Method for producing 2-m-hydroxyphenylacetic acid, and 2-m-hydroxyphenylacetic acid

Abstract

[Problem] The present invention provides: a method for safely and efficiently producing 2-m-hydroxyphenylacetic acid; and 2-m-hydroxyphenylacetic acid. [Solution] A method for producing 2-m-hydroxyphenylacetic acid, which is one aspect of the present invention, comprises: a first step in which m-hydroxybenzaldehyde and a Wittig reactant that is represented by general formula (I) and in an amount equal to or greater than 2 molar equivalents with respect to the m-hydroxybenzaldehyde are reacted with each other so as to produce an m-hydroxystyryl methyl ether; a second step in which 2-(m-hydroxyphenyl)acetaldehyde is generated by an acid hydrolysis reaction of the m-hydroxystyryl methyl ether; and a third step in which the 2-(m-hydroxyphenyl)acetaldehyde is treated with an oxidant. In addition, in this method for producing 2-m-hydroxyphenylacetic acid, the second step and the third step are performed in-situ.　General formula (I): H3C-O-CH=PPh3

Description

Method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid

[0001] The present invention relates to a method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid.

[0002] 2-m-Hydroxyphenylacetic acid is a very useful chemical product as a starting material for at least preparations for the prevention or treatment of allergic inflammatory skin diseases or skin barrier dysfunction (Patent Document 1), a chemical substance for maintaining the freshness of plants and / or promoting their continued growth (Patent Document 2), and methyl carboxymethylphenylaminocarboxypropylphosphonate (also known as Nahlsgen (registered trademark)), an anti-aging agent that has been found to have activity as a GGT inhibitor (Patent Document 3) and is added to cosmetics and the like.

[0003] Incidentally, 2-m-hydroxyphenylacetic acid is thought to be a substance obtained by converting the methyl group of m-crezol to a halogen, converting the resulting m-hydroxyphenyl halide to m-hydroxyphenyl cyanide, and then hydrolyzing it using a CN (cyanide) source (NaCN or KCN). Furthermore, the development of another CN source, TMSCN (trimethylsilyl cyanide), has made it possible to use it as a naked CN source using F anions (Y. Yamasaki et al., Chem Lett. 1985, 1387-1390, and the references cited in).

[0004] The possibility of producing 2-m-hydroxyphenylacetic acid using the Willgerodt reaction has also been disclosed in the past (Non-Patent Document 2), in which a sulfur (S)-based reactant is used.

[0005] Patent No. 6550656 Patent No. 6457292 Patent No. 5082102

[0006] J Am Chem Soc, 2008, 130, 13110 J Am Chem Soc, 1946, 68 (12), 2633-2634

[0007] However, at least in Japan, where safety regulations are strict, it is not practical to use a CN (cyanide) source in the production process. Even if TMSCN could be used, the TMSCN and reaction medium are expensive, which may cause problems with production costs as well as safety.

[0008] Furthermore, even if the sulfur-based reactant disclosed in Non-Patent Document 2 is used, it is difficult to adopt it from an industrial point of view because it requires equipment to deal with the odor of sulfur-based gas and the number of steps required to obtain 2-m-hydroxyphenylacetic acid is large.

[0009] The present inventors have intensively researched a method for producing 2-m-hydroxyphenylacetic acid, based on the awareness of the need to improve safety and reduce the number of steps compared to the above-mentioned known techniques. As a result of repeated trial and error as well as meticulous analysis and investigation, the present inventors have concluded that using m-hydroxybenzaldehyde or an alkali metal salt of said m-hydroxybenzaldehyde as a starting material and employing the Wittig reaction from among many possible reactions may enable the production of 2-m-hydroxyphenylacetic acid safely and with fewer steps, and have therefore continued their research.

[0010] However, the inventors encountered a major obstacle while conducting research into a new production method. Specifically, when m-hydroxybenzaldehyde, which is commercially available and therefore easily available, is used as a starting material, it is difficult to apply the Wittig reaction to the starting material, which is a derivative that generally has an acidic proton, such as a hydroxy group, in its molecule, because the Wittig reaction is a non-aqueous reaction.

[0011] Furthermore, when the above-mentioned m-hydroxybenzaldehyde or an alkali metal salt of the m-hydroxybenzaldehyde is used as a starting material, there arises a problem that it becomes difficult to remove the reaction mixture resulting from the Wittig reaction by separation and filtration using a known mineral oil solvent. More specifically, when the above-mentioned starting materials are used in the Wittig reaction, triphenylphosphine oxide (Ph), a typical by-product of the reaction, is easily produced. ３ It has become apparent that removal of reaction mixtures containing PO (triphenylphosphine oxide) is difficult.

[0012] Therefore, the present inventors attempted to react m-hydroxybenzaldehyde as a starting material with a Wittig reagent represented by the following general formula (I), which is a 2-methoxymethyl triphenylphosphazene derivative, in an amount that greatly exceeds the reaction equivalent of the Wittig reaction.

[0013]

[0014] As a result, it was discovered that the following two unique effects (a) and (b) can occur: (a) A portion of the Wittig reagent can substitute a phosphinium group for the proton of the hydroxy group of the starting material m-hydroxybenzaldehyde. (b) Another portion of the Wittig reagent can react with the aldehyde group of the starting material to generate an enol derivative, increasing the carbon number by one (one-carbon homologation reaction).

[0015] Generally, those skilled in the art would consider the Wittig reaction to be incompatible with starting materials having hydroxy groups because the reaction is non-aqueous. However, the notable feature of the above-mentioned attempt is that by introducing a Wittig reagent in an amount that greatly exceeds the reaction equivalent of the Wittig reaction, the above-mentioned effect (a), i.e., the substitution of the hydroxy group proton with a phosphinium group derived from the Wittig reagent, makes it possible to use starting materials having hydroxy groups, which were previously considered incompatible.

[0016] In addition, the Wittig reactant H ３ C-O-CH=PPh ３ is not limited to being used as a preformed compound. For example, (methoxymethyl)triphenylphosphonium chloride (H ３ C-O-CH ２ -P ＋ (Cl － ) Ph ３ ) with a strong base (e.g., potassium tert-butoxide) in situ to give the Wittig reagent H ３ C-O-CH=PPh ３ Therefore, in the present application, the Wittig reaction of the Wittig reagent that can be produced from the raw material compound with m-hydroxybenzaldehyde, which is the starting material, can also be carried out by the Wittig reaction of H ３ C-O-CH=PPh ３ as a Wittig reaction agent.

[0017] The above attempt is for the first step (reaction step) of obtaining 2-m-hydroxyphenylacetic acid by the following chemical reaction formula (II). As described above, the Wittig reactant is reacted with the above-mentioned m-hydroxybenzaldehyde in an amount that greatly exceeds the reaction equivalent of the Wittig reaction (X in the following chemical reaction formula (II)). １It is worth noting that by using the above-mentioned reaction formula (II), it is possible to make the Wittig reagent play the two roles described above. ３ C-O-CH=PPh ３ This is the reaction equation when

[0018]

[0019] Here, X in the above chemical reaction formula (II) １ In order to realize the step (chemical reaction step) shown in Figure 1 with high accuracy, it is a preferred embodiment to react the m-hydroxybenzaldehyde with a Wittig reaction agent in an amount of at least twice (more preferably more than twice, and even more preferably at least 2.1 times) the reaction equivalent of the Wittig reaction. This is because if the starting material m-hydroxybenzaldehyde remains in the reaction system, it will be difficult to obtain a sufficient amount of the Z reaction product in the subsequent step. １ This is because, in the oxidation reaction shown in step (2), the remaining m-hydroxybenzaldehyde is oxidized to produce m-hydroxybenzoic acid, which then produces a mixture with 2-m-hydroxyphenylacetic acid. Because m-hydroxybenzoic acid and 2-m-hydroxyphenylacetic acid differ only by a single methylene chain, it is virtually impossible to distinguish 2-m-hydroxyphenylacetic acid through various analytical methods or to isolate and extract only 2-m-hydroxyphenylacetic acid. As a result, the desired 2-m-hydroxyphenylacetic acid and m-hydroxybenzoic acid are mixed together, resulting in problems such as reduced utility as a chemical product, as described in the Background Art section above.

[0020] On the other hand, X in the above chemical reaction formula (II) １ There is no particular upper limit to the amount of Wittig reagent introduced in order to achieve with high accuracy the step (reaction step) shown in (1). Note that, from the viewpoint of the economic disadvantage of introducing an unnecessarily large amount, the prevention or suppression of the effects of side reactions, and / or optimization of the accompanying purification step, it is a preferred embodiment that the amount of Wittig reagent is 3 times or less (more preferably 2.5 times or less) the reaction equivalent amount of the Wittig reagent.

[0021] Furthermore, in the course of the research, the inventors have found that Y in the chemical reaction formula (II) １ and Z １ In order to reliably realize each step (reaction step) shown in the table below, i.e., the step of obtaining 2-m-hydroxyphenylacetic acid from the produced enol derivative via acid hydrolysis, a new obstacle had to be overcome.

[0022] Specifically, the enol derivative is easily hydrolyzed under acidic conditions. Therefore, it is possible to produce 2-(m-hydroxyphenyl)acetaldehyde, which is one carbon atom larger than the starting material m-hydroxybenzaldehyde. However, it has been confirmed that 2-(m-hydroxyphenyl)acetaldehyde is an unstable compound that is very difficult to isolate.

[0023] As a result of further research and analysis, the present inventors have found that 2-m-hydroxyphenylacetic acid can be produced by carrying out an oxidation reaction in situ in the reaction medium of the acid hydrolysis reaction without isolating the 2-(m-hydroxyphenyl)acetaldehyde.

[0024] As a result, the present inventors have found that 2-m-hydroxyphenylacetic acid can be produced safely and efficiently from commercially available starting materials without using any toxic CN-source reactants or sulfur-based reactants that require odor control, and without going through multiple steps. One aspect of the present invention was created based on the above-mentioned perspective and process.

[0025] One method for producing 2-m-hydroxyphenylacetic acid of the present invention comprises the following steps: a first step of producing m-hydroxystyryl methyl ether by reacting m-hydroxybenzaldehyde with a Wittig reagent represented by general formula (I) in an amount of 2 molar equivalents or more relative to the m-hydroxybenzaldehyde; a second step of producing 2-(m-hydroxyphenyl)acetaldehyde by acid hydrolysis of the m-hydroxystyryl methyl ether; and a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent. Additionally, in this method for producing 2-m-hydroxyphenylacetic acid, the second and third steps are carried out in situ.

[0026]

[0027] According to this method for producing 2-m-hydroxyphenylacetic acid, in the first step (X in the above-mentioned chemical reaction formula (II)), １ In the second step (corresponding to the reaction step (II)), by reacting 2 molar equivalents or more of the Wittig reagent with the starting material m-hydroxybenzaldehyde, it is possible to produce m-hydroxystyryl methyl ether from the starting material with high accuracy. In other words, it is possible to reduce the amount of the starting material remaining after the first step with high accuracy. １ The third step (corresponding to the reaction step of Z in the above-mentioned chemical reaction formula (II)) １ By carrying out the above steps in situ (corresponding to the reaction step (a) of (b)) and (c) in situ, 2-m-hydroxyphenylacetic acid can be produced with high accuracy. Note that, when this production method is adopted, it is not necessary to prepare an alkali metal salt of m-hydroxybenzaldehyde in advance, as compared with another production method of 2-m-hydroxyphenylacetic acid that uses an alkali metal salt of m-hydroxybenzaldehyde as a starting material, as will be described later. From this perspective, materials for such preparation are not required, and the production process can be simplified.

[0028] Furthermore, in the course of research, the present inventors attempted to use an alkali metal salt of m-hydroxybenzaldehyde as a starting material in place of m-hydroxybenzaldehyde, which is the starting material in the above-mentioned Step 1. As a result, it became clear that the amount of the Wittig reaction agent represented by the above-mentioned general formula (I) used could be reduced.

[0029] The following chemical reaction formula (III) is a reaction formula when a sodium (Na) salt of m-hydroxybenzaldehyde, which is an example of an alkali metal salt of m-hydroxybenzaldehyde, is used. As shown in chemical reaction formula (III), when a sodium (Na) salt of m-hydroxybenzaldehyde is used as a starting material, the Wittig reagent does not essentially need to play the role (a) of the two roles (a) and (b) described above. Therefore, the present inventors have discovered that by introducing the Wittig reagent in an amount necessary to play the role (b), in other words, to play the carbon-increasing reaction, it is possible to achieve the same effect as in the first step of the above-mentioned method for producing 2-m-hydroxyphenylacetic acid when m-hydroxybenzaldehyde is used as a starting material.

[0030]

[0031] In the above description, the sodium (Na) salt of m-hydroxybenzaldehyde is described as an example of an alkali metal salt of m-hydroxybenzaldehyde, but the alkali metal salt of m-hydroxybenzaldehyde is not limited to the sodium (Na) salt of m-hydroxybenzaldehyde. Potassium (K) salt of m-hydroxybenzaldehyde can also achieve the same results as the sodium (Na) salt.

[0032] Therefore, X in the above chemical reaction formula (III) ２The amount of Wittig reagent introduced to achieve the step (reaction step) shown in (1) with high accuracy may be equal to or greater than the reaction equivalent of the alkali metal salt of m-hydroxybenzaldehyde. The upper limit of the amount introduced is not particularly limited. However, from the viewpoint of the economic disadvantage of introducing an unnecessarily large amount, preventing or suppressing the effects of side reactions, and / or optimizing the accompanying purification step, it is a preferred embodiment to use an amount less than 2 times the reaction equivalent of the Wittig reagent (more preferably 1.5 times or less).

[0033] In addition, Y in the chemical reaction formula (III) ２ and Z ２ The technical problems in each step (reaction step) shown in the above are the same as those in the case where m-hydroxybenzaldehyde is used as the starting material, and the present inventors have found that these problems can be overcome by employing the same means for solving the problems as described above.

[0034] As a result, the present inventors have found that by using an alkali metal salt of m-hydroxybenzaldehyde as a starting material, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without using any toxic CN-source reactants or sulfur-based reactants that require odor control. Another aspect of the present invention was created based on this viewpoint and process.

[0035] Another method for producing 2-m-hydroxyphenylacetic acid of the present invention comprises the following steps: a first step of producing m-hydroxystyryl methyl ether by reacting an alkali metal salt of m-hydroxybenzaldehyde with a Wittig reactant represented by general formula (I) in an amount equal to or greater than a reactive equivalent of the alkali metal salt; a second step of producing 2-(m-hydroxyphenyl)acetaldehyde by acid hydrolysis of the m-hydroxystyryl methyl ether; and a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent. Additionally, in this method for producing 2-m-hydroxyphenylacetic acid, the second and third steps are carried out in situ.

[0036]

[0037] According to this production method, by using an alkali metal salt of m-hydroxybenzaldehyde as a starting material in the first step, the amount of the Wittig reactant when reacting the alkali metal salt with the Wittig reactant represented by the general formula (I) described above is sufficient as long as it is equal to or greater than the reaction amount. In other words, it is possible to reduce the amount of the Wittig reactant to a level lower than when m-hydroxybenzaldehyde is used as a starting material. Furthermore, in the second step of this production method (Y in the chemical reaction formula (III) described above), ２ The third step (corresponding to the reaction step of Z in the above-mentioned chemical reaction formula (III)) ２ By carrying out the above steps in situ (corresponding to the reaction step (a) above), 2-m-hydroxyphenylacetic acid can be produced with high accuracy.

[0038] Furthermore, the 2-m-hydroxyphenylacetic acid composition of the present invention contains less than 0.1 wt % of m-hydroxybenzaldehyde.

[0039] By employing the above-described method for producing 2-m-hydroxyphenylacetic acid, this 2-m-hydroxyphenylacetic acid composition can produce highly pure 2-m-hydroxyphenylacetic acid in which the amount of the starting material m-hydroxybenzaldehyde, i.e., the residual amount of m-hydroxybenzaldehyde, is reduced to less than 0.1 wt%. Furthermore, this 2-m-hydroxyphenylacetic acid composition is highly safe because it does not contain toxic CN-source reactants or sulfur-based reactants that require odor control. In this application, the term "2-m-hydroxyphenylacetic acid composition" refers to a composition that may contain, in addition to 2-m-hydroxyphenylacetic acid, other substances (e.g., the starting material m-hydroxybenzaldehyde or an alkali metal salt of said m-hydroxybenzaldehyde, or by-products generated during the production process of said 2-m-hydroxyphenylacetic acid), and the composition of the "2-m-hydroxyphenylacetic acid composition" is not particularly limited.

[0040] According to one method for producing 2-m-hydroxyphenylacetic acid of the present invention, m-hydroxystyryl methyl ether can be produced with high accuracy from the starting material. Furthermore, by performing the second step (corresponding to the acid hydrolysis step) and the third step (corresponding to the oxidation step) of this production method in situ, 2-m-hydroxyphenylacetic acid can be produced with high accuracy, in which a carbon-increasing reaction is realized from the starting material. Additionally, according to this production method, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without using any toxic CN-source reactants or sulfur-based reactants that require odor control.

[0041] Furthermore, one 2-m-hydroxyphenylacetic acid composition of the present invention can produce highly pure 2-m-hydroxyphenylacetic acid in which the amount of m-hydroxybenzaldehyde (the starting material), i.e., the residual amount of m-hydroxybenzaldehyde, is reduced to less than 0.1 wt %. Furthermore, this 2-m-hydroxyphenylacetic acid composition is highly safe because it does not contain any toxic CN-source reactants or sulfur-based reactants that require odor control.

[0042] FIG. 1 is a diagram of HPLC (high performance liquid chromatography) at an intermediate stage of the first step immediately after the completion of the dropwise addition of m-hydroxybenzaldehyde, a starting material, into the reaction mixture under predetermined temperature conditions after the preparation of the Wittig reaction agent in Example 1. FIG. 2 is a diagram of HPLC after the first step (Wittig reaction) in Example 1. FIG. 3 is a diagram of HPLC after the second step (acid hydrolysis reaction) in Example 1. FIG. 4 is a diagram of HPLC after the third step (oxidation reaction) in Example 1. FIG. 5 is a diagram of proton nuclear magnetic resonance (NMR) of the purified product obtained after the third step (oxidation reaction) in Example 1. １ 1H NMR) spectrum of the purified product obtained after the third step (oxidation reaction) in Example 1. １３ 1 is a diagram of the IR spectrum (infrared absorption spectrum) of the purified product obtained after the third step (oxidation reaction) in Example 1.

[0043] First Embodiment Hereinafter, a method for producing 2-m-hydroxyphenylacetic acid in this embodiment and the 2-m-hydroxyphenylacetic acid will be described.

[0044] <Method for Producing 2-m-Hydroxyphenylacetic Acid> In this embodiment, a method for producing 2-m-hydroxyphenylacetic acid using m-hydroxybenzaldehyde as a starting material will be described.

[0045] In this embodiment, the Wittig reactant H ３ C-O-CH=PPh ３ In order to carry out the Wittig reaction of m-hydroxybenzaldehyde as a starting material with (methoxymethyl)triphenylphosphonium chloride (H), the following reaction steps (A) and (B) are carried out in a solvent (e.g., toluene or tetrahydrofuran) commonly used in Wittig reactions. Therefore, the reaction steps (A) and (B) are carried out in situ, so to speak. (A) The starting compound (methoxymethyl)triphenylphosphonium chloride (H) is commercially available. ３ C-O-CH ２ -P ＋ (Cl － ) Ph ３ (B) reacting m-hydroxybenzaldehyde with a strong base (e.g., potassium tert-butoxide) to form the Wittig reagent; and (C) subsequent to the reaction in (A), carrying out a Wittig reaction between m-hydroxybenzaldehyde and the Wittig reagent to form m-hydroxystyryl methyl ether.

[0046] More specifically, after the above-mentioned reaction step (A), i.e., the step of producing the Wittig reactant, the starting material m-hydroxybenzaldehyde can be introduced into a vessel (e.g., a flask) containing the Wittig reactant, thereby realizing the production of m-hydroxystyryl methyl ether based on an in-situ Wittig reaction. By carrying out reaction steps (A) and (B) in-situ as in this embodiment, commercially available raw material compounds can be used, and there is no need to isolate the Wittig reactant, making it possible to produce m-hydroxystyryl methyl ether very efficiently and with little waste in terms of yield.

[0047] Here, from the viewpoint of ensuring a high degree of certainty in the above-mentioned reaction step (B), it is a preferred embodiment that the amount of the Wittig reactant produced in the above-mentioned reaction step (A) is an amount that greatly exceeds the reaction equivalent in the Wittig reaction relative to the starting material, more specifically, 2 molar equivalents or more, or that the amounts of the above-mentioned raw material compound and strong base are adjusted to achieve such an amount. As already mentioned, reducing the amount of the starting material (m-hydroxybenzaldehyde) remaining after the reaction step (B) as much as possible leads to a high degree of certainty in preventing the production of m-hydroxybenzoic acid, an unnecessary and difficult-to-isolate by-product, after the third step described below.

[0048] From the viewpoint of more reliably preventing the production of m-hydroxybenzoic acid as a by-product, it is a more preferred embodiment to react m-hydroxybenzaldehyde as a starting material with the Wittig reagent in an amount of more than 2 molar equivalents (more preferably 2.1 molar equivalents or more) relative to the m-hydroxybenzaldehyde.

[0049] In addition, in both the reaction step (A) and the reaction step (B), it is preferable to carry out the reaction while cooling and stirring. In addition, the reaction step (B) is the first step in this embodiment (X in the chemical reaction formula (II) already explained). １ (This corresponds to the reaction process shown above.)

[0050] In this embodiment, the organic layer is obtained by separating the reaction mixture containing m-hydroxystyryl methyl ether obtained in step 1 (including unreacted compounds) with aqueous hydrochloric acid having a concentration of several wt %. After separating the organic layer with aqueous hydrochloric acid and water, the solvent from step 1 is distilled off under reduced pressure, and a solution of an ester such as ethyl acetate is added and stirred. The precipitated solid is then filtered under cooling. The solution of ester such as ethyl acetate is then distilled off from the obtained organic layer under reduced pressure to obtain a viscous solid, which is the crude m-hydroxystyryl methyl ether. In this embodiment, the viscous solid is a mixture (i.e., a viscous mixture) of the crude m-hydroxystyryl methyl ether and a portion of the by-products of the Wittig reaction produced in step 1 described above.

[0051] Then, in this embodiment, the second step (already explained, Y １ (corresponding to the reaction step of

[0052] As a specific example, the second step is a step of diluting the viscous mixture containing m-hydroxystyryl methyl ether obtained in the first step with, for example, an organic solvent (e.g., acetonitrile), and then adding hydrochloric acid to the container containing the mixture to cause an acid hydrolysis reaction. Note that, although hydrochloric acid is used for the acid hydrolysis reaction in this embodiment, at least some of the effects of this embodiment can be achieved even if dilute sulfuric acid, methylsulfonic acid, p-toluenesulfonic acid, or the like is used instead of hydrochloric acid.

[0053] In this embodiment, after a sufficient time has elapsed to cause the acid hydrolysis reaction of m-hydroxystyryl methyl ether, the reaction mixture (typically 2-(m-hydroxyphenyl)acetaldehyde) is not taken out, that is, the subsequent third step (Z in the chemical reaction formula (II) as already explained) is carried out in situ. １ (corresponding to the reaction step of

[0054] As a specific example, the third step is a step of adding an oxidizing agent to the reaction system in which the second step has been carried out under appropriate temperature control, and the oxidation reaction of 2-(m-hydroxyphenyl)acetaldehyde with the oxidizing agent produces a reaction mixture containing 2-m-hydroxyphenylacetic acid.

[0055] In this embodiment, the solid is filtered from the reaction mixture, and the organic solvent is removed from the filtrate under reduced pressure. An ester solution such as ethyl acetate and sodium hydroxide (NaOH) are then added and stirred to obtain an alkaline aqueous solution through phase separation. This embodiment employs the organic layer obtained by adding the ester solution and concentrated hydrochloric acid to the aqueous solution and performing phase separation. The ester solution is removed from the organic layer under reduced pressure to obtain a viscous solid crude product of 2-m-hydroxyphenylacetic acid.

[0056] The crude product can be purified, for example, by heating the crude product under reflux with a large amount of organic solvent (e.g., toluene), filtering the product, and cooling the filtrate to precipitate a light brown solid substance, which is purified 2-m-hydroxyphenylacetic acid.

[0057] The third step, which involves treatment with an oxidizing agent, is preferably carried out at a temperature of −10° C. or higher and 10° C. or lower. If the third step is carried out at a temperature below −10° C., the conversion of the produced 2-(m-hydroxyphenyl)acetaldehyde to the target 2-m-hydroxyphenylacetic acid in situ is extremely slow and industrially impractical. If the third step is carried out at a temperature above 10° C., oxygen radicals attack the methylene carbon, which is the carbon that has been increased, causing a cleavage reaction and then providing an oxidation reaction, which can give m-hydroxybenzoic acid (the same compound as the oxidation product of the starting material).

[0058] The type of oxidizing agent capable of realizing the reaction in the third step is not limited as long as it satisfies the following requirements (x) and (y): (x) an oxidizing agent capable of realizing a reaction that converts the aldehyde group in 2-(m-hydroxyphenyl)acetaldehyde into a carboxyl group; and (y) an oxidizing agent that is unlikely to cause a secondary reaction with a functional group other than the aldehyde group.

[0059] In view of the above, it is a preferred aspect of this embodiment that the oxidizing agent used in the third step is at least one selected from the group consisting of peroxides including hydroxyperoxide and Oxone (registered trademark) (2KHSO.KHSO.KSO). Of the two examples of oxidizing agents mentioned above, the use of Oxone is particularly preferred as it most reliably produces the effects of this embodiment.

[0060] By employing the method for producing 2-m-hydroxyphenylacetic acid of this embodiment, m-hydroxystyryl methyl ether can be produced with high accuracy from the starting material m-hydroxybenzaldehyde. In other words, the amount of the starting material remaining after the first step can be reduced with high accuracy. Furthermore, by performing the second and third steps of this production method in situ, 2-m-hydroxyphenylacetic acid can be produced with high accuracy. It is also noteworthy that by employing the method for producing 2-m-hydroxyphenylacetic acid of this embodiment, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without using any toxic CN source reactants or sulfur-based reactants that require odor control, and without going through multiple steps.

[0061] In addition, by employing the method for producing 2-m-hydroxyphenylacetic acid of this embodiment, the amount of the remaining starting material can be reduced with high certainty, as described above, and therefore the amount of m-hydroxybenzaldehyde contained in the 2-m-hydroxyphenylacetic acid composition produced by this production method can be reduced to less than 0.1 wt %.

[0062] Second Embodiment Hereinafter, a method for producing 2-m-hydroxyphenylacetic acid in this embodiment, which is different from that in the first embodiment, will be described.

[0063] <Method for Producing 2-m-Hydroxyphenylacetic Acid> In this embodiment, a method for producing 2-m-hydroxyphenylacetic acid using an alkali metal salt of m-hydroxybenzaldehyde as a starting material will be described.

[0064] As already explained, chemical reaction formula (III) is a reaction formula when sodium (Na) salt of m-hydroxybenzaldehyde, which is an example of an alkali metal salt of m-hydroxybenzaldehyde, is used. Note that although a pre-existing alkali metal salt of m-hydroxybenzaldehyde may be used as a starting material, one embodiment that can be adopted is to produce an alkali metal salt of m-hydroxybenzaldehyde from a raw material compound of the alkali metal salt of m-hydroxybenzaldehyde.

[0065] As described above, in this embodiment, an alkali metal salt of m-hydroxybenzaldehyde is used as a starting material. The synthesis example of m-hydroxybenzaldehyde sodium salt, which is a representative example of an alkali metal salt of m-hydroxybenzaldehyde, from the raw material compound m-hydroxybenzaldehyde is as follows.

[0066] The raw material compound m-hydroxybenzaldehyde (Mw=122.12, 204.7 mmol) is placed in 100 mL (milliliters) of methanol, and 39.5 g of a 28 wt % sodium methoxide methanol solution (Mw=54.01, 204.7 mmol) is added dropwise while stirring at a temperature of 0°C to 5°C. This process produces a reaction mixture.

[0067] The reaction mixture was then returned to room temperature, and the methanol solvent was distilled off under reduced pressure. The resulting solid was dried under reduced pressure at 50°C for approximately 12 hours to obtain m-hydroxybenzaldehyde sodium (Na) salt (Mw = 144.1, 29.49 g) as a pale yellow crystal, which is the starting material of this embodiment.

[0068] <Synthesis process of starting material> The m-hydroxybenzaldehyde sodium (Na) salt synthesized as described above is reacted with a Wittig reactant, H ３ C-O-CH=PPh ３ m-Hydroxystyryl methyl ether is produced by a reaction with (Wittig reaction) (first step in this embodiment).

[0069] In this embodiment, unlike the first embodiment, the amount of the Wittig reagent introduced may be equal to or greater than the reaction equivalent of the alkali metal salt of m-hydroxybenzaldehyde (sodium salt in the above example). This is because, in the starting material of this embodiment, the protons of the hydroxy groups have already been substituted with sodium groups, and therefore the influence of the hydroxy groups during the Wittig reaction is substantially eliminated.

[0070] The subsequent second step in this embodiment (already described, Y in chemical reaction formula (III) ２ The second step of the first embodiment (corresponding to the acid hydrolysis reaction step of Y in chemical reaction formula (II) as already explained) １ This is the same step as the subsequent third step in this embodiment (corresponding to the acid hydrolysis reaction step of Z in chemical reaction formula (III) as already explained). ２ The third step of the first embodiment (corresponding to the oxidation reaction step of Z in chemical reaction formula (II)) corresponds to the oxidation reaction step of １ This is the same process as the acid hydrolysis reaction process in (corresponding to the acid hydrolysis reaction process in (1)).

[0071] As described above, even when the starting material is an alkali metal salt of m-hydroxybenzaldehyde, 2-m-hydroxyphenylacetic acid can be produced with high accuracy by performing the second and third steps in situ, as in Embodiment 1. It is also noteworthy that by employing the method for producing 2-m-hydroxyphenylacetic acid of this embodiment, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without using any toxic CN source reactants or sulfur-based reactants that require odor control, as in Embodiment 1.

[0072] EXAMPLES The above-described embodiments will be described in detail through the following examples, but the scope of the present invention and the embodiments is not limited by the descriptions of the examples.

[0073] (Example 1) [Method for producing 2-m-hydroxyphenylacetic acid when m-hydroxybenzaldehyde is used as the starting material]

[0074] (Production of Wittig Reagent Used in Step 1) In this example, 206 g (0.6 mol) of the raw material compounds (methoxymethyl)triphenylphosphonium chloride and 74.1 g (0.66 mol) of potassium tert-butoxide were reacted in a flask containing 300 mL of an organic solvent (toluene) while flowing nitrogen gas and controlling the temperature of the reaction system to 5° C. or less. As a result, the Wittig reagent, H ３ C-O-CH=PPh ３ is generated.

[0075] (Step 1) Then, 30.6 g (0.251 mol) of m-hydroxybenzaldehyde was added to the reaction system in which the Wittig reagent had been produced, with the temperature of the reaction system controlled to 20° C. or less, and the mixture was stirred at room temperature. In this example, the amount of the Wittig reagent produced in the step of producing the Wittig reagent was approximately 2.4 molar equivalents of the starting material m-hydroxybenzaldehyde.

[0076] Thereafter, the first reaction mixture (containing unreacted compounds) from the first step was cooled to about 10° C., and the organic layer was separated using 100 g of ice and 200 g of 5% aqueous hydrochloric acid. After further separation of the organic layer using aqueous hydrochloric acid and water, the organic solvent toluene was distilled off under reduced pressure, and 100 mL of ethyl acetate was added and stirred at a temperature of about 0° C. As a result, a viscous mixture (first mixture) containing a crude m-hydroxystyryl methyl ether and a by-product of the Wittig reaction was obtained.

[0077] FIG. 1 is an HPLC (high performance liquid chromatography) diagram of the intermediate stage of Step 1 in this example, immediately after the dropwise addition of the starting material, m-hydroxybenzaldehyde, to the reaction mixture under predetermined temperature conditions after preparation of the Wittig reactant. FIG. 2 is an HPLC diagram of Step 1 (Wittig reaction) in this example. In the diagram, P1 is the Wittig reactant, and Q1 is the starting material (m-hydroxybenzaldehyde). R1 ​​is a by-product of the Wittig reaction, and S1 is m-hydroxystyryl methyl ether, the product of the Wittig reaction. T1 is toluene, the solvent. In HPLC diagrams other than FIG. 1, common symbols are used for common compounds unless otherwise noted.

[0078] 1 and 2, as the Wittig reaction proceeds, the Q1 peak, which indicates the starting material, becomes smaller, and after the first step in this example, the Q1 peak becomes so small that it is barely detectable. Therefore, as described above, the amount of the Wittig reaction agent in the Wittig reaction, which is 2 or more molar equivalents (e.g., about 2.4 molar equivalents) of m-hydroxybenzaldehyde, the starting material, reacts with the starting material, making it possible to reduce the amount of the remaining starting material with high accuracy.

[0079] (Second Step) After that, the first mixture was diluted with 300 ml of acetonitrile, and then hydrochloric acid prepared by adding 5 g of concentrated hydrochloric acid to 5 g of water was added to the container containing the first mixture, and the mixture was stirred at room temperature to carry out an acid hydrolysis reaction (the already explained Y in chemical reaction formula (II)). １ This reaction corresponds to the reaction step (

[0080] 3 is an HPLC diagram after the second step (acid hydrolysis reaction) in this example, where U1 is 2-(m-hydroxyphenyl)acetaldehyde and V1 is residual ethyl acetate.

[0081] In this example, after a sufficient time (for example, 12 hours) has elapsed until the second step is completed, the reaction mixture (second mixture) containing 2-(m-hydroxyphenyl)acetaldehyde is not taken out, that is, the subsequent third step (Z in the chemical reaction formula (II) already explained) is carried out in situ. １ (corresponding to the reaction step of

[0082] (Third Step) As described above, 153.7 g of Oxone (registered trademark) (2KHSO.KHSO.KSO) serving as an oxidizing agent was added in situ to a vessel containing the second mixture at a temperature of 0° C. or higher and 5° C. or lower, followed by stirring, to obtain a reaction mixture (third mixture) containing 2-m-hydroxyphenylacetic acid.

[0083] The acetonitrile was distilled off under reduced pressure from the filtrate obtained by filtering the solid from the third mixture, and then 240 mL of ethyl acetate and a 10 wt % aqueous solution of sodium hydroxide (NaOH) were added and stirred, and an alkaline aqueous solution was obtained through liquid separation.

[0084] Thereafter, 300 mL of ethyl acetate and approximately 80 g of concentrated hydrochloric acid were added to the aqueous solution and stirred, and the organic layer obtained by separation was distilled under reduced pressure to remove the ethyl acetate, yielding a crude product of 2-m-hydroxyphenylacetic acid as a viscous solid.

[0085] To purify the crude product, toluene in an amount approximately 10 times the volume of the crude product and a small amount of activated carbon were added to the container containing the crude product, and the mixture was heated to reflux and then filtered. In this example, the filtrate obtained by the filtration was cooled to obtain 19.65 g of 2-m-hydroxyphenylacetic acid, a light brown solid. The yield in this example was approximately 51.6%.

[0086] 4 shows the HPLC trace of the purified light brown solid material after the third step (oxidation reaction) in this example, where W1 represents 2-m-hydroxyphenylacetic acid.

[0087] As shown in Figure 4, excluding the by-product of the Wittig reaction (R1), only the peak of 2-m-hydroxyphenylacetic acid (W1) can be seen, indicating that only very small amounts of other compounds remain.

[0088] FIG. 5 shows the proton nuclear magnetic resonance (NMR) spectra of the purified product obtained after the third step (oxidation reaction) in this example. １ 1 H NMR) spectrum of the purified product obtained after the third step (oxidation reaction) in this example. １３ 7 is a diagram of the IR spectrum (infrared absorption spectrum) of the purified product obtained after the third step (oxidation reaction) in this example.

[0089] 5 to 7, the purified 2-m-hydroxyphenylacetic acid contains almost no m-hydroxybenzaldehyde, the starting material. More specifically, it was revealed that the amount of m-hydroxybenzaldehyde contained in the 2-m-hydroxyphenylacetic acid composition is less than 0.1 wt %.

[0090] (Example 2) [Method for producing 2-m-hydroxyphenylacetic acid when the starting material is an alkali metal salt of m-hydroxybenzaldehyde]

[0091] First, in the same manner as in Example 1, a Wittig reactant, H ３ C-O-CH=PPh ３ To produce this compound, 37.8 g (0.11 mol) of the raw material compound (methoxymethyl)triphenylphosphonium chloride and 13.5 g (0.12 mol) of potassium tert-butoxide were reacted under nitrogen gas flow while the temperature of the reaction system was controlled to 5° C. or less. Note that since the starting material was an alkali metal salt of m-hydroxybenzaldehyde, the amounts of the raw material compound and the potassium tert-butoxide were both about 20% by molar ratio relative to Example 1.

[0092] (Step 1) In this Example, thereafter, 14.4 g (0.10 mol) of m-hydroxybenzaldehyde sodium (Na) salt, which was the starting material described in the second embodiment, was added to the reaction system in which the Wittig reagent had been produced, while the temperature of the reaction system was controlled to 20° C. or less, and the mixture was stirred at room temperature.

[0093] The amount of starting material in this example is about 40% in molar ratio compared to Example 1. Therefore, as described above, in this example, the amount of Wittig reagent introduced is a relatively small amount, that is, more than the reaction equivalent of the alkali metal salt of m-hydroxybenzaldehyde (more specifically, a small excess of the reaction equivalent; a typical example is about 1.2 equivalents).

[0094] In the subsequent second and third steps, the amount of compound used in each step was adjusted to about 40% of the amount of compound in Example 1, and then each treatment (including purification treatment) described in the second embodiment was carried out. As a result, a reaction similar to that described in Example 1 was carried out, and 7.76 g of 2-m-hydroxyphenylacetic acid, a light brown solid substance, was obtained. The yield in this example was about 51.0%. In addition, in this example, various HPLC analyses, proton nuclear magnetic resonance ( １ H NMR) spectral analysis, C-13 nuclear magnetic resonance ( １３ C NMR spectroscopy and IR spectroscopy were performed, and the results were similar to those in Example 1.

[0095] The above-described embodiments and examples do not limit the present invention in any way. Modifications within the scope of the present invention, including other combinations of the above-described embodiments and examples, are also included in the scope of the claims.

[0096] The method for producing 2-m-hydroxyphenylacetic acid of the present invention and the 2-m-hydroxyphenylacetic acid of the present invention can be widely used as a useful chemical substance or its production method for materials with a variety of applications (for example, functional materials or intermediates thereof used in various pharmaceuticals or cosmetics, etc.).

Claims

1. A method for producing 2-m-hydroxyphenylacetic acid, comprising: a first step of producing m-hydroxystyryl methyl ether by reacting m-hydroxybenzaldehyde with a Wittig reactant represented by general formula (I) in an amount of 2 molar equivalents or more relative to the m-hydroxybenzaldehyde; a second step of producing 2-(m-hydroxyphenyl)acetaldehyde by acid hydrolysis of the m-hydroxystyryl methyl ether; and a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent, wherein the second and third steps are carried out in situ.

2. A method for producing 2-m-hydroxyphenylacetic acid, comprising: a first step of producing m-hydroxystyryl methyl ether by reacting an alkali metal salt of m-hydroxybenzaldehyde with a Wittig reactant represented by general formula (I) in an amount equal to or greater than a reactive amount of the alkali metal salt; a second step of producing 2-(m-hydroxyphenyl)acetaldehyde by an acid hydrolysis reaction of the m-hydroxystyryl methyl ether; and a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent, wherein the second and third steps are carried out in situ.

3. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1, comprising reacting said m-hydroxybenzaldehyde with more than 2 molar equivalents of said Wittig reactant relative to said m-hydroxybenzaldehyde.

4. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 or 2, wherein the third step is carried out at a temperature of -10°C or higher and 10°C or lower.

5. The oxidizing agent is a peroxide, including hydroperoxide, and Oxone® (2KHSO 5 .KHSO 4 .K 2 SO 4 3. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 or 2, wherein the compound is at least one selected from the group consisting of 6. 2-m-hydroxyphenylacetic acid, wherein the composition contains less than 0.1 wt% m-hydroxybenzaldehyde.

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