JP2007129952A - Method for producing biphenol derivative and diphenoquinone derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for simply producing a biphenol derivative precursor and a biphenol derivative by polymerizing a phenol derivative in the presence of an enzyme in high yield without using a radical transfer agent or an oxidizing agent. <P>SOLUTION: A reaction for carrying out oxidative polymerization of phenols using an oxidase is provided. The biphenol derivative is produced in good yield by mixing an organic solvent with an aqueous solvent at a ratio within a specific range such as 1-25 (vol.)% for use. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing a biphenol derivative and a diphenoquinone derivative.

  Biphenol derivatives are widely used as resin materials such as epoxy resins, engineering plastics, photoresists, and antioxidants. Among these, various methods have been proposed for biphenol derivatives using an enzyme because they do not generate harmful formalin.

  For example, a method for producing a biphenol derivative is proposed in which a substituted aromatic compound having a substituent such as a hydroxyl group is reacted in an aqueous medium in the presence of a peroxidase enzyme peroxide and a radical transfer agent (see Patent Document 1). ).

  In addition, a production method for synthesizing a low molecular weight polymer of phenol by using a two-phase mixed solvent composed of a water-insoluble or water-insoluble organic solvent and water has been proposed (see Patent Document 2).

Further, a dialkoxyquinone dimer comprising a dialkoxyquinone dimer by reacting a dialkoxyphenol having an alkoxy group having 1 to 4 carbon atoms, manganese peroxidase, an oxidizing agent, and a divalent manganese ion in an aqueous medium. A process for producing a dialkoxyphenol dimer characterized by comprising a first step of obtaining a product and a second step of adding a reducing agent to the first product subsequent to the first step is proposed. (See Patent Document 3).
Japanese National Patent Publication No. 11-503021 JP 2000-41691 A JP 2005-229944 A

  However, the method described in Patent Document 1 requires the use of phenol, mono-alkylphenol, thiophenol, aniline, or the like as a radical transfer agent. For this reason, after the reaction, a part of these radical transfer agents is dimerized and produced as a by-product. As a result, a separate step of extracting only the target biphenol derivative from the product is necessary. Furthermore, since this method uses peroxidase as an enzyme, it was necessary to add an oxidizing agent to the reaction, and thus the production cost was high.

Further, in the method using the two-layer mixed solvent described in Patent Document 2, phenol as a monomer is dissolved in a slightly water-soluble or water-insoluble organic solvent phase. Therefore, the reactivity between the enzyme dissolved on the water side and the monomer dissolved on the organic solvent side was very low, and the dimer yield was very low. Furthermore, since this method also uses peroxidase as an enzyme, it is necessary to add a peroxide as an oxidizing agent in the reaction.
Furthermore, the method described in Patent Document 3 adds a phenol derivative, an enzyme, and an oxidant because the formation of polyphenylene alkoxide may proceed if the phenol derivative, the enzyme, and the oxidant are added and then left standing for a long time. Later, a process of adding a reducing agent was essential, and precise manufacturing control was required.

  Therefore, the problem to be solved by the present invention is to easily produce a biphenol derivative precursor and a biphenol derivative by polymerizing a phenol derivative in a high yield in the presence of an enzyme without using a radical transfer agent or an oxidizing agent. It is to provide a method.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have conducted a reaction in which an oxidase is used to oxidize phenols, and an organic solvent is mixed with an aqueous solvent at a specific ratio. Thus, the inventors have found that a biphenol derivative can be produced with high yield, and have completed the present invention.

  That is, the present invention relates to the following general formula (1) in a mixed solvent containing an aqueous solvent and an organic solvent.

(In the formula, R represents an alkyl group having 1 to 8 carbon atoms.) A phenol derivative represented by the following formula (2) is reacted with an oxidase.

(Wherein R represents an alkyl group having 1 to 8 carbon atoms), a step (1) for producing a diphenoquinone derivative represented by:
A reducing agent is added to the solution containing the diphenoquinone derivative obtained in the step (1), and the following general formula (3)

(Wherein R represents an alkyl group having 1 to 8 carbon atoms) and a step (2) for producing a biphenol derivative represented by the formula: Provided is a method for producing a biphenol derivative, wherein the solvent concentration is in the range of 1 to 25 (vol)%.

  In addition, the present invention provides the following general formula (1) in a mixed solvent containing an aqueous solvent and an organic solvent.

(In the formula, R represents an alkyl group having 1 to 8 carbon atoms.) A phenol derivative represented by the following formula (2) is reacted with an oxidase.

(Wherein R represents an alkyl group having 1 to 8 carbon atoms), and the organic solvent concentration in the mixed solvent is 1 to 25 (vol)%. The present invention provides a method for producing a biphenoquinone derivative characterized by being in a range.

According to the production method of the present invention, a phenol derivative can be polymerized in the presence of an enzyme to obtain a biphenol derivative precursor and a biphenol derivative in high yield. Moreover, since the production | generation of a by-product can be suppressed and the refinement | purification process of a by-product can be skipped, a biphenol derivative precursor and a biphenol derivative can be obtained simply and at low cost.
In addition, a biphenol derivative can be stably produced using a phenol derivative as a material, and can be produced under efficient conditions of low temperature throughout the production process.
Furthermore, in the production method of the present invention, even if a phenol derivative, an enzyme, and an oxidizing agent are added to produce a diphenoquinone derivative and then left for a long time, for example, about 1 to 3 hours, the production of polyphenylene alkoxide does not proceed. For this reason, after adding a phenol derivative, an enzyme, and an oxidizing agent to produce a diphenoquinone derivative, a process of adding a reducing agent is no longer essential, and precise manufacturing control is unnecessary.

1. Process (1)
The production method of the biphenol derivative and the diphenoquinone derivative of the present invention is carried out in a mixed solvent containing an aqueous solvent and an organic solvent (hereinafter simply referred to as “mixed solvent”), with the following general formula (1):

(Wherein R represents an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms) and a oxidase is reacted with a phenol derivative (hereinafter simply referred to as “phenol derivative”). Let the following general formula (2)

(Wherein, R represents an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms), a process for producing a diphenoquinone derivative (hereinafter simply referred to as “diphenoquinone derivative”) ( Perform 1). The present invention is characterized in that the organic solvent concentration in the mixed solvent in the step (1) is in the range of 1 to 25 (vol)%.

-Substrate As the substrate used in the present invention, the general formula (1)

In the phenol derivative represented by the above, R includes an alkyl group having 1 to 8 carbon atoms.
More specifically, examples of the alkyl group having 1 to 8 carbon atoms include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, and the like. May be linear or branched. Of these, the alkyl group having 1 to 8 carbon atoms is preferably a methyl group.

  Although the said phenol derivative may be used independently or may use 2 or more types together, it is used independently from a viewpoint of the convenience at the time of applying the diphenoquinone derivative thru | or biphenol derivative obtained to various uses. preferable.

  The concentration of the phenol derivative represented by the general formula (1) with respect to the mixed solvent (hereinafter sometimes referred to as “substrate concentration”) has a lower limit of 0.1 mM or more at the start of the reaction, and further yield aspects. To 1 mM or more, preferably 5 mM or more. On the other hand, the upper limit is more preferably 30 mM or less, and 20 mM or less in terms of yield.

Enzyme Examples of the oxidase used in the present invention include catechol oxidase, ascorbate oxidase, bilirubin oxidase, tyrosinase, laccase, polyphenol oxidase and the like. Among them, laccase is preferable in terms of the yield of phenol dimers. It is mentioned as a thing. In the present invention, the oxidase may be used alone or in combination of two or more.

  The laccase is known to exist widely in plants, animals, and microorganisms, and any of them can be used. Among them, laccases derived from plants and microorganisms are preferable.

  As plant-derived laccase, laccase derived from lacquer wood is preferred. Examples of the laccase derived from microorganisms include those derived from bacteria and fungi (including filamentous fungi and yeasts), and laccase derived from basidiomycetes such as white rot fungi and fungi. Are particularly preferred.

  Specific examples of such laccase include Aspergillus genus, Neurospora genus, P. oryzae genus Pyricularia genus, Trametes bilosa (T. villosa), T. versiccolor and other genus Trametes, R. solani and other Rhizotonia genus, C. cinereus and other Crinus genus Derived from the genus Coriolus, such as C. hirsutus) and C. versicolor Shall, and the like.

Examples of commercially available laccase include “Laccase Daiwa Y120” (trade name, manufactured by Daiwa Kasei Co., Ltd.).
These laccases may be used alone or in combination of two or more.

The concentration of oxidase with respect to the mixed solvent (hereinafter sometimes referred to as “enzyme concentration”) may be appropriately adjusted depending on the enzyme activity within a range not impairing the effects of the present invention, and is not particularly limited. For example, the lower limit of the mixed solvent is 1 × 10 ⁵ POU / L or more, preferably 6 × 10 ⁵ POU / L or more. On the other hand, the upper limit value may be an excessive amount and is not particularly limited, but is 4 × 10 ⁷ POU / L or less, more preferably 3 × 10 ⁷ POU / L or less from an economical viewpoint. It is.
However, when 1 oxidase is reacted with 4-aminoantipyrine and phenol at pH 4.5 and 30 ° C., 1 POU has an absorbance at 505 nm of a quinoneimine dye produced by an oxidative condensation reaction catalyzed by the oxidase at 0.1 min in the initial reaction. Let's say the amount of enzyme needed to increase.

-Solvent The mixed solvent used for this invention contains an aqueous solvent and an organic solvent. Representative examples of the organic solvent that can be used here include acetone, methanol, ethanol, and 2-propanol. As the aqueous solvent, water or a pH buffer solution is used. Examples of the pH buffer include malonate buffer, oxalate buffer, tartrate buffer, acetate buffer, succinate buffer, citrate buffer, phosphate buffer, and the like.

  The ratio of the organic solvent in the mixed solvent is 1 to 25 (vol)%, preferably 1 to 20 (vol)%, more preferably 7 to 13 (vol)%, particularly preferably 9 to 11 (vol)%. It is. If the ratio of the organic solvent is in the range of 1 to 25 (vol)%, the amount of the trimer or higher polymer produced as a by-product can be kept low. As a result, the diphenoquinone derivative in the product The production rate can be increased. Furthermore, in the range of 7 to 13 (vol)%, in addition to the above reason, the substrate conversion rate can be maintained higher, and the yield of the diphenoquinone derivative can be further improved. Furthermore, if it is the range of 9-11 (vol)%, in addition to said reason, only the diphenoquinone derivative can be produced | generated, without producing | generating the polymer more than a trimer.

1.4) Reaction conditions In the step (1) of the present invention, the preparation of a reaction solution containing a mixed solvent, a phenol derivative and an oxidase is not particularly limited unless the oxidase deactivates and impairs the effects of the present invention. For example, the following method can be mentioned.

I) Add an oxidase to an aqueous solvent to prepare a solution in which the oxidase is dissolved or dispersed. On the other hand, add a phenol derivative to an organic solvent to prepare a solution in which the phenol derivative is dissolved or dispersed. A reaction solution can be prepared.

II) A phenol derivative is added to an organic solvent to prepare a solution in which the phenol derivative is dissolved or dispersed. After the aqueous solvent is added to the resulting solution, an oxidase or a solution containing the oxidase dissolved or dispersed in the aqueous solvent is further added. The reaction solution can be prepared by adding.

III) Add a phenol derivative to an aqueous solvent to prepare a solution in which the phenol derivative is dissolved or dispersed, add an organic solvent to the resulting solution, and then add an oxidase or a solution containing the oxidase dissolved or dispersed in the aqueous solvent. The reaction solution can be prepared by adding.

The reaction solution prepared as described above is controlled to a desired reaction temperature, pH and the like, and an enzyme reaction of a phenol derivative is performed.
The reaction temperature can be appropriately adjusted according to the substrate concentration, the type of oxidase, and the enzyme concentration, but can be set to a relatively low temperature, preferably 5 to 70 ° C, and preferably 20 to 60 ° C. Particularly preferred.
Although pH can be suitably prepared according to the kind of oxidase, pH 3.0-8.0 is preferable and pH 3.5-7.0 is especially preferable.
The reaction time is preferably 30 minutes to 24 hours, particularly preferably 1 hour to 20 hours.
In this step, it may be in a water bath or in an air stream as long as the above conditions are satisfied and stirring is performed.

2. Process (2)
The manufacturing method of the biphenol derivative of this invention adds a reducing agent to the solution containing the diphenoquinone derivative obtained at the said process (1), and is represented by following General formula (3)

（式中、Ｒは炭素原子数１〜８のアルキル基を示す。）で表されるビフェノール誘導体を製造する工程（２）を行う。
・還元剤
本発明で用いる還元剤は、本発明の効果を損なわない範囲であれば従来公知のものを使用することができ、特に限定されるものではないが、例えば、水素化ホウ素ナトリウム、亜ジチオン酸ナトリウムなどが挙げられる。
還元剤の添加量は、前記工程（１）で得られたジフェノキノン誘導体を含む溶液において、該ジフェノキノン誘導体の濃度の当量以上とすることが好ましい。

(Wherein, R represents an alkyl group having 1 to 8 carbon atoms) (2) for producing a biphenol derivative represented by
-Reducing agent The reducing agent used in the present invention may be a conventionally known reducing agent as long as it does not impair the effects of the present invention, and is not particularly limited. For example, sodium borohydride, And sodium dithionate.
The amount of the reducing agent added is preferably equal to or higher than the equivalent concentration of the diphenoquinone derivative in the solution containing the diphenoquinone derivative obtained in the step (1).

-Reaction conditions In the process (2) of this invention, the solution containing the diphenoquinone derivative obtained at the said process (1) may use the reaction solution after completion | finish of the reaction obtained at the said process (1) as it is. The reaction solution after completion of the reaction obtained in the step (1) is once purified, and then the diphenoquinone derivative obtained in the step (1) is added to a solvent in which the diphenoquinone derivative can be dissolved to newly add a diphenoquinone derivative. A solution containing may be prepared.
In the former case, during the step (1), the absorbance of the diphenoquinone derivative in the vicinity of a wavelength of 470 nm is measured over time, and the above reaction rate is calculated. For example, when the reaction rate reaches the maximum, etc. Depending on the situation, a reducing agent may be added to complete the step (1) and start the step (2). In this way, the biphenol derivative can be obtained with higher reliability and higher yield. However, since the reaction rate is obtained from the formula (3) described later, the time when the reaction rate reaches the maximum can be confirmed as the maximum absorption point in the time-lapse measurement of the diphenoquinone derivative near the wavelength of 470 nm.

  The solution containing the diphenoquinone derivative prepared as described above is controlled to a desired reaction temperature, and the diphenoquinone derivative is reduced to a biphenol derivative.

At this time, the reaction temperature is preferably 0 ° C. or higher in order to obtain a biphenol derivative stably. In terms of production efficiency and suppression of by-product formation, the reaction temperature is preferably low, and is preferably 25 ° C. or less. In the step (2), since a sufficient yield can be obtained, the reaction temperature is preferably around 23 ° C. (room temperature) in terms of the balance between the yield and the production efficiency.
The reaction time is preferably 30 seconds or less, more preferably 5 to 10 seconds, starting from the time when the reducing agent is added. In the method for producing a biphenol derivative of the present invention, a sufficient yield of the biphenol derivative can be obtained even if the reaction time in step (2) is very short as described above.

  In the method for producing a biphenol derivative of the present invention, the pH can be appropriately adjusted according to the type of oxidase, etc., but it is preferably pH 2.5 to 6.5, particularly preferably pH 4.0 to 5.0. .

-Purification When the by-product is contained in the biphenol derivative obtained in said process (2), you may isolate | separate and refine | purify a biphenol derivative by a well-known and usual method. As the separation / purification method, for example, since the biphenol derivative is insoluble in water, it can be recovered and purified by filtration or centrifugation. In addition, a biphenol derivative with a higher degree of purification can be obtained by adding a reducing agent and then extracting with an organic solvent.
Further, as described in JP-A No. 2003-327554, a biphenol derivative and a trimer or higher polymer are added with alcohol under acidic conditions of pH 2.5 to 5, mixed and stirred, and filtered or centrifuged. Thus, the biphenol derivative can be separated and purified from a trimer or higher polymer.

Examples of the organic solvent used for extraction include ethyl acetate, acetone, acetonitrile and the like, and ethyl acetate is preferable because it can be separated from the aqueous phase. The amount of ethyl acetate used is preferably 0.5 to 10 times, particularly preferably equivalent to 5 times the amount of the reaction solution used in step (2). The temperature at that time is most preferably room temperature. Furthermore, the stirring method at that time may be any of shaking, stirring using a rotor or a stirring blade.
A biphenol derivative is obtained by removing ethyl acetate from the ethyl acetate extract thus obtained by concentration under reduced pressure.

3. Applications Biphenol derivatives obtained by the production method of the present invention can be used in various fields, for example, as raw materials for thermoplastic resins such as polycarbonate, or as raw materials for thermosetting resins such as polyester, epoxy resin, and phenol resin. These resins can be used as flame retardants, antioxidants, etc., and also widely used in other applications where aromatic diols are used. Can do.

  Hereinafter, the present invention will be described in more detail based on examples. However, the present invention is not limited to the following examples.

(Preparation of laccase-containing solution)
Laccase powder (trade name “Lacase Daiwa Y120” manufactured by Daiwa Kasei Co., Ltd.) in a buffer solution (pH 4.5) of 50 mM citric acid (special grade reagent manufactured by Wako Pure Chemical Industries, Ltd.) is 1.2 × 10 ⁷ POU / L. The supernatant obtained by suspending the solution and removing the precipitate by centrifugation was prepared as a solution containing laccase (hereinafter referred to as “laccase-containing solution”).

(Preparation of phenol-containing solution)
2,6-dimethylphenol was added to acetone so that the concentration was 1 mM to prepare a solution containing 2,6-dimethylphenol (hereinafter referred to as “phenol-containing solution”).

(Preparation of reaction solution and synthesis of diphenoquinone derivative)
A mixed solvent (80 ml) containing a phenol-containing solution (10 ml), a laccase-containing solution (10 ml), a 50 mM citrate buffer solution (pH 4.5) and acetone adjusted so that the aqueous solvent and the organic solvent have the ratio shown in Table 1. A reaction solution was prepared by mixing, and immediately the reaction solution was controlled at 50 ° C. to start the reaction.

(Synthesis of biphenol derivatives)
One hour after the start of the reaction, an excessive amount of hydrosulfite sodium (manufactured by Wako Pure Chemicals Co., Ltd., a special grade reagent) is added as a reducing agent, and the reaction product containing a biphenol derivative is extracted by extraction with 5 times the amount of acetonitrile Obtained.

(Measurement of production amount)
The extract was subjected to high performance liquid chromatography (HPLC) analysis under the following conditions.

Pump: Shimadzu Corporation LC-10ADvp
Column: Inertsil ODS-3 manufactured by GL Sciences Inc.
Detector: Shimadzu Corporation SPD-M10Avp
Developing solvent: water: acetonitrile = 80: 20 → 0: 100 (linear gradient)
Temperature: 40 ° C
Liquid feeding speed: 1.0 mL / min
Detection wavelength: 267 nm, 271 nm

(Yield of 3,3 ′, 5,5′-tetramethylbiphenol)
Depending on the intensity of the absorption peak detected in the HPLC measurement under the above conditions, the molar concentration α of the substrate 2,6-dimethylphenol contained in the product and 3,3 ′, 5,5′-tetramethylbiphenol of the reaction product The molar concentration β was determined, and the substrate conversion rate, dimer yield, and polymer yield of trimer or higher (hereinafter simply referred to as “polymer yield”) were determined by the following formulas (Table 1 and FIG. 1). ). In addition, it confirmed using H-NMR that the absorption peak which calculated | required molar concentration (beta) was a reaction product 3,3 ', 5,5'-tetramethylbiphenol (FIG. 2).

(Dimer yield) [%] = β / [(1/2) × (2,6-dimethylphenol molar concentration supplied as a substrate)] × 100

  The value represented by the ratio between the molar concentration α and the concentration of 2,6-dimethylphenol supplied as a substrate is defined as 2,6-dimethylphenol residual ratio (hereinafter referred to as “residual ratio”). Calculated by the formula.

(Substrate conversion ratio) [%] = [1-α / (2,6-dimethylphenol molar concentration supplied as a substrate)] × 100

  Furthermore, it is a value represented by the ratio between the amount of 2,6-dimethylphenol supplied as a substrate used for the production of a trimer or higher polymer and the concentration of 2,6-dimethylphenol supplied as a substrate. The polymer yield of a certain 2,6-dimethylphenol was calculated by the following formula using the dimer yield and the residual rate.

(Polymer yield) [%] = (Substrate conversion)-(Dimer yield)

  From the results shown in Table 1, it was found that the yield of the dimer with respect to the substrate conversion rate was specifically and significantly higher when the acetone-water mixed solvent system reaction was used as compared with Comparative Example 1. . Therefore, it was shown that the dimer yield is much improved by using the mixed solvent system reaction according to the present invention.

It is a graph showing the relationship of the substrate conversion rate in the manufacturing method of this invention, a dimer yield, and the polymer yield of a trimer or more. It is the H-NMR chart which confirmed existence of a reaction product (3,3 ', 5,5'-tetramethylbiphenol).

Claims (6)

In a mixed solvent containing an aqueous solvent and an organic solvent, the following general formula (1)

(In the formula, R represents an alkyl group having 1 to 8 carbon atoms.) A phenol derivative represented by the following formula (2) is reacted with an oxidase.

(Wherein R represents an alkyl group having 1 to 8 carbon atoms), a step (1) for producing a diphenoquinone derivative represented by:
A reducing agent is added to the solution containing the diphenoquinone derivative obtained in the step (1), and the following general formula (3)

(Wherein R represents an alkyl group having 1 to 8 carbon atoms) and a step (2) for producing a biphenol derivative represented by the formula: A method for producing a biphenol derivative, wherein the solvent concentration is in the range of 1 to 25 (vol)%. The method for producing a biphenol derivative according to claim 1, wherein the concentration of the phenol derivative in the mixed solvent at the start of the reaction is in the range of 0.1 to 30 mM. The method for producing a biphenol derivative according to claim 1 or 2, wherein the organic solvent is one or more organic solvents selected from the group consisting of acetone, 2-propanol, methanol, and ethanol. The method for producing a biphenol derivative according to any one of claims 1 to 3, wherein the oxidase is laccase. The method for producing a biphenol derivative according to any one of claims 1 to 4, wherein the phenol derivative is 2,6-dimethylphenol. In a mixed solvent containing an aqueous solvent and an organic solvent, the following general formula (1)

(In the formula, R represents an alkyl group having 1 to 8 carbon atoms.) A phenol derivative represented by the following formula (2) is reacted with an oxidase.

(Wherein R represents an alkyl group having 1 to 8 carbon atoms), and the organic solvent concentration in the mixed solvent is 1 to 25 (vol)%. The manufacturing method of the biphenoquinone derivative characterized by being in the range.

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