JP2007230975A - Method for purifying di-substituted bisphenol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a di-substituted bisphenol, which is a high yield simple method using a low cost material. <P>SOLUTION: The high yield high purity method for purifying di-substituted bisphenol comprises reacting a crude di-substituted bisphenol, obtained by oxidative coupling reaction of a p-substituted phenol, with a lower carboxylic acid to provide an ester derivative which can be distilled, separating esters of byproduct percoupling products by distillation, and hydrolyzing the obtained di-substituted ester derivative. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for purifying di-substituted bisphenols with high yield and purity.

  Di-substituted bisphenols are useful as compounds having melanin production-inhibiting effects, antibacterial properties and antioxidant effects. For example, 2,2′-dihydroxy-5,5′-dipropylbiphenyl was isolated from Kokaku It is synthesized by reducing magnolol (Non-patent Document 1). Several production methods by oxidative coupling have been reported, but reactions with substrates having no substituent at the ortho-position generally have low coupling yield and regioselectivity. As one of highly selective production methods, for example, a method (Non-patent Document 2) in which alkylphenol is reacted in a chloroform solvent in the presence of aluminum chloride and ferric chloride has been proposed.

  However, the method for producing di-substituted bisphenols shown in the above prior art uses a highly corrosive reagent that uses expensive raw materials extracted and isolated from crude drugs by a complicated method as raw materials, and requires careful handling. In addition, there are disadvantages such as the use of a toxic solvent in which environmental pollution is a concern and a low yield.

  As a production method capable of solving these problems, a method of producing by oxidative coupling reaction in the presence of a copper salt-amine compound complex (Non-patent Document 3) has been proposed, but this method is used. The only substrate present is 2-naphthol and no p-alkylphenol is described.

  Also, as a new proposal, a method in which p-alkylphenol forms a complex with a copper salt-amine compound in an organic solvent and selectively undergoes an oxidative coupling reaction to obtain dialkylbisphenols in a high yield (Patent Literature) Although 1) has been proposed, although the operation and the economy are relatively improved compared to the above method, the crude product obtained by the oxidative coupling reaction is extracted with an organic solvent such as ethyl acetate. The yield of di-substituted bisphenols obtained by washing with water and recrystallizing in a hydrocarbon-based organic solvent after washing with water is about 60 to 89%, and the maximum purity is not as high as about 98%. This is because purification by recrystallization in an organic solvent causes di-substituted bisphenol, which is the target substance, to dissolve in the recrystallization mother liquor, and about 10% in terms of yield is lost. This is because impurities such as tri-substituted trisphenol and tetra-substituted tetrakisphenol, which are by-products at the time of ringing, cannot be completely removed, and there is room for further improvement.

  Furthermore, a method (Patent Document 2) has been proposed in which p-propylphenol is subjected to oxidative coupling reaction in the presence of laccase to obtain 2,2′-dihydroxy-5,5′-dipropylbiphenyl. The purpose was to reduce the amount of reagents and solvents used, and the yield was about 20% and the purity was not as high as 95%, and there was still room for improvement.

Herbal medicine magazine, 39 (1), 76-79, 1985 Tetrahedron, 48 (43), 9483-9494, 1992 Tetrahedron, 41, 3313, 1985 JP 2004-292392 A Japanese Patent Application No. 2005-150899

  An object of the present invention is to provide a method for purifying di-substituted bisphenols with high yield and high purity using inexpensive raw materials.

  In order to solve the above problems, the present inventors have conducted extensive studies on the purification method. As a result, the present inventors have obtained a crude product obtained by oxidative coupling reaction of the p-substituted phenol represented by the above formula (2). A di-substituted bisphenol represented by the formula (1) is reacted with a lower carboxylic acid to obtain a distillable ester derivative of the formula (3), and then by-products such as tri-substituted trisphenol and tetra-substituted tetrakisphenol. It is found that the di-substituted bisphenols can be obtained in high yield and high purity by separating the ester form of the overcoupling product such as by distillation and hydrolyzing the di-substituted ester derivative. The present invention has been completed.

  Thus, the present invention provides the following formula (2)

(In the formula, R1 represents a C1-C5 linear or branched alkyl or alkenyl group.)
A crude formula (1) obtained by oxidative coupling reaction of a p-substituted phenol represented by formula (1)

(Wherein R1 has the same meaning as above).
A di-substituted bisphenol represented by formula (3) is reacted with a lower carboxylic acid.

(Wherein R1 has the same meaning as above, and R2 represents a hydrogen atom, a methyl group or an ethyl group.)
Purification of the di-substituted bisphenol represented by the above formula (1), wherein the ester derivative is represented by the following formula: A method can be provided.

  According to the present invention, it is possible to provide an industrial-scale purification method for di-substituted bisphenols having high yield and high purity.

Hereinafter, the present invention will be described in more detail.
The present invention can be represented by the following reaction formula A.

  The p-alkylphenols represented by the above formula (2) used in the present invention can be easily obtained on the market. For example, the corresponding acylphenol can be easily reacted with hydrogen in the presence of a palladium catalyst. They can also be synthesized (J. Am. Chem. Soc., 56 (1), 158-159, 1934).

  Specific examples of p-alkylphenols include, for example, p-methylphenol, p-ethylphenol, p-propylphenol, p-isopropylphenol, p-butylphenol, p-isobutylphenol, p-pentylphenol, p-isopentyl. Phenol and the like can be mentioned.

  Moreover, as a specific example of the manufacturing method of the di-substituted bisphenol represented by the crude formula (1) obtained by oxidative coupling of the p-substituted phenol represented by the formula (2) of the present invention, for example, Oxidative coupling reaction of p-propylphenol in the presence of laccase to obtain 2,2′-dihydroxy-5,5′-dipropylbiphenyl, or oxidation in the presence of a copper salt-amine compound complex And a method of producing by a chemical coupling reaction.

  Copper salts and amine compounds used in the latter method are also readily available on the market. Specific examples of the copper salt include cuprous chloride, cupric chloride, cupric sulfate, and cupric nitrate. These copper salts can be used in the form of anhydrides or hydrates, but hydrates are preferred because they are easier to handle. Although it does not specifically limit as an amine compound, For example, a C2-C7 linear or branched alkylamine, cyclic alkylamines, and aromatic amines are preferable, As an example, ethylamine, propylamine, Examples include isopropylamine, butylamine, isobutylamine, t-butylamine, isoamylamine, hexylamine, cyclohexylamine, aniline, benzylamine, and pyridine. In the present invention, an organic solvent is used for the reaction, and the type of the organic solvent is not particularly limited, but it is preferable that the formed copper salt-amine compound complex is easily dissolved or dispersed. Examples of the organic solvent in which the formed copper salt-amine compound complex is easily dissolved or dispersed include alcohols, and preferred examples include lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and isobutanol. .

  The amount of these raw materials used can be appropriately selected, and the copper salt is about 0.8 to 2.0 moles, more preferably 0.9 to 1.5 moles relative to the raw material compound of formula (2) About twice the amount, the amine compound is about 1.6 to 3.0 mole times, more preferably about 1.8 to 2.5 mole times, and the organic solvent is, for example, about 3 to 20 times by weight, more preferably Can be exemplified by about 4 to 10 times by weight.

  As a more specific embodiment of the oxidative coupling reaction performed using the above raw materials, for example, a copper salt and an amine compound are added to an organic solvent and stirred at a temperature of 10 ° C. to 50 ° C. for 10 to 60 minutes. Examples of the method include forming a salt-amine compound complex, adding p-alkylphenol at a temperature of 10 ° C. to 80 ° C., and stirring for 3 to 24 hours. In addition, since reaction is accelerated | stimulated by presence of oxygen, it is preferable to react, introducing air in a reaction liquid mixture.

  After completion of the reaction, the desired product can be obtained by a conventional method. For example, after cooling the reaction mixture to room temperature or lower, the insoluble part is collected by filtration, this insoluble part is rinsed 1 to 3 times with an extraction solvent such as ethyl ether or ethyl acetate, and then the insoluble part is transferred to another flask. 2M-hydrochloric acid is added to make it acidic, and crude di-substituted bisphenols can be obtained as oils. In addition to the target di-substituted bisphenol, this oil contains about 10 to 12% of overcoupling products such as tri-substituted trisphenol and tetra-substituted tetrakisphenol which are reaction byproducts. These impurities can be removed by esterification of the oil and distillation purification.

  Next, it is a method for producing a crude ester derivative represented by the formula (3) obtained by reacting the obtained crude di-substituted bisphenol represented by the formula (1) with a lower carboxylic acid. For example, a method of adding a mixed solution of acetic anhydride and phosphoric acid to a crude di-substituted bisphenol and reacting at 70 to 100 ° C, or a crude di-substituted bisphenol in a mixed solution of acetic anhydride and pyridine. And can be carried out by a method of reacting at 5 to 30 ° C.

  Next, the crude ester derivative represented by the formula (3) is separated from the by-product by purification by distillation to obtain a purified ester derivative. However, this is not a special method, but a normal vacuum distillation apparatus or thin film. This can be carried out using a vacuum distillation apparatus (molecular distillation apparatus). For example, the distillation is performed at a reduced pressure of 0.001 kPa to 0.5 kPa. By distilling and purifying ester derivatives such as tri-substituted trisphenol and tetra-substituted tetrakisphenol, which are by-products in the production of the compound of formula (1), present in the crude ester derivative, the difference in boiling point is reduced. Easy to use and can be completely removed.

  Next, the ester derivative hydrolysis method is not a special method, and can be carried out, for example, by adding caustic soda and stirring at 30 to 80 ° C. for 1 to 3 hours. It is also possible to use a solvent such as methanol that dissolves the ester body and caustic soda water during the reaction. After the reaction, an acid is added to adjust the pH to 4 to 5, and di-substituted bisphenol crystals can be easily precipitated and separated.

  A di-substituted bisphenol represented by the above formula (1) having a yield of 88 to 95% and a purity of 99.9% or more is obtained.

  Specific examples of the di-substituted bisphenols of the above formula (1) obtained by the production method of the present invention include, for example, 2,2′-dihydroxy-5,5′-dimethylbiphenyl, 2,2′-dihydroxy-5. , 5'-diethylbiphenyl, 2,2'-dihydroxy-5,5'-dipropylbiphenyl, 2,2'-dihydroxy-5,5'-diisopropylbiphenyl, 2,2'-dihydroxy-5,5'- Dibutylbiphenyl, 2,2′-dihydroxy-5,5′-diisobutylbiphenyl, 2,2′-dihydroxy-5,5′-dipentylbiphenyl, 2,2′-dihydroxy-5,5′-diisopentylbiphenyl, etc. Can be illustrated.

The above-mentioned di-substituted bisphenols can be used for pharmaceuticals, cosmetics, other chemicals and the like by utilizing their melanin production inhibitory effect, antibacterial property, and antioxidant effect.
Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples.

Example 1
Oxidative coupling reaction
In a 2000 ml four-necked flask, 102 g of cupric chloride dihydrate and 600 g of methanol were added, 142 g of cyclohexylamine was added, and the mixture was stirred at 20-30 ° C. for 40 minutes. A solution obtained by dissolving 82 g of p-propylphenol in 200 g of methanol was added to this mixed solution, air was bubbled into the mixed solution of the flask (500 ml / min), and the mixture was vigorously stirred at 20 to 30 ° C. for 4 hours to be reacted. . After completion of the reaction, the reaction solution was filtered to remove insoluble matters, which were rinsed three times with 360 g of ethyl acetate. The insoluble matter after rinsing was put in a 3000 ml flask, acidified by adding 625 g of 2M hydrochloric acid, and the aqueous layer was separated to obtain 81 g of an oily substance (crude 2,2′-dihydroxy-5,5′-dipropylbiphenyl). Got.
The obtained oil was directly used for the next esterification reaction.

Esterification reaction (acetate derivative)
41 g of the oily substance was placed in a 250 ml four-necked flask, a mixed solution of 32 g of acetic anhydride and 1 g of 85% phosphoric acid was added, and the reaction was stirred at 70 to 100 ° C. for 1 hour.
After cooling the reaction solution, water was added and stirred, and then the aqueous layer was separated, the oil layer was washed with water, neutralized with 10% soda ash and washed with water to obtain 52.5 g of a crude oily acetate derivative. A pure acetate derivative was obtained by distillation purification of 52.5 g of a crude product of the acetate derivative. Boiling point: 165 to 170 ° C./0.13 kPa, 47 g of acetate derivative (yield 88%, GLC purity 99.9%).

Hydrolysis reaction Acetate derivative 47 g was placed in a 250 ml four-necked flask, 125 g of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 to 70 ° C. for 1 hour. The reaction solution became a homogeneous phase and hydrolysis was completed. After cooling the reaction solution to room temperature, 50% aqueous sulfuric acid was added to make it acidic (pH = 4 to 5), and crystals of the desired dipropylbisphenol were precipitated. The crystals were filtered, and the crystals were further washed with pure water. The obtained crystals were dried to remove moisture under reduced pressure, and 35.8 g of pure 2,2′-dihydroxy-5,5′-dipropylbiphenyl crystals (Example 1: 99.9% yield, GLC purity) 99.9% or more) was obtained.

Comparative Example 1
40 g of 81 g of the oily substance obtained by the oxidative coupling reaction of Example 1 was taken, 450 g of ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes, and then the organic layer was separated. The organic layer was washed with 310 g of 1M hydrochloric acid and then washed twice with 200 g of water. The organic layer was heated under normal pressure to recover ethyl acetate. 160 g of toluene was added thereto, and the mixture was heated to reflux with stirring to completely dissolve the solid matter, and then cooled to 0 ° C. to precipitate crystals. The precipitated crystals were filtered and dried under reduced pressure to obtain 32.4 g of 2,2′-dihydroxy-5,5′-dipropylbiphenyl having a purity of 98% by HPLC method (Comparative Example 1: 80% yield, GLC purity 98.0%).

Examples 2-6 and Comparative Examples 2-6
In Example 1, instead of p-propylphenol, other p-alkylphenols shown in Table 1 were similarly used for the reaction and post-treatment, and 2,2′-dihydroxy-5,5′-dialkylbiphenyls (implementation) Examples 2 to 6) were synthesized. In addition, about half of the oily substance (crude 2,2′-dihydroxy-5,5′-dialkylbiphenyl) obtained by oxidative coupling in Examples 2 to 6 was treated in the same manner as in Comparative Example 1, and purified product was obtained. (Comparative Examples 2 to 6). The above results are shown in Table 1.

(Note 1) Alkyl group of p-alkylphenol As shown in Table 1, in all cases of Examples 1 to 6, the yield was improved by about 10% as compared with the methods of Comparative Examples 1 to 6. Moreover, in Examples 1-6, the purity which was 95.5-98.0% in the comparative example was 99.9% or more of high purity products.

Claims (1)

Following formula (2)

(In the formula, R1 represents a C1-C5 linear or branched alkyl or alkenyl group.)
A crude formula (1) obtained by oxidative coupling reaction of a p-substituted phenol represented by formula (1)

(Wherein R1 has the same meaning as above).
A di-substituted bisphenol represented by formula (3) is reacted with a lower carboxylic acid.

(Wherein R1 has the same meaning as above, and R2 represents a hydrogen atom, a methyl group or an ethyl group.)
Purification of the di-substituted bisphenol represented by the above formula (1), wherein the ester derivative is represented by the following formula: Method.