JP4908070B2 - Method for producing di-substituted bisphenol - Google Patents

Description

  The present invention relates to a method for producing a di-substituted bisphenol in a good yield, high purity and simply.

  Di-substituted bisphenols are useful as antibacterial and antioxidant compounds. For example, 2,2'-dihydroxy-5,5'-dipropylbiphenyl reduces magnolol isolated from Kokaku. (See 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 in which alkylphenol is reacted in a chloroform solvent in the presence of aluminum chloride and ferric chloride (see Non-Patent Document 2) 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 an oxidative coupling reaction in the presence of a copper salt-amine compound complex (see Non-Patent Document 3) has been proposed. The only substrate present is 2-naphthol, and no p-substituted phenol is described.

  Furthermore, the present inventors have proposed a method for producing a di-substituted bisphenol by oxidative coupling reaction of p-substituted phenol in an organic solvent in the presence of a copper salt-amine compound complex (see Patent Document 1). ).

Herbal medicine magazine, 39 (1), 76-79, 1985 Tetrahedron, 48 (43), 9483-9 494, 1992 Tetrahedron, 41, 3313, 1985 JP 2004-292392 A

  An object of the present invention is to provide a method for producing a di-substituted bisphenol in a good yield, high purity and simply using an inexpensive raw material.

As a result of a detailed study on a method for producing the di-substituted bisphenol of the above formula (1) on an industrial scale using the method described in the above-mentioned Patent Document 1, surprisingly, as a result, By adopting a charging order not specifically shown in Document 1, it was found that the yield and purity were remarkably excellent, and the present invention was completed.
Accordingly, the present invention provides the following formula (2):

(In the formula, R represents a C1 to C8 linear or branched alkyl or alkenyl group.)
P-substituted phenol represented by the following formula (1)

(In the formula, R is as defined above.)
In the method for producing a di-substituted bisphenol represented by formula (2), after dissolving the p-substituted phenol of the above formula (2) in an organic solvent in advance, an amine compound is added, and then a copper salt is added to react. The present invention provides a method for producing a di-substituted bisphenol of the above formula (1).

  According to the present invention, a di-substituted bisphenol can be produced in a good yield, high purity and simply using an inexpensive raw material.

  The di-substituted bisphenol of the above formula (1) according to the present invention can be obtained easily and profitably by dissolving the p-substituted phenol of the formula (2) in an organic solvent and then adding and reacting with an amine compound and a copper salt. Can be manufactured with high purity.

  The p-substituted phenol represented by the above formula (2) used in the reaction can be easily obtained on the market. For example, it can be easily obtained by reacting the corresponding acylphenol with hydrogen in the presence of a palladium catalyst. They can also be synthesized (J. Am. Chem. Soc., 56 (1), 158-159, 1934). This reaction is represented by the following reaction formula.

  Specific examples of p-substituted phenol include, for example, p-methylphenol, p-ethylphenol, p-propylphenol, p-isopropylphenol, p-butylphenol, p-isobutylphenol, p-pentylphenol, p-isopentyl. Phenol, p-hexylphenol, p-allylphenol, p-isopropenylphenol, p-2-ethylhexylphenol and the like can be mentioned.

  Moreover, the copper salt and amine compound used by this invention are also easily 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. 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. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and isobutanol can be preferably exemplified. .

  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 the 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, 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.

  In the reaction, after dissolving the p-substituted phenol of formula (2) in an organic solvent in advance, an amine compound is added thereto, and then a copper salt is added, followed by stirring at a temperature of 10 ° C. to 80 ° C. for 3 hours to 24 hours. Can be done. In addition, since reaction is accelerated | stimulated by presence of oxygen, it is preferable to react, introducing air in a reaction liquid mixture. By adopting this reaction method, the method specifically described in Patent Document 1 (a method in which a copper salt and an amine compound are added to an organic solvent and dissolved, and then reacted by adding a p-substituted phenol). Compared with yield and purity, it is remarkably superior. The reason for this is not clear, but by adopting the method of the present invention, formation of a copper salt-amine compound complex is advantageous, and as a result, the yield and purity are considered to be improved.

  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, and the insoluble part is dissolved in an extraction solvent such as ethyl ether or ethyl acetate and then sufficiently washed with water. Di-substituted bisphenol can be obtained with good yield. If necessary, recrystallized in a hydrocarbon solvent such as hexane, cyclohexane or toluene can give a very high-purity target product.

Specific examples of the di-substituted bisphenol 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′-dibutyl Biphenyl, 2,2′-dihydroxy-5,5′-diisobutylbiphenyl, 2,2′-dihydroxy-5,5′-dipentylbiphenyl, 2,2′-dihydroxy-5,5′-diisopentylbiphenyl, 2, 2,2′-dihydroxy-5,5′-dihexylbiphenyl, 2,2′-dihydroxy-5,5′-diallylbiphenyl, 2,2′-dihydroxy-5,5′-diiso Examples thereof include propenyl biphenyl, 2,2′-dihydroxy-5, 5′-di- (2-ethylhexyl) biphenyl, and the like.
Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1
After dissolving 800 g of methanol and 82 g of p-propylphenol in a 2000 ml four-necked flask, add 142 g of cyclohexylamine, then add 102 g of cupric chloride dihydrate, and bubble air into the mixed solution of the flask. (500 mL / min) and vigorously stirred at 20 to 30 ° C. for 4 hours for reaction. 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 washed insoluble material was put into a 3 L flask, 625 g of 2M hydrochloric acid and 902 g of ethyl acetate were 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 625 g of 1M hydrochloric acid and then washed twice with 400 g of water. The organic layer was heated under normal pressure to recover ethyl acetate. To this was added 328 g of toluene and the mixture was heated and stirred to reflux 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 2,2′-dihydroxy-5,5′-dipropylbiphenyl having a purity of 99.5% by HPLC method. (Yield 92%)
Comparative Example 1 (Method described in Example of Patent Document 1)
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 prepared 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 same treatment as in Example 1 was performed to obtain 2,2′-dihydroxy-5,5′-dipropylbiphenyl having a purity of 98% by HPLC method (yield 80%).

Examples 2-5
In Example 1, 2,2′-hydroxy-5,5′-dipropylbiphenyl was synthesized by reacting in the same manner using other amines and copper salts in place of cyclohexylamine and cupric chloride. The results are shown in Table 1.

Examples 6-12
In Example 1, the reaction and post-treatment were performed in the same manner using other p-substituted phenol instead of p-propylphenol to synthesize 2,2′-dihydroxy-5,5′-di-substituted biphenyls. . The results are shown in Table 2.

Claims (1)

Following formula (2)

(In the formula, R represents a C1 to C8 linear or branched alkyl or alkenyl group.)
P-substituted phenol represented by the following formula (1)

(In the formula, R is as defined above.)
In represented by di - a process for preparing substituted bisphenols were dissolved beforehand the formula p- substituted phenol (2) in an organic solvent, adding an amine compound, followed by the addition of copper salt, oxidative method for producing a substituted bisphenol - divinyl of formula characterized Rukoto by coupling reaction (1).