butanone; Ethers such as diisopropyl ether are used.

The reaction temperature of the hydrolysis reaction in reaction step iv is 20 to 100 ° C., particularly 60 to 100 ° C.

The acid used as a neutralizing agent to obtain the compound of formula 1 from the reaction solution hydrolyzed in reaction step iv is an aqueous hydrochloric acid solution; Inorganic acids such as aqueous bromic acid solution; Organic acids such as acetic acid are used.

4'-hydroxy-4-biphenylcarboxylic acid according to the present invention can be used as a high functional material such as liquid crystal, liquid crystal polymer, high heat dissipation, high heat-resistant resin, and will be described in detail in the following examples. However, the following examples are intended to illustrate the present specification, and the scope of the present specification is not limited thereto.

Example 1 Preparation of Compound of Formula 4

Production Example 1 Preparation of 4-acetoxybiphenyl

30 g of 4-phenylphenol was dissolved in 120 ml of dichloromethane, 21.6 g of triethylamine was added, followed by cooling to 10, and then 18.5 g of acetic anhydride was dropped dropwise over 30 minutes. After stirring for 4 hours, it was confirmed that 4-phenylphenol was exhausted by thin layer chromatography analysis. The solution was adjusted to pH 2 by adding 10% aqueous hydrochloric acid, and the layers were separated. 120 ml of water was added to the organic layer, the layers were washed and separated. Then, the organic layer was dried with anhydrous sodium sulfate. After filtering over anhydrous sodium sulfate, the filtrate was concentrated at atmospheric pressure, crystallized with isopropanol, filtered and dried to give 35.1 g of a light white 4-acetoxybiphenyl (yield 93.8%).

1H nmr (300MHz, DMSO d6) δ ppm: 2.33 (s, 3H), 7.15 ~ 7.18 (m, 2H), 7.32 ~ 7.46 (m, 3H), 7.55 ~ 7.60 (m, 4H)

Production Example 2 Preparation of 4-benzoyloxybiphenyl

30 g of 4-phenylphenol, 21.6 g of triethylamine, and 25.5 g of benzoyl chloride were prepared in the same manner as in (Preparation Example 1), to obtain 44.5 g of an off-white 4-benzoyloxybiphenyl (yield 92%).

1H nmr (300MHz, DMSO d6) δ ppm: 7.31 ~ 7.66 (m, 12H), 8.22 ~ 8.24 (d, 2H)

Example 2 Preparation of Compound of Chemical Formula 3

Preparation Example 3 Preparation of 4-Acetoxy-4 '-(2-chloroacetyl) biphenyl

12.5 g of 4-acetoxybiphenyl and 9.9 g of 2-chloroacetyl chloride prepared in Production Example 1 were dissolved in 80 ml of dichloromethane, cooled to 5 ° C. or lower, and then 17.9 g of anhydrous aluminum chloride was added while maintaining 10 ° C. or lower. After stirring for 4 hours and confirming that all raw materials are consumed by gas chromatography analysis, 200 ml of 5% aqueous hydrochloric acid solution is added and stirred for 3 hours. After standing for 2 hours, the organic layer was separated, and 200 ml of water was further added to the organic layer, the mixture was stirred for 1 hour, and allowed to stand for 1 hour. The organic layer was separated, anhydrous sodium sulfate was added, the mixture was sufficiently stirred to remove the organic layer, and then filtered. The organic layer was heated and distilled to concentrate most solvents, 100 ml of isopropanol was added, crystallized, filtered, and dried under atmospheric pressure. Gas chromatography analysis 4-Acetoxy-4 '-(2-chloroacetyl) biphenyl light brown powder 15.2 with purity of 94.2% g (89.2% yield) was obtained.

1H nmr (300MHz, DMSO d6) δ ppm: 2.26 (s, 3H), 5.19 (s, 2H), 7.21 ~ 7.24 (d, 2H), 7.75 ~ 7.78 (d, 2H), 7.81 ~ 7.84 (d, 2H ), 8.0 to 8.04 (d, 2H)

Preparation Example 4 Preparation of 4-benzoyloxy-4 '-(2-chloroacetyl) biphenyl

Using the same method as in Preparation Example 4, using 16.1 g of 4-benzoyloxybiphenyl prepared in Preparation Example 2, 9.9 g of 2-chloroacetyl chloride, and 17.9 g of anhydrous aluminum chloride, the gas chromatography analysis showed that the 4 'was 88.2% pure. A pale yellow powder of 19.1 g (88.6% yield) of -benzoyloxy-4- (2-chloroacetyl) biphenyl was obtained.

1 H nmr (300 MHz, DMSO d6) δ ppm: 4.75 (s, 2H), 7.33-7.36 (d, 2H), 7.51-7.56 (t, 2H), 7.63-7.74 (m, 5H), 8.04-8.07 (d , 2H), 8.22-8.25 (d, 2H)

Example 3 Preparation of Compound of Chemical Formula 2

Preparation Example 5 Preparation of 4-acetoxy-4 ′-(2-pyridiniumacetyl) biphenyl chloride

15.2 g of 4-acetoxy-4 '-(2-chloroacetyl) biphenyl prepared in Preparation Example 3 was added to 60 ml of pyridine, and the mixture was refluxed for 3 hours, followed by thin layer chromatography (ethyl acetate 1: hexane 2). It was confirmed that the exhaustion. The reaction solution was cooled to room temperature, filtered, washed with 50 ml of ethyl acetate, and dried at 60 for 8 hours to give 15.9 g (82.2% yield) of brown powder 4-acetoxy-4 '-(2-pyridiniumacetyl) biphenyl chloride. Got.

1 H nmr (300 MHz, DMSO d6) δ ppm: 2.27 (s, 3H), 6.59 (s, 2H), 7.25-7.28 (d, 2H), 7.81-7.84 (d, 2H), 7.94-7.97 (d, 2H) ), 8.1 to 8.13 (d, 2H), 8.23 to 8.28 (t, 3H), 8.68 to 8.74 (t, 1H), 9.05 to 9.07 (d, 2H)

Preparation Example 6 Preparation of 4-acetoxy-4 '-[2- (4-methylmorpholinium) acetyl] biphenyl chloride

15.2 g of 4-acetoxy-4 '-(2-chloroacetyl) biphenyl prepared in Production Example 4 was added to 60 ml of 4-methylmorpholine, and then refluxed for 3 hours to perform thin layer chromatography (ethyl acetate 1: hexane 2). Analysis confirmed that the raw material was used up. The reaction solution was cooled to room temperature, filtered, washed with 50 ml of ethyl acetate and dried at 60 for 8 hours to give brown powder 4-acetoxy-4 '-[2- (4-methylmorpholinium) acetyl] biphenyl chloride 17.1 g (83.4% yield) was obtained.

1 H nmr (300 MHz, DMSO d6) δ ppm: 2.31 (s, 3H), 3.45 (s, 3H), 3.73-4.1 (m, 8H), 5.52 (s, 2H), 7.28-7.31 (d, 2H), 7.84 ~ 7.86 (d, 2H), 7.94 ~ 7.97 (d, 2H), 8.09 ~ 8.12 (d, 2H)

Example 4 Preparation of Compound of Formula 1

Production Example 7 Preparation of 4'-hydroxy-4-biphenylcarboxylic acid

13.6 g of 4-acetoxy-4 '-(2-pyridiniumacetyl) biphenyl chloride prepared in Preparation Example 5 was added to 300 ml of water, 6.5 ml of 50% aqueous sodium hydroxide solution was added thereto, and the mixture was refluxed for 3 hours to perform thin layer chromatography. Analysis confirmed that 4-acetoxy-4 '-(2-pyridiniumacetyl) biphenyl chloride was used up, and then cooled to room temperature. The mixture was adjusted to pH 2 by dropwise dropping the concentrated aqueous hydrochloric acid solution while stirring the cooled aqueous solution. After 1 hour of further stirring, the resulting solid was filtered, washed with 50 ml of 50% acetone aqueous solution, dried at 80 for 8 hours, and then subjected to gas chromatography for analysis of light brown powder 4'-hydroxy-4-biphenylcarboxylic acid of 98.5% purity. 6.9 g (87.1% yield) were obtained.

1 H nmr (300 MHz, DMSO d6) δ ppm: 6.86-6.89 (d, 2H), 7.56-7.59 (d, 2H), 7.69-7.72 (d, 2H), 7.95-7.98 (d, 2H)

Production Example 8 Preparation of 4'-hydroxy-4-biphenylcarboxylic acid

17.1 g of 4-acetoxy-4 '-[2- (4-methylmorpholinium) acetyl] biphenyl chloride prepared in Production Example 6 was prepared in the same manner as in Example 7 to give a light brown powder 4'-hydroxy- 6.8 g (86.9% yield) of 4-biphenylcarboxylic acid were obtained.

1 H nmr (300 MHz, DMSO d6) δ ppm: 6.86-6.89 (d, 2H), 7.56-7.59 (d, 2H), 7.69-7.72 (d, 2H), 7.95-7.98 (d, 2H)

Claims (10)

1. Method for producing a 4'-hydroxy-4-biphenylcarboxylic acid of the general formula (1) characterized in that it is prepared through a hydrolysis reaction from a compound of the general formula (2):

   [Formula 1]

   

   [Formula 2]

   

   In Chemical Formula 2,

   R ¹ is an alkyl, cycloalkyl, or aryl group having 1 to 6 carbon atoms,

   R is hydrogen or an alkyl group,

   X is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, benzenesulfonate, toluenesulfonate,

   Quaternary amine salts are amine salts consisting of three identical or different alkyl groups or aromatic hydrocarbons, or cyclized aromatic amine salts such as pyridine.
2. The method for producing 4'-hydroxy-4-biphenylcarboxylic acid according to claim 1, wherein the hydrolysis is performed in an aqueous alkali solution or a mixed solution of an alkaline aqueous solution and an organic solvent.
3. 4. The 4'-hydroxy according to claim 3, wherein the alkali used for hydrolysis is selected from the group consisting of NaOH, KOH, CsOH, Na ₂ CO ₃ , K ₂ CO ₃ , and Cs ₂ CO _3. Process for the preparation of -4-biphenylcarboxylic acid.
4. 4. The preparation of 4'-hydroxy-4-biphenylcarboxylic acid according to claim 2 or 3, wherein the alkali used for the hydrolysis is used in 2 to 5 equivalents relative to the compound of formula (2). Way.
5. The method for producing 4'-hydroxy-4-biphenylcarboxylic acid according to claim 1, wherein the hydrolysis reaction is performed at 60 to 100 ° C.
6. The method of claim 1, wherein the compound of Formula 2 is prepared by the reaction of a compound of Formula 3 with a tertiary amine:

   [Formula 3]

   

   In Chemical Formula 3,

   R ¹ is an alkyl, cycloalkyl or aryl group having 1 to 6 carbon atoms,

   R is hydrogen or an alkyl group,

   X is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, benzenesulfonate, toluenesulfonate.
7. The method of claim 6

   The tertiary amine reacted with the compound of Formula 3 may include tertiary amines consisting of three identical or different alkyl groups or aromatic hydrocarbons; Or a cyclized aromatic amine. A process for producing 4'-hydroxy-4-biphenylcarboxylic acid.
8. The method of claim 6, wherein the reaction of the compound of Formula 3 with the tertiary amine is carried out at 80 ° C. to 120 ° C. 8.
9. The 4'-hydroxy-4 according to any one of claims 6 to 8, wherein the compound of Formula 3 is prepared by a catalytic condensation reaction of a compound of Formula 4 with a compound of Formula 5 Process for the preparation of biphenylcarboxylic acid:

   [Formula 4]

   

   [Formula 5]

   

   In the above formula,

   R ¹ is an alkyl, cycloalkyl or aryl group having 1 to 6 carbon atoms,

   R is hydrogen or an alkyl group,

   X is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, benzenesulfonate, toluenesulfonate.
10. The method for producing 4'-hydroxy-4-biphenylcarboxylic acid according to claim 9, wherein the catalyst used in the catalyst condensation reaction is a Lewis acid catalyst.