WO2023195222A1 - Method for producing 3,5-di-tertiary-butylsalicylic acid - Google Patents

Method for producing 3,5-di-tertiary-butylsalicylic acid Download PDF

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WO2023195222A1
WO2023195222A1 PCT/JP2023/003512 JP2023003512W WO2023195222A1 WO 2023195222 A1 WO2023195222 A1 WO 2023195222A1 JP 2023003512 W JP2023003512 W JP 2023003512W WO 2023195222 A1 WO2023195222 A1 WO 2023195222A1
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tert
reaction
butylsalicylic acid
producing
butylphenol
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PCT/JP2023/003512
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French (fr)
Japanese (ja)
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良一 川▲崎▼
崇光 戸川
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大阪新薬株式会社
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Priority to CN202380023324.4A priority Critical patent/CN118786111A/en
Publication of WO2023195222A1 publication Critical patent/WO2023195222A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids

Definitions

  • the present invention relates to a method for producing 3,5-di-tert-butylsalicylic acid.
  • 3,5-di-tert-butylsalicylic acid has been used as a useful chemical substance, for example, as an intermediate for pharmaceuticals.
  • complex materials derived from 3,5-di-tert-butylsalicylic acid compounds are employed as toner additives in copying machines.
  • a typical example of the method for producing 3,5-di-tert-butylsalicylic acid is the dibutylation reaction of salicylic acid, or the so-called Kolbe-Schmidt reaction, in which an alkali salt of 2,4-di-tert-butylphenol is reacted with carbon dioxide.
  • Patent Documents 1 to 5 Non-Patent Documents 1 to 3
  • Non-Patent Documents 2 and 3 require an additional step of alkylation reaction or protection/deprotection to impart regioselectivity, which is disadvantageous for industrialization. .
  • the reaction is performed under conditions of high temperature and high pressure (for example, 150° C. or higher, 5 MPa or higher), and when alkali phenoxylation is performed by Kolbe-Schmidt reaction, the alkali phenoxylated compound is Since it becomes insolubilized in commonly used aromatic solvents such as benzene, toluene, and xylene, the reaction becomes nonuniform, resulting in a problem that high yield and purity cannot be obtained.
  • high temperature and high pressure for example, 150° C. or higher, 5 MPa or higher
  • Patent Documents 3 and 4 also propose a method for reducing the heterogeneous reaction caused by insolubilization by the above-mentioned alkali phenoxidation.
  • NMP N-methylpyrrolidone
  • 3-methyl-2-oxazolidinone 1,3-
  • a method is disclosed in which dimethyl-2-imidazolidinone or the like is employed as an additive solvent.
  • a technique that employs N,N-methylacetamide as a solvent is also disclosed.
  • Patent Document 5 may contribute to reducing environmental loads to some extent.
  • the substrate phenol derivative including its role as a reaction solvent, is extremely sensitive to the alkali metal compound in order to uniformly stir the alkali phenoxy derivative produced during the reaction.
  • the reaction solvent is used in excess. Therefore, not only is an additional recovery process required, but the recovery rate is also not high.
  • the invention requires an extremely high reaction temperature of 160° C. or higher, and the product is not easy to purify, so the technical idea disclosed in the invention is also disadvantageous for industrialization.
  • the present invention provides a method for producing 3,5-di-tert-butylsalicylic acid that achieves extremely high purity and high yield, is suitable for industrialization, and is environmentally friendly, by solving the above-mentioned technical problems. can greatly contribute to the realization of
  • the present inventors conducted a follow-up test based on the disclosure of the invention disclosed in Patent Document 1. As a result, the present inventors found that the invention disclosed in Patent Document 1 is not suitable for industrialization because it solidifies when a dehydration step is performed after alkali phenoxylation, and it is necessary to take out the solid and perform a pulverization step. It was confirmed that this is disadvantageous.
  • the powder obtained by the pulverization process is charged into an autoclave, and the reaction conditions are severe, specifically, a high temperature of 140° C. to 160° C. and 13 Kgf/cm 2 (that is, 1.
  • the Kolbe-Schmidt reaction which absorbs carbon dioxide, will take place under high pressure conditions (3 MPa). Since the Kolbe-Schmidt reaction is a heterogeneous reaction, the problem of reaction inhibition due to precipitation of solids occurs, similar to or even more so than when using the above-mentioned aromatic organic solvent.
  • the present inventors faced each of the above-mentioned technical issues and conducted various studies and analyses. As a result, the present inventors focused on the importance of the solvent for producing 3,5-di-tert-butylsalicylic acid. Specifically, if it is possible to employ a solvent that can achieve a reaction in which solid matter does not precipitate during the reaction process, it is possible to achieve a substantially uniform reaction by, for example, proceeding with the reaction while continuously stirring the solution. It becomes possible.
  • the inventors of the present invention were able to realize a reaction in a substantially homogeneous solution with high accuracy by employing a specific solvent, and compared it with conventional technology. As a result, it was found that 3,5-di-tert-butylsalicylic acid can be produced even under conditions of lower pressure and lower temperature.
  • One method for producing 3,5-di-tert-butylsalicylic acid of the present invention is to use 4-methyltetrahydropyran as a reaction solvent, and alkali metal hydroxide and 2,4-di-tert-salicylic acid represented by the chemical formula (1).
  • the salt of 3,5-di-tert-butylsalicylic acid is produced by pressurizing carbon dioxide into a heated container containing the reaction solvent and the alkali salt of 2,4-di-tert-butylphenol.
  • 3,5-di-tert-butylsalicylic acid of the present invention it is possible to realize the reaction in a substantially homogeneous solution with high accuracy, and at the same time, it is possible to realize the reaction in a substantially homogeneous solution under conditions of lower pressure and temperature than in the prior art. 3,5-di-tert-butylsalicylic acid can be produced. Moreover, according to this manufacturing method, not only can extremely high purity and yield be achieved, but also the environmental impact of the waste liquid caused by this manufacturing method can be extremely reduced.
  • FIG. 2 is an optical photograph of the reaction solution after the first step in Example 1.
  • FIG. 2 is a high performance liquid chromatograph (HPLC) diagram after the third step in Example 1.
  • 3 is an optical photograph of the reaction solution after the first step in Comparative Example 1.
  • 3 is an optical photograph of the reaction solution after the first step in Comparative Example 2.
  • the 3,5-di-tert-butylsalicylic acid of this embodiment can be produced by a production method including the following steps (a) to (c).
  • steps (a) to (c) By reacting an alkali metal hydroxide with 2,4-di-tert-butylphenol represented by the following chemical formula (1) using 4-methyltetrahydropyran as a reaction solvent, the following chemical formula (2 )
  • a first step of producing the 2,4-di-tert-butylphenol salt (where X is an alkali metal)
  • the reaction solvent and the 2,4-di-tert-butylphenol salt are -
  • a second step of producing a salt of 3,5-di-tert-butylsalicylic acid by pressurizing carbon dioxide into a heated container sealed with an alkali salt of tert-butylphenol.
  • the present inventors employed 2,4-di-tert-butylphenol represented by the above chemical formula (1) as a starting material.
  • the present inventors adopted 4-methyltetrahydropyran as a reaction solvent for use in all of the first, second, and third steps.
  • the present inventors decided to use one of the less toxic tetrahydropyran derivatives that are commercially available as the reaction solvent. did.
  • this embodiment by particularly employing 4-methyltetrahydropyran among tetrahydropyran derivatives, it contributes to the realization of a reaction in a substantially homogeneous solution and a reaction under conditions of lower pressure and lower temperature than known techniques. The present inventors have confirmed that this is possible.
  • 4-methyltetrahydropyran can be recovered by simple distillation, it is possible to reduce the manufacturing cost and to significantly reduce the environmental burden of the finally produced waste liquid.
  • an alkali metal hydroxide preferably sodium hydroxide (NaOH) or potassium hydroxide (KOH), more preferably sodium hydroxide (NaOH)
  • KOH potassium hydroxide
  • 2,4-di - React with tert-butylphenol preferably sodium hydroxide (NaOH) or potassium hydroxide (KOH), more preferably sodium hydroxide (NaOH)
  • 2,4-di-tert-butylphenol salt represented by the above chemical formula (2) (where X is an alkali metal) is produced by carrying out the reaction in a substantially homogeneous solution. Ru.
  • the mass ratio of the above-mentioned reaction solvent (4-methyltetrahydropyran) to the starting material (2,4-di-tert-butylphenol) that may be employed in the first step is not particularly limited; It is a preferable aspect that the mass ratio of the materials is 0.5 or more and 3 or less from the viewpoint of economic rationality and reducing the influence on subsequent processing steps.
  • reaction in the first step for example, an alkali metal hydroxide, 2,4-di-tert-butylphenol, and 4-methyltetrahydropyran as a reaction solvent were introduced into an autoclave reactor connected to a reflux device. Thereafter, the mixture is heated to a predetermined temperature (for example, 105° C. to 120° C.), and the reaction of the first step is continued until distillation of the water produced by the reaction can no longer be confirmed.
  • a predetermined temperature for example, 105° C. to 120° C.
  • the reaction in the reaction process in the first step, the reaction can be realized in a substantially uniform solution.
  • the solute in the solution can be prevented from becoming a slurry or solidifying, or from being precipitated with high certainty.
  • the second step described above is performed. Specifically, the above-mentioned reaction solvent and the salt of 2,4-di-tert-butylphenol produced in the first step are sealed, and a predetermined reaction temperature (for example, 90° C. or higher and 130° C. or lower) is achieved. Carbon dioxide is pressurized into the heated container under a predetermined pressure (0.01 MPa or more and 0.6 MPa or less). As a result, a salt of 3,5-di-tert-butylsalicylic acid can be produced.
  • a predetermined reaction temperature for example, 90° C. or higher and 130° C. or lower
  • Carbon dioxide is pressurized into the heated container under a predetermined pressure (0.01 MPa or more and 0.6 MPa or less).
  • the reaction in the second step is carried out, for example, after the reflux path of the reflux device employed in the first step is shut off.
  • the product in the container is continuously stirred, and then the product is stirred under reduced pressure conditions (for example, about 15 kPa or more and 30 kPa or less).
  • the reaction solvent 4-methyltetrahydropyran is distilled off. In this embodiment, we have succeeded in recovering 90% or more (more narrowly, 94% or more) of this reaction solvent.
  • the pH value is then adjusted using a pH value adjuster (for example, sulfuric acid) so that the pH value is less than 4 (more preferably, the pH value is 2 or more and 3 or less).
  • a value adjustment process is performed. Specifically, the pH value of the aqueous layer obtained by the above recovery by distilling off the reaction solvent 4-methyltetrahydropyran used in the reactions up to the second step is adjusted. As a result, 3,5-di-tert-butylsalicylic acid can be produced by filtering and drying the precipitated solid.
  • the manufacturing method of this embodiment it is possible to realize a reaction in a substantially homogeneous solution with high accuracy, and even under conditions of lower pressure and temperature than before, 3,5-di-tertiary It becomes possible to produce butylsalicylic acid.
  • the purity is very high (for example, 99% or more) and the yield is very high (80% or more (more specifically, 80% or more in terms of mole). The same applies hereinafter. ), in a more narrow sense, 90% or more), and because the solvent is hardly mixed into the finally produced waste liquid, it is possible to improve the manufacturing process of 3,5-di-tert-butylsalicylic acid. It has become clear that the environmental impact of the aqueous waste liquid produced by this process is extremely small. This also makes waste liquid treatment easier, that is, lower costs.
  • Example 1 This example is an example for obtaining 3,5-di-tert-butylsalicylic acid in an amount suitable for example in a laboratory.
  • FIG. 1 is an optical photograph of the reaction solution after the first step in Example 1. Arrows in Figure 1 are drawn to point to the reaction solution. As shown in the photograph of FIG. 1, it was confirmed that the reaction solution in the autoclave reactor was in a substantially uniform state, in other words, highly uniform, and highly transparent.
  • a third step was carried out in which sulfuric acid was introduced to adjust the pH value to below 4. Note that the pH value in this example was about 2 to about 3.
  • FIG. 2 is a diagram of a high performance liquid chromatograph (HPLC) after the third step in this example. As shown in FIG. 2, it can be seen that extremely high purity 3,5-di-tert-butylsalicylic acid was produced.
  • Example 2 This example is an example for obtaining 3,5-di-tert-butylsalicylic acid in an amount that can be produced, for example, on a trial basis or in mass production.
  • a third step was carried out in which sulfuric acid was introduced to adjust the pH value to below 4. Note that the pH value in this example was about 2 to about 3.
  • the precipitated white solid was filtered, washed, and dried to obtain about 34.7 kg of 3,5-di-tert-butylsalicylic acid.
  • the yield of 3,5-di-tert-butylsalicylic acid in the solid material of this example was about 92.8%, and the purity was about 99.8%.
  • Comparative example 1 In this comparative example, each treatment was carried out under the same conditions as in the first example, except that 150 g of toluene was used as the reaction solvent in place of 4-methyltetrahydropyran as the reaction solvent in the above-mentioned example 1. It was conducted.
  • FIG. 3 is an optical photograph of the reaction solution (or reaction mixture) after the first step in this comparative example. Arrows in Figure 3 are drawn to point to the reaction solution. As shown in FIG. 3, it was clearly different from the photograph in FIG. 1, and it was confirmed that transparency was lost and solidification or precipitation of the solute was very advanced. Thereafter, the present inventors continued stirring even in the above-mentioned state, and then performed the second and third steps.
  • the precipitated white solid was filtered, washed, and dried to obtain about 59.3 g of 3,5-di-tert-butylsalicylic acid.
  • the yield of 3,5-di-tert-butylsalicylic acid in the solid material of this example was about 36.2%, and its purity was about 96.6%.
  • Comparative example 2 In this comparative example, the conditions were the same as in Example 1, except that 150 g of toluene and 15 g of NMP, a polar solvent, were used as the solvents instead of 4-methyltetrahydropyran, the reaction solvent in Example 1. Each treatment was performed under the following conditions.
  • FIG. 4 is an optical photograph of the reaction solution (or reaction mixture) after the first step in this comparative example. Arrows in Figure 4 are drawn to point to the reaction solution. As shown in FIG. 4, which is clearly different from the photograph in FIG. 1, it was confirmed that transparency was lost and at least a portion of the solute was solidified or precipitated. Thereafter, the present inventors continued stirring even in the above-mentioned state, and then performed the second and third steps.
  • the precipitated white solid was filtered, washed, and dried to obtain about 65.7 g of 3,5-di-tert-butylsalicylic acid.
  • the yield of 3,5-di-tert-butylsalicylic acid in the solid material of this example was about 40.1%, and its purity was about 98.4%.
  • Comparative example 3 In this comparative example, the present inventors performed the same method as the method described in Example 1 of Patent Document 2, except that no reaction solvent was used (that is, no solvent was used). An attempt was made to perform each treatment under the same conditions as those of .
  • the method for producing 3,5-di-tert-butylsalicylic acid of the present invention can be used as a method for producing useful chemical substances, and for producing materials for various uses (for example, intermediates for pharmaceuticals or toner additives for copying machines). It can be widely used as a method or a part thereof.

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Abstract

The method for producing 3,5-di-tertiary-butylsalicylic acid according to one aspect of the present invention comprises: a first step for reacting an alkali metal hydroxide with 2,4-di-tertiary-butylphenol using 4-methyltetrahydropyran as a reaction solvent to produce a salt of the 2,4-di-tertiary-butylphenol (wherein X represents an alkali metal); a second step for injecting carbon dioxide into a container that is heated and has the reaction solvent and the alkali salt of the 2,4-di-tertiary-butylphenol enclosed therein to produce a salt of 3,5-di-tertiary-butylsalicylic acid, subsequent to the first step; and a third step for performing a pH value adjustment process for adjusting the pH value to a value of less than 4 to produce a solid matter containing the 3,5-di-tertiary-butylsalicylic acid, subsequent to the second step.

Description

３，５－ジ－ターシャリーブチルサリチル酸の製造方法Method for producing 3,5-di-tert-butylsalicylic acid
　本発明は、３，５－ジ－ターシャリーブチルサリチル酸の製造方法に関する。 The present invention relates to a method for producing 3,5-di-tert-butylsalicylic acid.
　従来から、３，５－ジ－ターシャリーブチルサリチル酸は、有用な化学物質として、例えば医薬品の中間体に用いられている。また、３，５－ジ－ターシャリーブチルサリチル酸の化合物から派生して製造される錯体材料は、複写機のトナー添加物等として採用されている。 Conventionally, 3,5-di-tert-butylsalicylic acid has been used as a useful chemical substance, for example, as an intermediate for pharmaceuticals. Furthermore, complex materials derived from 3,5-di-tert-butylsalicylic acid compounds are employed as toner additives in copying machines.
　この３，５－ジ－ターシャリーブチルサリチル酸の製造方法の代表例は、サリチル酸のジブチル化反応、又は２，４－ジターシャリーブチルフェノールのアルカリ塩を二酸化炭素と反応せしめる、所謂コルベシュミット反応である。（特許文献１～５，非特許文献１～３） A typical example of the method for producing 3,5-di-tert-butylsalicylic acid is the dibutylation reaction of salicylic acid, or the so-called Kolbe-Schmidt reaction, in which an alkali salt of 2,4-di-tert-butylphenol is reacted with carbon dioxide. (Patent Documents 1 to 5, Non-Patent Documents 1 to 3)
特開昭６２－６１９４９号公報Japanese Patent Application Publication No. 62-61949 特開２００７－３２０８８０号公報JP2007-320880A 特開平１０－５９８９７号公報Japanese Patent Application Publication No. 10-59897 特開平１０－８７５６２号公報Japanese Patent Application Publication No. 10-87562 ＷＯ２００４／０３１１１３号公報WO2004/031113 publication
　しかし、上述において説明した２つの製造方法のうち、前者の方法を採用すると、ジブチル化処理を行う際に、反応が複雑であるとともに副生成物が多く生成するため、精製工程が難しくなる。加えて、望まない副生成物であるトリターシャリーブチル化誘導体が含まれることによって使用が困難となる場合がある。また、非特許文献２及び３に開示される方法によれば、アルキル化の反応または位置選択性を持たせるための保護・脱保護の工程が追加的に必要になるため、工業化に不利である。 However, among the two production methods described above, if the former method is adopted, the reaction is complicated and many by-products are generated during the dibutylation treatment, making the purification process difficult. In addition, the inclusion of tritert-butylated derivatives, which are undesirable by-products, may make them difficult to use. Furthermore, the methods disclosed in Non-Patent Documents 2 and 3 require an additional step of alkylation reaction or protection/deprotection to impart regioselectivity, which is disadvantageous for industrialization. .
　一方、後者の方法を採用すると、高温及び高圧（例えば１５０℃以上、５ＭＰａ以上）の条件下における反応であり、コルベシュミット反応によるアルカリフェノキシ化が行われると、該アルカリフェノキシ化された化合物は、一般的に用いられるベンゼン、トルエン、キシレン等の芳香族溶媒に不溶化して反応が不均一となるため、高い収率及び純度を得ることができなくなるという問題が生じる。 On the other hand, when the latter method is adopted, the reaction is performed under conditions of high temperature and high pressure (for example, 150° C. or higher, 5 MPa or higher), and when alkali phenoxylation is performed by Kolbe-Schmidt reaction, the alkali phenoxylated compound is Since it becomes insolubilized in commonly used aromatic solvents such as benzene, toluene, and xylene, the reaction becomes nonuniform, resulting in a problem that high yield and purity cannot be obtained.
　なお、特許文献３及び４においては、上述のアルカリフェノキシ化による不溶化によって生じる不均一反応を軽減するための方法も提案されている。その１つは、上述の芳香族溶媒と均一になり、アルカリフェノキシ化の親和性に富む一種の非プロトン性極性溶媒、Ｎ－メチルピロリドン（ＮＭＰ）、３－メチルー２－オキサゾリジノン、１，３－ジメチルー２－イミダゾリジノン等を添加溶媒として採用する方法が開示されている。また、Ｎ，Ｎ－メチルアセトアミドを溶媒として採用する技術も開示されている。 Note that Patent Documents 3 and 4 also propose a method for reducing the heterogeneous reaction caused by insolubilization by the above-mentioned alkali phenoxidation. One of them is N-methylpyrrolidone (NMP), 3-methyl-2-oxazolidinone, 1,3- A method is disclosed in which dimethyl-2-imidazolidinone or the like is employed as an additive solvent. Also disclosed is a technique that employs N,N-methylacetamide as a solvent.
　しかしながら、上述の各提案によれば、採用する極性溶媒を回収することができないために、最終的には水性廃液に混合されることになることから、環境への負荷が大きくなるという問題がある。 However, according to each of the above-mentioned proposals, since the polar solvents used cannot be recovered, they end up being mixed into the aqueous waste liquid, which poses a problem of increasing the burden on the environment. .
　特許文献５において開示される発明は、多少は環境負荷の軽減への貢献があるかも知れない。しかしながら、該発明は、コルベシュミット反応工程において、反応途中に生成されるアルカリフェノキシ誘導体が均一に攪拌される状態にするために、反応溶媒の役目も含め基質フェノール誘導体をアルカリ金属化合物に対して極めて過剰に用いるという反応溶媒を採用している。そのため、回収工程が追加的に必要となるだけでなく、その回収率も高くない。加えて、該発明は、１６０℃以上という極めて高い反応温度が必要であるとともに、生成物の精製が容易ではないため、該発明が開示する技術思想も工業化には不利である。 The invention disclosed in Patent Document 5 may contribute to reducing environmental loads to some extent. However, in the Kolbe-Schmidt reaction step, the substrate phenol derivative, including its role as a reaction solvent, is extremely sensitive to the alkali metal compound in order to uniformly stir the alkali phenoxy derivative produced during the reaction. The reaction solvent is used in excess. Therefore, not only is an additional recovery process required, but the recovery rate is also not high. In addition, the invention requires an extremely high reaction temperature of 160° C. or higher, and the product is not easy to purify, so the technical idea disclosed in the invention is also disadvantageous for industrialization.
　本発明は、上述の各技術課題を解決することにより、非常に高い純度と高い収率を実現しつつ、工業化に適するとともに環境にも優しい、３，５－ジ－ターシャリーブチルサリチル酸の製造方法の実現に大きく貢献し得る。 The present invention provides a method for producing 3,5-di-tert-butylsalicylic acid that achieves extremely high purity and high yield, is suitable for industrialization, and is environmentally friendly, by solving the above-mentioned technical problems. can greatly contribute to the realization of
　本発明者らは、特許文献１において開示される発明の開示に基づいて追試を行った。その結果、本発明者らは、アルカリフェノキシ化後に脱水工程が行われると固体化するため、その固体を取り出して粉砕工程を行うことが必要となることから、特許文献１が開示する発明は工業化には不利であることを確認した。 The present inventors conducted a follow-up test based on the disclosure of the invention disclosed in Patent Document 1. As a result, the present inventors found that the invention disclosed in Patent Document 1 is not suitable for industrialization because it solidifies when a dehydration step is performed after alkali phenoxylation, and it is necessary to take out the solid and perform a pulverization step. It was confirmed that this is disadvantageous.
　さらに、特許文献１が開示する発明においては、その粉砕工程によって得られる粉末をオートクレーブに仕込み、厳しい反応条件、具体的には１４０℃～１６０℃の高温、且つ１３Ｋｇｆ／ｃｍ２（すなわち、１．３ＭＰａ）という高圧の条件下で二酸化炭素を吸収させるコルベシュミット反応が行われることになる。該コルベシュミット反応は不均一な反応であることから、上述の芳香性有機溶媒を用いる場合と同様、又はそれ以上に、固形物の析出による反応阻害の問題が発生する。 Furthermore, in the invention disclosed in Patent Document 1, the powder obtained by the pulverization process is charged into an autoclave, and the reaction conditions are severe, specifically, a high temperature of 140° C. to 160° C. and 13 Kgf/cm 2 (that is, 1. The Kolbe-Schmidt reaction, which absorbs carbon dioxide, will take place under high pressure conditions (3 MPa). Since the Kolbe-Schmidt reaction is a heterogeneous reaction, the problem of reaction inhibition due to precipitation of solids occurs, similar to or even more so than when using the above-mentioned aromatic organic solvent.
　本発明者らは、上述の各技術課題に直面し、様々な検討と分析を重ねた。その結果、本発明者らは、３，５－ジ－ターシャリーブチルサリチル酸を製造するための溶媒の重要性に着眼した。具体的には、反応過程において固形物が析出しない反応を実現し得る溶媒を採用することができれば、例えば、溶液を継続して撹拌しつつ反応を進めることによって略均一な反応を実現することが可能となる。 The present inventors faced each of the above-mentioned technical issues and conducted various studies and analyses. As a result, the present inventors focused on the importance of the solvent for producing 3,5-di-tert-butylsalicylic acid. Specifically, if it is possible to employ a solvent that can achieve a reaction in which solid matter does not precipitate during the reaction process, it is possible to achieve a substantially uniform reaction by, for example, proceeding with the reaction while continuously stirring the solution. It becomes possible.
　そこで、本発明者らが鋭意、研究と分析に取り組み、また試行錯誤を重ねた結果、ある特定の溶媒を採用することにより、略均一な溶液における反応を確度高く実現できるとともに、従来技術と比較して、より低い圧力とより低い温度の条件下においても、３，５－ジ－ターシャリーブチルサリチル酸を製造することが可能となることが分かった。 Therefore, as a result of intensive research and analysis and repeated trial and error, the inventors of the present invention were able to realize a reaction in a substantially homogeneous solution with high accuracy by employing a specific solvent, and compared it with conventional technology. As a result, it was found that 3,5-di-tert-butylsalicylic acid can be produced even under conditions of lower pressure and lower temperature.
　さらに、大変興味深いことに、上述の溶媒を採用すると、非常に高い純度及び収率を実現することができるだけではなく、その溶媒が最終的に生成される廃液には殆ど混入しないため、３，５－ジ－ターシャリーブチルサリチル酸の製造過程によって生成される水性廃液による環境負荷が非常に小さくなることが明らかとなった。これは、廃液処理の容易化、すなわち低コスト化をも実現し得ることになる。本発明は、そのような視点と経緯により創出された。 Furthermore, it is very interesting to note that by employing the above-mentioned solvents, not only can very high purity and yields be achieved, but also the solvents are hardly mixed into the final waste liquid, 3,5 - It has become clear that the environmental impact of the aqueous waste liquid produced during the production process of di-tert-butylsalicylic acid is extremely small. This also makes waste liquid treatment easier, that is, lower costs. The present invention was created from such a viewpoint and background.
　本発明の１つの３，５－ジ－ターシャリーブチルサリチル酸の製造方法は、４－メチルテトラヒドロピランを反応溶媒として、アルカリ金属水酸化物と化学式（１）で表わされる２，４－ジ－ターシャリーブチルフェノールとを反応させることにより、化学式（２）で表わされる該２，４－ジ－ターシャリーブチルフェノールの塩（但し、Ｘはアルカリ金属）を生成する第１工程と、該第１工程の後、該反応溶媒と、該２，４－ジ－ターシャリーブチルフェノールのアルカリ塩とを封入した、加熱した容器内に二酸化炭素を圧入することによって、３，５－ジ－ターシャリーブチルサリチル酸の塩を生成する第２工程と、該第２工程の後、ｐＨ値が４未満となるようにｐＨ値を調整するｐＨ値調整工程を行うことによって、化学式（３）で表わされる前述の３，５－ジ－ターシャリーブチルサリチル酸を含む固形物を得る第３工程と、を含む。
Figure JPOXMLDOC01-appb-C000002
 One method for producing 3,5-di-tert-butylsalicylic acid of the present invention is to use 4-methyltetrahydropyran as a reaction solvent, and alkali metal hydroxide and 2,4-di-tert-salicylic acid represented by the chemical formula (1). A first step of producing the salt of 2,4-di-tert-butylphenol represented by the chemical formula (2) (wherein, X is an alkali metal) by reacting it with l-butylphenol, and after the first step. , the salt of 3,5-di-tert-butylsalicylic acid is produced by pressurizing carbon dioxide into a heated container containing the reaction solvent and the alkali salt of 2,4-di-tert-butylphenol. The above-mentioned 3,5- and a third step of obtaining a solid containing di-tert-butylsalicylic acid.
Figure JPOXMLDOC01-appb-C000002
　この３，５－ジ－ターシャリーブチルサリチル酸の製造方法によれば、上述の反応溶媒を採用することにより、略均一な溶液における反応を確度高く実現できるとともに、従来技術と比較して、より低い圧力とより低い温度の条件下において３，５－ジ－ターシャリーブチルサリチル酸を製造することができる。また、該製造方法によれば、非常に高い純度及び収率を実現することができるだけではなく、該反応溶媒が最終的に生成される廃液には殆ど混入しないため、該廃液よる環境負荷が非常に小さくなる。従って、廃液処理の容易化、すなわち低コスト化をも実現し得る。 According to this method for producing 3,5-di-tert-butylsalicylic acid, by employing the above-mentioned reaction solvent, it is possible to realize the reaction in a substantially homogeneous solution with high accuracy, and to achieve a lower 3,5-di-tert-butylsalicylic acid can be produced under conditions of pressure and lower temperature. In addition, according to this production method, not only can extremely high purity and yield be achieved, but also the reaction solvent is hardly mixed into the waste liquid finally produced, so the environmental burden of the waste liquid is extremely low. becomes smaller. Therefore, waste liquid treatment can be facilitated, that is, costs can be reduced.
　本発明の１つの３，５－ジ－ターシャリーブチルサリチル酸の製造方法によれば、略均一な溶液における反応を確度高く実現できるとともに、従来技術と比較して、より低い圧力及び温度の条件下において３，５－ジ－ターシャリーブチルサリチル酸を製造することができる。また、該製造方法によれば、非常に高い純度及び収率を実現することができるだけではなく、該製造方法による該廃液の環境への負荷を非常に小さくすることができる。 According to one of the methods for producing 3,5-di-tert-butylsalicylic acid of the present invention, it is possible to realize the reaction in a substantially homogeneous solution with high accuracy, and at the same time, it is possible to realize the reaction in a substantially homogeneous solution under conditions of lower pressure and temperature than in the prior art. 3,5-di-tert-butylsalicylic acid can be produced. Moreover, according to this manufacturing method, not only can extremely high purity and yield be achieved, but also the environmental impact of the waste liquid caused by this manufacturing method can be extremely reduced.
実施例１における第１工程後の、反応溶液の光学写真である。2 is an optical photograph of the reaction solution after the first step in Example 1. 実施例１における第３工程後の高速液体クロマトグラフ（ＨＰＬＣ）の図である。FIG. 2 is a high performance liquid chromatograph (HPLC) diagram after the third step in Example 1. 比較例１における第１工程後の、反応溶液の光学写真である。3 is an optical photograph of the reaction solution after the first step in Comparative Example 1. 比較例２における第１工程後の、反応溶液の光学写真である。3 is an optical photograph of the reaction solution after the first step in Comparative Example 2.
＜第１の実施形態＞
　つぎに、本発明の実施形態について説明する。 <First embodiment>
Next, embodiments of the present invention will be described.
　本実施形態の３，５－ジ－ターシャリーブチルサリチル酸は、次の（ａ）～（ｃ）に示す各工程を含む製造方法により製造することができる。
　（ａ）４－メチルテトラヒドロピランを反応溶媒として、アルカリ金属水酸化物と、以下の化学式（１）で表わされる２，４－ジ－ターシャリーブチルフェノールとを反応させることにより、以下の化学式（２）で表わされる該２，４－ジ－ターシャリーブチルフェノールの塩（但し、Ｘはアルカリ金属）を生成する第１工程
　（ｂ）第１工程の後、該反応溶媒と、該２，４－ジ－ターシャリーブチルフェノールのアルカリ塩とを封入した、加熱した容器内に二酸化炭素を圧入することによって、３，５－ジ－ターシャリーブチルサリチル酸の塩を生成する第２工程
　（ｃ）第２工程の後、ｐＨ値が４未満となるようにｐＨ値を調整するｐＨ値調整工程を行うことによって、以下の化学式（３）で表わされる前述の３，５－ジ－ターシャリーブチルサリチル酸を含む固形物を得る第３工程 The 3,5-di-tert-butylsalicylic acid of this embodiment can be produced by a production method including the following steps (a) to (c).
(a) By reacting an alkali metal hydroxide with 2,4-di-tert-butylphenol represented by the following chemical formula (1) using 4-methyltetrahydropyran as a reaction solvent, the following chemical formula (2 ) A first step of producing the 2,4-di-tert-butylphenol salt (where X is an alkali metal) (b) After the first step, the reaction solvent and the 2,4-di-tert-butylphenol salt are - A second step of producing a salt of 3,5-di-tert-butylsalicylic acid by pressurizing carbon dioxide into a heated container sealed with an alkali salt of tert-butylphenol. After that, by performing a pH value adjustment step to adjust the pH value to less than 4, a solid substance containing the above-mentioned 3,5-di-tert-butylsalicylic acid represented by the following chemical formula (3) is obtained. The third step to obtain
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　次に、上述の各工程について詳細に説明する。 Next, each of the above steps will be explained in detail.
　まず、第１工程においては、本発明者らは、出発材として、上記の化学式（１）で表わされる２，４－ジ－ターシャリーブチルフェノールを採用した。また、本発明者らは、第１工程、第２工程、及び第３工程の全ての工程に亘って用いるための反応溶媒として、４－メチルテトラヒドロピランを採用した。 First, in the first step, the present inventors employed 2,4-di-tert-butylphenol represented by the above chemical formula (1) as a starting material. In addition, the present inventors adopted 4-methyltetrahydropyran as a reaction solvent for use in all of the first, second, and third steps.
　本発明者らは、上述のとおり、研究と分析に鋭意取り組み、また試行錯誤を重ねた結果、反応溶媒として、市販においても入手し得る、毒性の低いテトラヒドロピラン誘導体の一つを採用することとした。本実施形態において、テトラヒドロピラン誘導体の中でも、特に４－メチルテトラヒドロピランを採用することにより、略均一な溶液における反応と、公知技術よりも低い圧力とより低い温度の条件下における反応の実現に貢献し得ることを本発明者らは確認した。また、４－メチルテトラヒドロピランは、単蒸留によって回収することが可能であることから、製造原価を抑えるとともに、最終的に生成される廃液による環境への負荷を顕著に軽減し得る。 As mentioned above, as a result of intensive research and analysis and repeated trial and error, the present inventors decided to use one of the less toxic tetrahydropyran derivatives that are commercially available as the reaction solvent. did. In this embodiment, by particularly employing 4-methyltetrahydropyran among tetrahydropyran derivatives, it contributes to the realization of a reaction in a substantially homogeneous solution and a reaction under conditions of lower pressure and lower temperature than known techniques. The present inventors have confirmed that this is possible. Furthermore, since 4-methyltetrahydropyran can be recovered by simple distillation, it is possible to reduce the manufacturing cost and to significantly reduce the environmental burden of the finally produced waste liquid.
　従って、第１工程においては、アルカリ金属水酸化物（好適には、水酸化ナトリウム（ＮａＯＨ）又は水酸化カリウム（ＫＯＨ）、より好適には、水酸化ナトリウム（ＮａＯＨ））と２，４－ジ－ターシャリーブチルフェノールとを反応させる。本実施形態においては、略均一な溶液における反応が行われることにより、上記の化学式（２）で表わされる該２，４－ジ－ターシャリーブチルフェノールの塩（但し、Ｘはアルカリ金属）が生成される。なお、第１工程において採用され得る、上述の反応溶媒（４－メチルテトラヒドロピラン）の出発材（２，４－ジ－ターシャリーブチルフェノール）に対する質量比は特に限定されないが、該反応溶媒に対する該出発材の質量比が０．５以上３以下であることは、経済的合理性、及びその後の処理工程への影響を軽減する観点から好適な一態様である。 Therefore, in the first step, an alkali metal hydroxide (preferably sodium hydroxide (NaOH) or potassium hydroxide (KOH), more preferably sodium hydroxide (NaOH)) and 2,4-di - React with tert-butylphenol. In this embodiment, the 2,4-di-tert-butylphenol salt represented by the above chemical formula (2) (where X is an alkali metal) is produced by carrying out the reaction in a substantially homogeneous solution. Ru. Note that the mass ratio of the above-mentioned reaction solvent (4-methyltetrahydropyran) to the starting material (2,4-di-tert-butylphenol) that may be employed in the first step is not particularly limited; It is a preferable aspect that the mass ratio of the materials is 0.5 or more and 3 or less from the viewpoint of economic rationality and reducing the influence on subsequent processing steps.
　第１工程における反応は、例えば、アルカリ金属水酸化物と、２，４－ジ－ターシャリーブチルフェノールと、反応溶媒である４－メチルテトラヒドロピランとを、還流器を接続したオートクレーブ反応器に導入した後、所定の温度（例えば、１０５℃～１２０℃）によって加熱し、該反応によって生成される水の留出が確認できなくなるまで、第１工程の反応を継続させる。 In the reaction in the first step, for example, an alkali metal hydroxide, 2,4-di-tert-butylphenol, and 4-methyltetrahydropyran as a reaction solvent were introduced into an autoclave reactor connected to a reflux device. Thereafter, the mixture is heated to a predetermined temperature (for example, 105° C. to 120° C.), and the reaction of the first step is continued until distillation of the water produced by the reaction can no longer be confirmed.
　ところで、第１工程における反応過程において、略均一な溶液における反応を実現できることは特筆に値する。換言すれば、本実施形態の第１工程においては、該溶液の溶質がスラリー化又は固形化すること、あるいは析出することが確度高く防止され得る、という効果が発揮される。この略均一な溶液を用いて反応を行うことによって、後述する、第２工程において従来よりも低い圧力とより低い温度の条件下における反応を実現し得るとともに、最終的に得られる３，５－ジ－ターシャリーブチルサリチル酸又はその化合物の収率及び純度を飛躍的に高めることが可能となる。 By the way, it is noteworthy that in the reaction process in the first step, the reaction can be realized in a substantially uniform solution. In other words, in the first step of the present embodiment, the solute in the solution can be prevented from becoming a slurry or solidifying, or from being precipitated with high certainty. By conducting the reaction using this approximately homogeneous solution, it is possible to realize the reaction under conditions of lower pressure and lower temperature than in the past in the second step, which will be described later, and to obtain the final 3,5- It becomes possible to dramatically increase the yield and purity of di-tert-butylsalicylic acid or its compound.
　その後、上述の第２工程が行われる。具体的には、上述の反応溶媒と、第１工程によって生成された２，４－ジ－ターシャリーブチルフェノールの塩とを封入し、所定の反応温度（例えば、９０℃以上１３０℃以下）となるように加熱した容器内に、二酸化炭素を所定の圧力（０．０１ＭＰａ以上０．６ＭＰａ以下）の条件下において圧入する。その結果、３，５－ジ－ターシャリーブチルサリチル酸の塩を生成することができる。 After that, the second step described above is performed. Specifically, the above-mentioned reaction solvent and the salt of 2,4-di-tert-butylphenol produced in the first step are sealed, and a predetermined reaction temperature (for example, 90° C. or higher and 130° C. or lower) is achieved. Carbon dioxide is pressurized into the heated container under a predetermined pressure (0.01 MPa or more and 0.6 MPa or less). As a result, a salt of 3,5-di-tert-butylsalicylic acid can be produced.
　第２工程における反応は、例えば、第１工程において採用された還流器の還流経路の遮断した後に行われる。上述のように該容器内に圧入した二酸化炭素が消費されなくなった後も該容器内の生成物を継続して撹拌したうえで、減圧した圧力条件（例えば、約１５ｋＰａ以上３０ｋＰａ以下）の下で、反応溶媒である４－メチルテトラヒドロピランを留去する。本実施形態においては、この反応溶媒を、９０％以上（より狭義には、９４％以上）回収することに成功している。 The reaction in the second step is carried out, for example, after the reflux path of the reflux device employed in the first step is shut off. As mentioned above, even after the carbon dioxide pressurized into the container is no longer consumed, the product in the container is continuously stirred, and then the product is stirred under reduced pressure conditions (for example, about 15 kPa or more and 30 kPa or less). , the reaction solvent 4-methyltetrahydropyran is distilled off. In this embodiment, we have succeeded in recovering 90% or more (more narrowly, 94% or more) of this reaction solvent.
　その後、上述の第３工程が行われる。なお、第２工程において得られた３，５－ジ－ターシャリーブチルサリチル酸の塩を含む固形物に、水と抽出溶媒（例えば、トルエン）とを加えて分液処理が行われることは好適な一態様である。 Thereafter, the third step described above is performed. Note that it is preferable that water and an extraction solvent (for example, toluene) be added to the solid material containing the salt of 3,5-di-tert-butylsalicylic acid obtained in the second step to perform a liquid separation treatment. This is one aspect.
　第３工程においては、その後、ｐＨ値調整剤（例えば、硫酸）を用いてｐＨ値が４未満（より好適には、ｐＨ値が２以上３以下）となるようにｐＨ値を調整する、ｐＨ値調整工程が行われる。具体的には、第２工程までの反応に用いた反応溶媒４－メチルテトラヒドロピランの留去による上述の回収によって得られた水層の該ｐＨ値を調製する。その結果、析出した固形物を濾過し、乾燥させることにより、３，５－ジ－ターシャリーブチルサリチル酸を製造するこができる。 In the third step, the pH value is then adjusted using a pH value adjuster (for example, sulfuric acid) so that the pH value is less than 4 (more preferably, the pH value is 2 or more and 3 or less). A value adjustment process is performed. Specifically, the pH value of the aqueous layer obtained by the above recovery by distilling off the reaction solvent 4-methyltetrahydropyran used in the reactions up to the second step is adjusted. As a result, 3,5-di-tert-butylsalicylic acid can be produced by filtering and drying the precipitated solid.
　上述のとおり、本実施形態の製造方法を採用することにより、略均一な溶液における反応を確度高く実現できるとともに、従来よりも低い圧力及び温度の条件下においても、３，５－ジ－ターシャリーブチルサリチル酸を製造することが可能となる。加えて、本実施形態に製造方法によれば、非常に高い純度（例えば、９９％以上）及び非常に高い収率（８０％以上（より詳細には、モル換算で８０％以上。以下同じ。）、より狭義には、９０％以上）を実現することができるだけではなく、その溶媒が最終的に生成される廃液には殆ど混入しないため、３，５－ジ－ターシャリーブチルサリチル酸の製造過程によって生成される水性廃液による環境負荷が非常に小さくなることが明らかとなった。これは、廃液処理の容易化、すなわち低コスト化をも実現し得ることになる。 As mentioned above, by adopting the manufacturing method of this embodiment, it is possible to realize a reaction in a substantially homogeneous solution with high accuracy, and even under conditions of lower pressure and temperature than before, 3,5-di-tertiary It becomes possible to produce butylsalicylic acid. In addition, according to the manufacturing method of the present embodiment, the purity is very high (for example, 99% or more) and the yield is very high (80% or more (more specifically, 80% or more in terms of mole). The same applies hereinafter. ), in a more narrow sense, 90% or more), and because the solvent is hardly mixed into the finally produced waste liquid, it is possible to improve the manufacturing process of 3,5-di-tert-butylsalicylic acid. It has become clear that the environmental impact of the aqueous waste liquid produced by this process is extremely small. This also makes waste liquid treatment easier, that is, lower costs.
［実施例］
　以下、上述の第１の実施形態をより詳細に説明するために、実施例１及び２を比較例１乃至３とともに説明するが、上述の実施形態及び変形例は、これらの例によって限定されるものではない。 [Example]
Examples 1 and 2 will be described below along with Comparative Examples 1 to 3 in order to explain the first embodiment described above in more detail, but the embodiments and modified examples described above are limited by these examples. It's not a thing.
（実施例１）
　本実施例は、例えば実験室において行われる程度の量の３，５－ジ－ターシャリーブチルサリチル酸を得るための例である。 (Example 1)
This example is an example for obtaining 3,5-di-tert-butylsalicylic acid in an amount suitable for example in a laboratory.
　本実施例においては、まず、反応溶媒である４－メチルテトラヒドロピラン１５０ｇと、２，４－ジターシャリーブチルフェノール１３５ｇと、４８．５％苛性ソーダ水（水酸化ナトリウム水溶液）５７ｇとを、還流器を接続したオートクレーブ反応器内に導入した。その後、撹拌しながら、約１１０℃に加熱することにより、水の留出がなくなるまで第１工程を継続した。この例においては、第１工程が約５時間行われた。 In this example, first, 150 g of 4-methyltetrahydropyran as a reaction solvent, 135 g of 2,4-ditertiary butylphenol, and 57 g of 48.5% caustic soda water (sodium hydroxide aqueous solution) were connected to a refluxer. was introduced into the autoclave reactor. Thereafter, the first step was continued by heating to about 110° C. while stirring until no water was distilled out. In this example, the first step was carried out for about 5 hours.
　図１は、実施例１における第１工程後の、反応溶液の光学写真である。図１中の矢印は、反応溶液を指すために描かれている。図１の写真に示すように、オートクレーブ反応器内の反応溶液は、略均一の状態、換言すれば均一性が高い状態であり、且つ透明度が高いことが確認できた。 FIG. 1 is an optical photograph of the reaction solution after the first step in Example 1. Arrows in Figure 1 are drawn to point to the reaction solution. As shown in the photograph of FIG. 1, it was confirmed that the reaction solution in the autoclave reactor was in a substantially uniform state, in other words, highly uniform, and highly transparent.
　その後、該還流器の還流経路を遮断し、反応温度が１０５℃～１１０℃となるように設定した状態で、内圧が０．５ＭＰａになるように二酸化炭素（ＣＯ２）を圧入する第２工程を行った。その後、二酸化炭素に消費が無くなったと考えられる状態になった後、前述の温度帯の条件下で、３時間継続的に撹拌した。その後、減圧下にて反応溶媒である４－メチルテトラヒドロピランを留去した。この段階での該反応溶媒の回収率は約９４％であった。 Thereafter, the reflux path of the reflux device is shut off, and while the reaction temperature is set at 105°C to 110°C, a second step is to pressurize carbon dioxide (CO 2 ) so that the internal pressure becomes 0.5 MPa. I did it. Thereafter, after reaching a state where it was considered that no consumption of carbon dioxide was reached, stirring was continued for 3 hours under the conditions of the above-mentioned temperature range. Thereafter, the reaction solvent 4-methyltetrahydropyran was distilled off under reduced pressure. The recovery rate of the reaction solvent at this stage was about 94%.
　第２工程を経ることによって得られた生成物（固体）を収容する反応容器内に、抽出溶媒（本実施例では、水）を導入することによって分液処理が施されたのち、ｐＨ値が４未満となるようにｐＨ値を調整するための硫酸が導入される第３工程が行われた。なお、本実施例のｐＨ値は約２～約３となった。 After a liquid separation process is performed by introducing an extraction solvent (in this example, water) into the reaction vessel containing the product (solid) obtained through the second step, the pH value is A third step was carried out in which sulfuric acid was introduced to adjust the pH value to below 4. Note that the pH value in this example was about 2 to about 3.
　その結果、析出した白色の固形物を濾過及び洗浄し、乾燥させると、３，５－ジ－ターシャリーブチルサリチル酸を約１３９ｇ得ることができた。なお、本実施例の固形物における３，５－ジ－ターシャリーブチルサリチル酸の収率は約８４．８％であり、その純度は約１００％であった。図２は、本実施例における第３工程後の高速液体クロマトグラフ（ＨＰＬＣ）の図である。図２に示すように、極めて高い純度の３，５－ジ－ターシャリーブチルサリチル酸が生成されていることが分かる。 As a result, the precipitated white solid was filtered, washed, and dried to obtain about 139 g of 3,5-di-tert-butylsalicylic acid. The yield of 3,5-di-tert-butylsalicylic acid in the solid material of this example was about 84.8%, and its purity was about 100%. FIG. 2 is a diagram of a high performance liquid chromatograph (HPLC) after the third step in this example. As shown in FIG. 2, it can be seen that extremely high purity 3,5-di-tert-butylsalicylic acid was produced.
（実施例２）
　本実施例は、例えば試作的、又は量産的に製造され得る量の３，５－ジ－ターシャリーブチルサリチル酸を得るための例である。 (Example 2)
This example is an example for obtaining 3,5-di-tert-butylsalicylic acid in an amount that can be produced, for example, on a trial basis or in mass production.
　本実施例においては、まず、反応溶媒である４－メチルテトラヒドロピラン４０Ｋｇと、２，４－ジターシャリーブチルフェノール３０．８Ｋｇと、４８．５％苛性ソーダ水１２．３Ｋｇとを、還流器を接続した２００Ｌが収容できるオートクレーブ反応器に導入した。その後、撹拌しながら、約１１０℃に加熱することにより、水の留出がなくなるまで第１工程を継続した。この例においては、第１工程が約６時間行われた。 In this example, first, 40 kg of 4-methyltetrahydropyran, which is a reaction solvent, 30.8 kg of 2,4-ditertiarybutylphenol, and 12.3 kg of 48.5% caustic soda water were added to a 200 L tank connected to a refluxer. was introduced into an autoclave reactor capable of accommodating Thereafter, the first step was continued by heating to about 110° C. while stirring until no water was distilled out. In this example, the first step was carried out for about 6 hours.
　その後、該還流器の還流経路を遮断し、反応温度が１０５℃～１１０℃となるように設定した状態で、内圧が０．５ＭＰａになるように二酸化炭素（ＣＯ２）を圧入する第２工程を行った。その後、二酸化炭素に消費が無くなったと考えられる状態になった後、前述の温度帯の条件下で、３時間継続的に撹拌した。その後、減圧下にて反応溶媒である４－メチルテトラヒドロピランを留去した。この段階での該反応溶媒の回収率は約９５％であった。 Thereafter, the reflux path of the reflux device is shut off, and while the reaction temperature is set at 105°C to 110°C, a second step is to pressurize carbon dioxide (CO 2 ) so that the internal pressure becomes 0.5 MPa. I did it. Thereafter, after reaching a state where it was considered that no consumption of carbon dioxide was reached, stirring was continued for 3 hours under the conditions of the above-mentioned temperature range. Thereafter, the reaction solvent 4-methyltetrahydropyran was distilled off under reduced pressure. The recovery rate of the reaction solvent at this stage was about 95%.
　第２工程を経ることによって得られた生成物（固体）を収容する反応容器内に、抽出溶媒（本実施例では、水）を導入することによって分液処理が施されたのち、ｐＨ値が４未満となるようにｐＨ値を調整するための硫酸が導入される第３工程が行われた。なお、本実施例のｐＨ値は約２～約３となった。 After a liquid separation process is performed by introducing an extraction solvent (in this example, water) into the reaction vessel containing the product (solid) obtained through the second step, the pH value is A third step was carried out in which sulfuric acid was introduced to adjust the pH value to below 4. Note that the pH value in this example was about 2 to about 3.
　その結果、析出した白色の固形物を濾過及び洗浄し、乾燥させると、３，５－ジ－ターシャリーブチルサリチル酸を約３４．７ｋｇ得ることができた。なお、本実施例の固形物における３，５－ジ－ターシャリーブチルサリチル酸の収率は約９２．８％であり、その純度は約９９．８％であった。 As a result, the precipitated white solid was filtered, washed, and dried to obtain about 34.7 kg of 3,5-di-tert-butylsalicylic acid. The yield of 3,5-di-tert-butylsalicylic acid in the solid material of this example was about 92.8%, and the purity was about 99.8%.
［比較例］
　次に、比較例について説明する。 [Comparative example]
Next, a comparative example will be explained.
（比較例１）
　本比較例においては、上述の実施例１における反応溶媒の４－メチルテトラヒドロピランの代わりに、トルエン１５０ｇを該溶媒として採用した点を除き、第１実施例の条件と同一の条件において各処理が行われた。 (Comparative example 1)
In this comparative example, each treatment was carried out under the same conditions as in the first example, except that 150 g of toluene was used as the reaction solvent in place of 4-methyltetrahydropyran as the reaction solvent in the above-mentioned example 1. It was conducted.
　その結果、第１工程の際に溶質が固化した。図３は、本比較例における第１工程後の、反応溶液（又は反応混合物）の光学写真である。図３中の矢印は、反応溶液を指すために描かれている。図３に示すように、図１の写真とは明らかに異なり、透明性が失われるとともに溶質の固化又は析出が非常に進んでいることが確認された。その後、本発明者らは、前述の状態であっても撹拌を継続し、その後、第２工程及び第３工程を行った。 As a result, the solute solidified during the first step. FIG. 3 is an optical photograph of the reaction solution (or reaction mixture) after the first step in this comparative example. Arrows in Figure 3 are drawn to point to the reaction solution. As shown in FIG. 3, it was clearly different from the photograph in FIG. 1, and it was confirmed that transparency was lost and solidification or precipitation of the solute was very advanced. Thereafter, the present inventors continued stirring even in the above-mentioned state, and then performed the second and third steps.
　その結果、析出した白色の固形物を濾過及び洗浄し、乾燥させると、３，５－ジ－ターシャリーブチルサリチル酸を約５９．３ｇ得ることができた。なお、本実施例の固形物における３，５－ジ－ターシャリーブチルサリチル酸の収率は約３６．２％であり、その純度は約９６．６％であった。 As a result, the precipitated white solid was filtered, washed, and dried to obtain about 59.3 g of 3,5-di-tert-butylsalicylic acid. The yield of 3,5-di-tert-butylsalicylic acid in the solid material of this example was about 36.2%, and its purity was about 96.6%.
（比較例２）
　本比較例においては、上述の実施例１における反応溶媒の４－メチルテトラヒドロピランの代わりに、トルエン１５０ｇ及び極性溶媒のＮＭＰ１５ｇを該溶媒として採用した点を除き、第１実施例の条件と同一の条件において各処理が行われた。 (Comparative example 2)
In this comparative example, the conditions were the same as in Example 1, except that 150 g of toluene and 15 g of NMP, a polar solvent, were used as the solvents instead of 4-methyltetrahydropyran, the reaction solvent in Example 1. Each treatment was performed under the following conditions.
　その結果、第１工程の際に溶質がスラリー化した。図４は、本比較例における第１工程後の、反応溶液（又は反応混合物）の光学写真である。図４中の矢印は、反応溶液を指すために描かれている。図４に示すように、図１の写真とは明らかに異なり、透明性が失われるとともに溶質の少なくとも一部の固化又は析出が進んでいることが確認された。その後、本発明者らは、前述の状態であっても撹拌を継続し、その後、第２工程及び第３工程を行った。 As a result, the solute became a slurry during the first step. FIG. 4 is an optical photograph of the reaction solution (or reaction mixture) after the first step in this comparative example. Arrows in Figure 4 are drawn to point to the reaction solution. As shown in FIG. 4, which is clearly different from the photograph in FIG. 1, it was confirmed that transparency was lost and at least a portion of the solute was solidified or precipitated. Thereafter, the present inventors continued stirring even in the above-mentioned state, and then performed the second and third steps.
　その結果、析出した白色の固形物を濾過及び洗浄し、乾燥させると、３，５－ジ－ターシャリーブチルサリチル酸を約６５．７ｇ得ることができた。なお、本実施例の固形物における３，５－ジ－ターシャリーブチルサリチル酸の収率は約４０．１％であり、その純度は約９８．４％であった。 As a result, the precipitated white solid was filtered, washed, and dried to obtain about 65.7 g of 3,5-di-tert-butylsalicylic acid. The yield of 3,5-di-tert-butylsalicylic acid in the solid material of this example was about 40.1%, and its purity was about 98.4%.
（比較例３）
　本比較例においては、本発明者らは、特許文献２の実施例１に記載された方法と同様に、反応溶媒を用いなかった（すなわち、無溶媒である）点を除き、第１実施例の条件と同一の条件において各処理を行おうと試みた。 (Comparative example 3)
In this comparative example, the present inventors performed the same method as the method described in Example 1 of Patent Document 2, except that no reaction solvent was used (that is, no solvent was used). An attempt was made to perform each treatment under the same conditions as those of .
　しかしながら、第１工程において固化が生じた結果、本発明者らは、工業的見地から継続不能あり、第２工程における圧力条件を採用することも不可能であると判断し、その後の処理を行うことを断念した。 However, as a result of solidification occurring in the first step, the present inventors determined that it was impossible to continue from an industrial standpoint, and that it was also impossible to adopt the pressure conditions in the second step, and therefore carried out the subsequent treatment. I gave up on that.
［各実施例と各比較例の一覧表］
　以下に、上述の各実施例及び各比較例の結果をまとめた表を示す。なお、表を見易くするために表内の数値については、「約」の文字が省略されている。また、比較例１及び２においては、既に説明したとおりの状況となったため、反応溶媒を回収することが困難又は不可能であった。 [List of Examples and Comparative Examples]
Below is a table summarizing the results of each of the above-mentioned Examples and Comparative Examples. In addition, in order to make the table easier to read, the character "about" has been omitted from the numerical values in the table. Furthermore, in Comparative Examples 1 and 2, the situation as already described occurred, and it was difficult or impossible to recover the reaction solvent.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　上述の実施形態及び各実施例は、本発明を何ら限定するものではない。上述の実施形態及び各実施例の他の組合せを含む本発明の範囲内に存在する変形例もまた、特許請求の範囲に含まれるものである。 The above-described embodiments and examples do not limit the present invention in any way. Variations that fall within the scope of the invention, including the embodiments described above and other combinations of the respective examples, are also within the scope of the claims.
　本発明の３，５－ジ－ターシャリーブチルサリチル酸の製造方法は、有用な化学物質の製造方法として、多様な用途の材料（例えば、医薬品の中間体又は複写機のトナー添加物等）の製造方法又はその一部として広く利用され得る。

  The method for producing 3,5-di-tert-butylsalicylic acid of the present invention can be used as a method for producing useful chemical substances, and for producing materials for various uses (for example, intermediates for pharmaceuticals or toner additives for copying machines). It can be widely used as a method or a part thereof.

Claims (4)

  1. 　４－メチルテトラヒドロピランを反応溶媒として、アルカリ金属水酸化物と化学式（１）で表わされる２，４－ジ－ターシャリーブチルフェノールとを反応させることにより、化学式（２）で表わされる該２，４－ジ－ターシャリーブチルフェノールの塩（但し、Ｘはアルカリ金属）を生成する第１工程と、
    　前記第１工程の後、前記反応溶媒と、前記２，４－ジ－ターシャリーブチルフェノールのアルカリ塩とを封入した、加熱した容器内に二酸化炭素を圧入することによって、３，５－ジ－ターシャリーブチルサリチル酸の塩を生成する第２工程と、
    　前記第２工程の後、ｐＨ値が４未満となるようにｐＨ値を調整するｐＨ値調整工程を行うことによって、化学式（３）で表わされる前記３，５－ジ－ターシャリーブチルサリチル酸を含む固形物を得る第３工程と、を含む、
    　３，５－ジ－ターシャリーブチルサリチル酸の製造方法。
    Figure JPOXMLDOC01-appb-C000001
         By reacting an alkali metal hydroxide with 2,4-di-tert-butylphenol represented by chemical formula (1) using 4-methyltetrahydropyran as a reaction solvent, the 2,4-di-tert-butylphenol represented by chemical formula (2) is produced. - a first step of producing a salt of di-tert-butylphenol (where X is an alkali metal);
    After the first step, carbon dioxide is pressurized into a heated container containing the reaction solvent and the alkali salt of 2,4-di-tert-butylphenol, thereby producing 3,5-di-tert-butylphenol. a second step of producing a salt of livtylsalicylic acid;
    After the second step, a pH value adjustment step is performed to adjust the pH value to less than 4, thereby containing the 3,5-di-tert-butylsalicylic acid represented by the chemical formula (3). a third step of obtaining a solid substance;
    A method for producing 3,5-di-tert-butylsalicylic acid.
    Figure JPOXMLDOC01-appb-C000001
  2. 　前記第２工程においては、前記二酸化炭素の圧力が０．０１ＭＰａ以上０．６ＭＰａ以下であり、且つ反応温度が９０℃以上１３０℃以下である、
    　請求項１に記載の３，５－ジ－ターシャリーブチルサリチル酸の製造方法。     In the second step, the pressure of the carbon dioxide is 0.01 MPa or more and 0.6 MPa or less, and the reaction temperature is 90° C. or more and 130° C. or less,
    A method for producing 3,5-di-tert-butylsalicylic acid according to claim 1.
  3. 　前記固形物の、前記３，５－ジ－ターシャリーブチルサリチル酸の収率が、８０％以上である、
    　請求項１又は請求項２に記載の３，５－ジ－ターシャリーブチルサリチル酸の製造方法。     The yield of the 3,5-di-tert-butylsalicylic acid in the solid is 80% or more;
    A method for producing 3,5-di-tert-butylsalicylic acid according to claim 1 or 2.
  4. 　前記反応溶媒の、前記２，４－ジ－ターシャリーブチルフェノールに対する質量比が、０．５以上３以下である、
    　請求項１又は請求項２に記載の３，５－ジ－ターシャリーブチルサリチル酸の製造方法。

          The mass ratio of the reaction solvent to the 2,4-di-tert-butylphenol is 0.5 or more and 3 or less,
    A method for producing 3,5-di-tert-butylsalicylic acid according to claim 1 or 2.
PCT/JP2023/003512 2022-04-06 2023-02-03 Method for producing 3,5-di-tertiary-butylsalicylic acid WO2023195222A1 (en)

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JPS6261949A (en) * 1985-09-11 1987-03-18 Daiei Kako Kk Production of 3,5-ditertiarybutylsalicylic acid
JPS63165341A (en) * 1986-12-27 1988-07-08 Honsyu Kagaku Kogyo Kk Production of 3,5-dialkylsalicylic acid
JPH0390047A (en) * 1989-09-01 1991-04-16 Yoshitomi Pharmaceut Ind Ltd Production of 3,5-dialkylsalicylic acid
JPH1087562A (en) * 1996-09-12 1998-04-07 Mitsui Petrochem Ind Ltd Production of 3,5-dialkyl salicylic acid
JPH10231271A (en) * 1996-10-02 1998-09-02 Mitsui Chem Inc Production of hydroxybenozoic acid
CN104086411A (en) * 2014-07-18 2014-10-08 甘肃省化工研究院 Method for synthesizing 3,5-di-tert-butyl-2-hydroxybenzoic acid

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JP6261949B2 (en) 2012-11-15 2018-01-17 住友化学株式会社 Resist composition and method for producing resist pattern
CN112020507B (en) 2018-04-24 2023-10-10 住友化学株式会社 Amide compound and method for producing polynucleotide using same

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Publication number Priority date Publication date Assignee Title
JPS6261949A (en) * 1985-09-11 1987-03-18 Daiei Kako Kk Production of 3,5-ditertiarybutylsalicylic acid
JPS63165341A (en) * 1986-12-27 1988-07-08 Honsyu Kagaku Kogyo Kk Production of 3,5-dialkylsalicylic acid
JPH0390047A (en) * 1989-09-01 1991-04-16 Yoshitomi Pharmaceut Ind Ltd Production of 3,5-dialkylsalicylic acid
JPH1087562A (en) * 1996-09-12 1998-04-07 Mitsui Petrochem Ind Ltd Production of 3,5-dialkyl salicylic acid
JPH10231271A (en) * 1996-10-02 1998-09-02 Mitsui Chem Inc Production of hydroxybenozoic acid
CN104086411A (en) * 2014-07-18 2014-10-08 甘肃省化工研究院 Method for synthesizing 3,5-di-tert-butyl-2-hydroxybenzoic acid

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