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

Abstract

To provide a producing method capable of safely and efficiently producing 2-m-hydroxyphenyl acetic acid and 2-m-hydroxyphenyl acetic acid.SOLUTION: A method for producing 2-m-hydroxyphenyl acetic acid of the present invention comprises: a first step of reacting m-hydroxybenzaldehyde and a Wittig reaction agent represented by a general formula (I) of two mole equivalent or more to the m-hydroxybenzaldehyde to generate m-hydroxy styryl methyl ether; a second step of generating 2-(m-hydroxyphenyl)acetaldehyde by acid hydrolysis reaction of the m-hydroxy styryl methyl ether; and a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidant. In addition, the producing method of the 2-m-hydroxyphenyl acetic acid performs the second step and the third step in-situ.SELECTED DRAWING: Figure 4

Description

[Technical field]

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

[0002] 2-m-Hydroxyphenylacetic acid is at least a very useful chemical product as a starting material for 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 for promoting their continued growth (Patent Document 2), and methyl carboxymethylphenylaminocarboxypropylphosphonate (also known as Nahlsgen (registered trademark)), an anti-aging agent added to cosmetics and the like due to its activity as a GGT inhibitor (Patent Document 3).

[0003] Incidentally, 2-m-hydroxyphenylacetic acid is considered to be a substance that can be obtained by, for example, using a CN (cyanide) source (NaCN or KCN), converting the methyl group of m-crezol into a halogen, converting the resulting m-hydroxyphenyl halide to m-hydroxyphenyl cyanide, and then hydrolyzing it. In addition, TMSCN (trimethylsilyl cyanide) has been developed as another CN source, and can be used 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 this reaction, a sulfur (S)-based reactant is used. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6550656 [Patent Document 2] Patent No. 6457292 [Patent Document 3] Patent No. 5082102 [Non-patent literature]

[0006] [Non-Patent Document 1] J Am Chem Soc,2008,130,13110 [Non-Patent Document 2] J Am Chem Soc,1946,68(12),2633-2634 Summary of the Invention [Problem to be solved by the invention]

[0007] However, at least in Japan, where safety regulations are strict, it is not realistic to use a CN (cyanide) source in the manufacturing process. Even if TMSCN could be used, TMSCN and the reaction medium are expensive, so there may be problems with manufacturing 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 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. [Means for solving the problem]

[0009] The present inventors have been working on research into a method for producing 2-m-hydroxyphenylacetic acid, based on the awareness of the problems of improving safety and reducing the number of steps compared to the above-mentioned known techniques. As a result of the inventors' repeated detailed analysis and investigations, together with trial and error, they have concluded that using m-hydroxybenzaldehyde or an alkali metal salt of said m-hydroxybenzaldehyde as a starting material and using 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, a major obstacle appeared while the present inventors were researching 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 having an acidic proton such as a hydroxyl group in the molecule, since the Wittig reaction is a non-aqueous reaction.

[0011] In addition, when the above-mentioned m-hydroxybenzaldehyde or an alkali metal salt of said m-hydroxybenzaldehyde is used as a starting material, a problem occurs in that it becomes difficult to remove the reaction mixture resulting from the Wittig reaction by separation and filtration using a known mineral oil solvent. In more detail, it has become clear that when the above-mentioned starting materials are used in the Wittig reaction, it becomes difficult to remove the reaction mixture containing triphenylphosphine oxide (PhPO), which is a typical by-product of the reaction.

[0012] Therefore, the present inventors attempted to react m-hydroxybenzaldehyde as a starting material with a Wittig reaction agent 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] [ka]

[0014] As a result, it became very interesting to discover that the following unique effects (a) and (b) could occur. (a) A portion of the Wittig reagent can replace the proton of the hydroxy group of the starting material m-hydroxybenzaldehyde with a phosphinium group. (b) Another portion of the Wittig reagent can react with the aldehyde group of the starting material to produce an enol derivative by increasing the carbon number by one, a one-carbon homologation reaction.

[0015] Generally, a person skilled in the art would think that the Wittig reaction is a non-aqueous reaction, and therefore the use of a starting material having a hydroxyl group is incompatible. However, the notable feature of the above attempt is that the above-mentioned action (a), that is, the replacement of the proton of the hydroxyl group with the phosphinium group derived from the Wittig reaction agent by the introduction of an amount of the Wittig reaction agent that greatly exceeds the reaction equivalent of the Wittig reaction, makes it possible to use a starting material having a hydroxyl group that was previously considered incompatible.

[0016] It should be noted that the Wittig reagent H3C-O-CH=PPh3 is not limited to being used as a preformed compound. For example, (methoxymethyl)triphenylphosphonium chloride (H3C-O-CH2-PPh3) can be used in a solvent commonly used in the Wittig reaction (e.g., toluene or tetrahydrofuran). + (Cl -)Ph3) with a strong base (e.g., potassium tert-butoxide) in-situ to produce the Wittig reagent H3C-O-CH=PPh3. Therefore, in this application, the use of H3C-O-CH=PPh3 as a Wittig reagent also includes the Wittig reaction of the Wittig reagent, which can be produced from a raw material compound, with the starting material m-hydroxybenzaldehyde.

[0017] Moreover, the above attempt is for the first step (reaction step) of obtaining 2-m-hydroxyphenylacetic acid by the following chemical reaction formula (II). As mentioned above, it is worth noting that by reacting the above-mentioned m-hydroxybenzaldehyde with a Wittig reactant in an amount that far exceeds the reaction equivalent of the Wittig reaction (X1 in the following chemical reaction formula (II)), it is possible to make the Wittig reactant fulfill the above-mentioned two roles. Note that the following chemical reaction formula (II) is a reaction formula when H3C-O-CH=PPh3, an example of a Wittig reactant, is used.

[0018] [ka]

[0019] Here, in order to realize the step (chemical reaction step) shown in X1 of the above-mentioned chemical reaction formula (II) with high accuracy, it is a preferred embodiment to react the m-hydroxybenzaldehyde with a Wittig reactant in an amount of at least twice the reaction equivalent of the Wittig reaction (more preferably more than twice, and even more preferably at least 2.1 times). This is because if the starting material m-hydroxybenzaldehyde remains in the reaction system, in the subsequent step shown in Z1, i.e., the oxidation reaction, the remaining m-hydroxybenzaldehyde is oxidized as it is to produce m-hydroxybenzoic acid, which produces a mixture with 2-m-hydroxyphenylacetic acid. Since the difference between m-hydroxybenzoic acid and 2-m-hydroxyphenylacetic acid is only one methylene chain, it is practically impossible to distinguish 2-m-hydroxyphenylacetic acid by various analyses 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, which can cause problems such as reduced utility as a chemical product, as explained in the Background Art section above.

[0020] On the other hand, in order to realize the step (reaction step) shown in X1 of the above-mentioned chemical reaction formula (II) with high accuracy, the upper limit of the amount of the Wittig reactant introduced is not particularly limited. From the viewpoint of the economic disadvantage of introducing an unnecessarily large amount, the prevention or suppression of the influence of side reactions, and / or optimization of the accompanying purification step, it is a preferred embodiment to set the amount of the Wittig reactant to 3 times or less (more preferably 2.5 times or less) the reaction equivalent amount.

[0021] Furthermore, in the course of the inventor's research, it became apparent that a new obstacle needed to be overcome in order to realize with high certainty each of the steps (reaction steps) shown as Y1 and Z1 in the chemical reaction formula (II) above, i.e., the steps of obtaining 2-m-hydroxyphenylacetic acid from the produced enol derivative via acid hydrolysis.

[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 increased from the starting material m-hydroxybenzaldehyde. However, it has been confirmed that the 2-(m-hydroxyphenyl)acetaldehyde is a compound that is very difficult to isolate due to its instability.

[0023] As a result of further research and analysis, the present inventors have found that 2-(m-hydroxyphenyl)acetaldehyde 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 safely and efficiently produced 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 of the present inventions has been created based on the above-mentioned viewpoints and circumstances.

[0025] A method for producing 2-m-hydroxyphenylacetic acid according to the present invention comprises the steps of: 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 to produce m-hydroxystyryl methyl ether; hydrolyzing the m-hydroxystyryl methyl ether with an acid to produce 2-(m-hydroxyphenyl)acetaldehyde; and treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent in a third step. In addition, the method for producing 2-m-hydroxyphenylacetic acid comprises carrying out the second and third steps in-situ. General formula (I)

[0026] [ka]

[0027] According to this method for producing 2-m-hydroxyphenylacetic acid, in the first step (corresponding to the reaction step of X1 in the above-mentioned chemical reaction formula (II)), by reacting 2 molar equivalents or more of the Wittig reactant with the starting material m-hydroxybenzaldehyde, it is possible to produce m-hydroxystyryl methyl ether from the starting material with high certainty. In other words, it is possible to reduce the amount of the starting material remaining after the first step with high certainty. In addition, by carrying out the second step (corresponding to the reaction step of Y1 in the above-mentioned chemical reaction formula (II)) and the third step (corresponding to the reaction step of Z1 in the above-mentioned chemical reaction formula (II)) in-situ in this production method, it is possible to produce 2-m-hydroxyphenylacetic acid with high certainty. Furthermore, when this production method is adopted, there is no need to prepare an alkali metal salt of m-hydroxybenzaldehyde in advance, as compared to another production method for 2-m-hydroxyphenylacetic acid that uses an alkali metal salt of m-hydroxybenzaldehyde as a starting material, as described below. From that perspective, materials for this purpose are not required and the production process can be simplified.

[0028] In the course of research, the present inventors also 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 first step, and 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 m-hydroxybenzaldehyde sodium (Na) salt, which is an example of an alkali metal salt of m-hydroxybenzaldehyde, is used. As shown in chemical reaction formula (III), when m-hydroxybenzaldehyde sodium (Na) salt is used as a starting material, the Wittig reactant does not substantially need to play the role (a) of the above-mentioned two roles, that is, roles (a) and (b). Therefore, the present inventors have found that by introducing the Wittig reactant in an amount necessary for playing the role (b), in other words, for playing the carbon-increasing reaction, it is possible to produce the same effect as the first step in the method for producing 2-m-hydroxyphenylacetic acid when m-hydroxybenzaldehyde is used as a starting material.

[0030] [ka]

[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. The potassium (K) salt of m-hydroxybenzaldehyde can also achieve the same results as the sodium (Na) salt.

[0032] Therefore, the amount of the Wittig reactant introduced to realize the step (reaction step) shown in X2 of the above-mentioned chemical reaction formula (III) with high certainty may be equal to or more than the reaction equivalent to 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, the prevention or suppression of the effects of side reactions, and / or the optimization of the accompanying purification step, it is a preferred embodiment to make the amount less than twice the reaction equivalent of the Wittig reactant (more preferably 1.5 times or less).

[0033] Furthermore, the technical problems in each step (reaction step) indicated by Y2 and Z2 in the chemical reaction formula (III) above are similar to those in the case where the starting material is m-hydroxybenzaldehyde, and the present inventors have found that the 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, it is possible to safely and efficiently produce 2-m-hydroxyphenylacetic acid without using any toxic CN source reactant or any sulfur-based reactant that requires odor control. Another aspect of the present invention was created based on this viewpoint and background.

[0035] Another method for producing 2-m-hydroxyphenylacetic acid of the present invention includes 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 the reaction amount 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. In addition, the second step and the third step of the method for producing 2-m-hydroxyphenylacetic acid are carried out in-situ. General formula (I)

[0036] [ka]

[0037] According to this manufacturing method, in the first step, by using an alkali metal salt of m-hydroxybenzaldehyde as a starting material, the amount of the Wittig reactant when reacting the alkali metal salt with the Wittig reactant represented by the above general formula (I) is sufficient as long as it is equal to or greater than the reaction amount. In other words, it is possible to suppress the amount of the Wittig reactant to be lower than when m-hydroxybenzaldehyde is used as a starting material. In addition, by carrying out the second step (corresponding to the reaction step of Y2 in the above chemical reaction formula (III)) and the third step (corresponding to the reaction step of Z2 in the above chemical reaction formula (III)) in this manufacturing method in-situ, 2-m-hydroxyphenylacetic acid can be manufactured with high accuracy.

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

[0039] According to this 2-m-hydroxyphenylacetic acid composition, by adopting the above-described method for producing 2-m-hydroxyphenylacetic acid, the amount of m-hydroxybenzaldehyde, which is the starting material, in other words the residual amount of m-hydroxybenzaldehyde, can be reduced to less than 0.1 wt%, thereby realizing high purity 2-m-hydroxyphenylacetic acid. In addition, this 2-m-hydroxyphenylacetic acid composition is highly safe because it does not contain any toxic CN source reactant or any sulfur-based reactant that requires odor control. In this application, the term "2-m-hydroxyphenylacetic acid composition" means a composition that may contain, in addition to 2-m-hydroxyphenylacetic acid, other substances (for example, m-hydroxybenzaldehyde or an alkali metal salt of said m-hydroxybenzaldehyde as a starting material, or by-products generated in the production process of said 2-m-hydroxyphenylacetic acid), and the composition of the "2-m-hydroxyphenylacetic acid composition" is not particularly limited. Effect of the Invention

[0040] According to one method for producing 2-m-hydroxyphenylacetic acid of the present invention, m-hydroxystyryl methyl ether can be produced from the starting material with high certainty. Moreover, by carrying out the second step (corresponding to the acid hydrolysis step) and the third step (corresponding to the oxidation step) in-situ, 2-m-hydroxyphenylacetic acid can be produced with high certainty by realizing the carbon-increasing reaction from the starting material. In addition, according to this production method, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without using any toxic CN source reactant or any sulfur-based reactant that requires odor control.

[0041] In addition, according to one of the 2-m-hydroxyphenylacetic acid compositions of the present invention, the amount of m-hydroxybenzaldehyde, which is the starting material, present, in other words, the residual amount of said m-hydroxybenzaldehyde, is reduced to less than 0.1 wt%, thereby realizing high purity 2-m-hydroxyphenylacetic acid. In addition, this 2-m-hydroxyphenylacetic acid composition is highly safe because it does not contain any toxic CN source reactant or any sulfur-based reactant that requires odor control. [Brief description of the drawings]

[0042] [Figure 1] FIG. 1 shows a HPLC (high performance liquid chromatography) diagram of the intermediate stage of the first step immediately after completion of the dropwise addition of the starting material m-hydroxybenzaldehyde to the reaction mixture under a specified temperature condition after the preparation of the Wittig reactant in Example 1. [Diagram 2] FIG. 2 is an HPLC diagram after the first step (Wittig reaction) in Example 1. [Diagram 3] FIG. 2 is an HPLC diagram after the second step (acid hydrolysis reaction) in Example 1. [Figure 4] FIG. 2 is an HPLC diagram after the third step (oxidation reaction) in Example 1. [Diagram 5] FIG. 2 is a proton nuclear magnetic resonance ( 1 H NMR) spectrum of the purified product obtained after the third step (oxidation reaction) in Example 1. [Figure 6]FIG. 1 is a diagram showing the C-13 nuclear magnetic resonance (C NMR) spectrum of the purified product obtained after the third step (oxidation reaction) in Example 1. [Figure 7] FIG. 2 is an IR spectrum (infrared absorption spectrum) of the purified product obtained after the third step (oxidation reaction) in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] <First embodiment> The method for producing 2-m-hydroxyphenylacetic acid in this embodiment and the 2-m-hydroxyphenylacetic acid will be described below.

[0044] <Method of producing 2-m-hydroxyphenylacetic acid> This embodiment describes a method for producing 2-m-hydroxyphenylacetic acid when the starting material is m-hydroxybenzaldehyde.

[0045] In this embodiment, in order to carry out the Wittig reaction between the Wittig reactant H3C-O-CH=PPh3 and the starting material m-hydroxybenzaldehyde, the following reaction steps (A) and (B) are carried out in a solvent (e.g., toluene or tetrahydrofuran) that is commonly used in the Wittig reaction. Therefore, the reaction steps (A) and (B) are carried out in situ, so to speak. (A) Commercially available starting compound (methoxymethyl)triphenylphosphonium chloride (H3C-O-CH2-P + (Cl - ) reacting Ph3) with a strong base (e.g., potassium tert-butoxide) to produce the Wittig reagent. (B) subsequent to the reaction of (A), a Wittig reaction of m-hydroxybenzaldehyde with the Wittig reactant to produce 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 is introduced into a vessel (e.g., a flask) containing the Wittig reactant, thereby realizing the production of m-hydroxystyryl methyl ether based on the in-situ Wittig reaction. By carrying out the reaction steps (A) and (B) in-situ as in this embodiment, it is possible to use commercially available raw material compounds and to eliminate the need to isolate the Wittig reactant, thereby enabling the production of m-hydroxystyryl methyl ether very efficiently and with little waste in terms of yield.

[0047] Here, in terms of ensuring that the reaction step (B) occurs, it is a preferred embodiment that the amount of the Wittig reactant produced in the reaction step (A) is an amount that is significantly greater than 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 raw material compound and strong base are adjusted to 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 ensuring that the production of m-hydroxybenzoic acid, an unnecessary and difficult-to-isolate by-product, is prevented after the third step described below.

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

[0049] In addition, in both the above-mentioned reaction step (A) and reaction step (B), it is preferable to carry out the reaction while cooling and stirring. In addition, the above-mentioned reaction step (B) corresponds to the first step in this embodiment (corresponding to the reaction step of X1 in the chemical reaction formula (II) already explained).

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

[0051] Thereafter, in this embodiment, the second step (corresponding to the reaction step of Y1 in chemical reaction formula (II) already explained) is carried out.

[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 a vessel 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 for the acid hydrolysis reaction of m-hydroxystyryl methyl ether to occur, the subsequent third step (corresponding to the reaction step of Z1 in chemical reaction formula (II) already explained) is carried out without taking out the reaction mixture (typically, 2-(m-hydroxyphenyl)acetaldehyde), i.e., in situ.

[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 reaction mixture containing 2-(m-hydroxyphenyl)acetic acid is obtained by the oxidation reaction of 2-(m-hydroxyphenyl)acetaldehyde with the oxidizing agent.

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

[0056] In order to purify the crude product, for example, the crude product is heated under reflux with a large amount of an organic solvent (e.g., toluene), filtered, and the filtrate is cooled to precipitate a light brown solid substance, which is purified 2-m-hydroxyphenylacetic acid.

[0057] The above-mentioned third step in which the treatment is performed using an oxidizing agent is preferably performed at a temperature of −10° C. or higher and 10° C. or lower. If the third step is performed under a temperature condition below −10° C., the conversion of the generated 2-(m-hydroxyphenyl)acetaldehyde to the target 2-m-hydroxyphenylacetic acid in situ is extremely slow and industrially impractical, whereas if the third step is performed under a temperature condition above 10° C., the oxygen radical attacks the methylene carbon, which is the increased carbon, causing a cleavage reaction and then providing an oxidation reaction, which may give m-hydroxybenzoic acid (the same compound as the oxidation product of the starting material).

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

[0059] From the above viewpoint, it is a preferred embodiment of the present invention 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) (2KHSO5.KHSO4.K2SO4). Among the above-mentioned two types of oxidizing agents, the use of Oxone (registered trademark) is particularly preferred as it most reliably produces the effects of the present invention.

[0060] By adopting the method for producing 2-m-hydroxyphenylacetic acid of this embodiment, m-hydroxystyryl methyl ether can be produced with high certainty 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 certainty. In addition, by carrying out the second and third steps in this production method in-situ, 2-m-hydroxyphenylacetic acid can be produced with high certainty. It is also worth noting that by adopting 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 reactant or any sulfur-based reactant that requires odor control.

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

[0062] <Second embodiment> A method for producing 2-m-hydroxyphenylacetic acid in this embodiment, which is different from that in the first embodiment, will be described below.

[0063] <Method of producing 2-m-hydroxyphenylacetic acid> This embodiment describes a method for producing 2-m-hydroxyphenylacetic acid when the starting material is an alkali metal salt of m-hydroxybenzaldehyde.

[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, it is also possible to use a form in which an alkali metal salt of m-hydroxybenzaldehyde is produced from a raw material compound of an alkali metal salt of m-hydroxybenzaldehyde.

[0065] <Starting material synthesis process> 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=122.12,204.7mmol) is placed in 100mL (milliliters) of methanol, and 39.5g (Mw=54.01,204.7mmol) of 28wt% sodium methoxide methanol solution is added dropwise while stirring at a temperature of 0℃ to 5℃. This process produces a reaction mixture.

[0067] The reaction mixture was then cooled to room temperature, and the solvent methanol was distilled off under reduced pressure. The resulting solid was dried under reduced pressure at 50° C. for about 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] <Starting material synthesis process> As in the first embodiment, the m-hydroxybenzaldehyde sodium (Na) salt synthesized as described above is reacted with a Wittig reactant H3C-O-CH=PPh3 (Wittig reaction) to produce m-hydroxystyryl methyl ether (Step 1 in this embodiment).

[0069] In this embodiment, unlike the first embodiment, the amount of the Wittig reactant 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 proton of the hydroxy group has already been substituted with a sodium group, and therefore the influence of the hydroxy group during the Wittig reaction is substantially eliminated.

[0070] The subsequent second step in this embodiment (corresponding to the acid hydrolysis step of Y2 in chemical reaction formula (III) as already explained) is the same as the second step in the first embodiment (corresponding to the acid hydrolysis step of Y1 in chemical reaction formula (II) as already explained). In addition, the subsequent third step in this embodiment (corresponding to the oxidation reaction step of Z2 in chemical reaction formula (III) as already explained) is the same as the third step in the first embodiment (corresponding to the acid hydrolysis step of Z1 in chemical reaction formula (III) as already explained).

[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 carrying out the second and third steps in situ, as in the first embodiment. It is also noteworthy that by adopting 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 reactant or any sulfur-based reactant that requires odor control, as in the first embodiment.

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

[0073] Example 1 [Production method of 2-m-hydroxyphenylacetic acid when starting material is m-hydroxybenzaldehyde]

[0074] (Preparation of Wittig Reagent Used in the First Step) 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 are 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 reactant H3C-O-CH=PPh3 is produced.

[0075] (1st step) Thereafter, 30.6 g (0.251 mol) of m-hydroxybenzaldehyde was added to the reaction system in which the Wittig reactant was 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 Wittig reactant produced in the Wittig reactant production step was approximately 2.4 molar equivalents of the starting material m-hydroxybenzaldehyde.

[0076] Thereafter, the first reaction mixture (including unreacted compounds) in 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 that, the organic layer was separated using aqueous hydrochloric acid and water, and 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 product of m-hydroxystyryl methyl ether and a by-product of the Wittig reaction was obtained.

[0077] FIG. 1 is a diagram of HPLC (high performance liquid chromatography) at an intermediate stage of the first step immediately after completion of the dropwise addition of the starting material m-hydroxybenzaldehyde into the reaction mixture under a predetermined temperature condition after the preparation of the Wittig reactant in this embodiment. FIG. 2 is a diagram of HPLC after the first step (Wittig reaction) in this embodiment. Here, P1 in the diagram 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, which is the product of the Wittig reaction. T1 is toluene, which is the solvent. In addition, in HPLC diagrams other than FIG. 1, common symbols are attached to common compounds unless otherwise specified.

[0078] As shown in Figures 1 and 2, as the Wittig reaction proceeds, the peak of Q1, which indicates the starting material, becomes smaller, and after the first step in this embodiment, the peak of Q1 becomes so small that it is almost undetectable. Therefore, as described above, the amount of the Wittig reaction agent in the Wittig reaction, which is 2 molar equivalents or more (for example, about 2.4 molar equivalents) reacts with the starting material m-hydroxybenzaldehyde, makes it possible to reduce the remaining amount of the starting material with high certainty.

[0079] (2nd process) Thereafter, the above-mentioned 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 a container containing the first mixture, and the mixture was stirred at room temperature to cause an acid hydrolysis reaction (corresponding to the reaction step Y1 in the chemical reaction formula (II) already explained).

[0080] 3 is a diagram of the HPLC results after the second step (acid hydrolysis reaction) in this example, in which U1 is 2-(m-hydroxyphenyl)acetaldehyde and V1 is the remaining ethyl acetate.

[0081] In this embodiment, after a sufficient time (e.g., 12 hours) had elapsed until the above-mentioned second step was completed, the subsequent third step (corresponding to the reaction step Z1 in chemical reaction formula (II) already explained) was carried out without taking out the reaction mixture (second mixture) containing 2-(m-hydroxyphenyl)acetaldehyde, i.e., in situ.

[0082] (3rd step) As described above, 153.7 g of the oxidizing agent Oxone (registered trademark) (2KHSO5.KHSO4.K2SO4) was added in situ to a container containing the second mixture under a temperature condition of 0°C or higher and 5°C or lower, and the mixture was stirred to obtain a reaction mixture (third mixture) containing 2-m-hydroxyphenylacetic acid.

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

[0084] Then, 300 mL of ethyl acetate and about 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 ethyl acetate, thereby obtaining a crude product of 2-m-hydroxyphenylacetic acid as a viscous solid.

[0085] After that, in order to purify the crude product, toluene having a volume about 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 under 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, which is a light brown solid substance. The yield in this example was about 51.6%.

[0086] Figure 4 shows the HPLC trace of the above-mentioned light brown solid material purified after the third step (oxidation reaction) in this example, where W1 is 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. 131C NMR spectrum of the purified product obtained after the third step (oxidation reaction) in this example. In addition, FIG. 7 is an IR spectrum (infrared absorption spectrum) of the purified product obtained after the third step (oxidation reaction) in this example.

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

[0090] Example 2 [Production method of 2-m-hydroxyphenylacetic acid when the starting material is an alkali metal salt of m-hydroxybenzaldehyde]

[0091] First, in order to generate the Wittig reactant H3C-O-CH=PPh3 in a flask containing 120 mL of organic solvent (toluene) (about 40% by volume relative to Example 1), 37.8 g (0.11 mol) of raw material compounds (methoxymethyl)triphenylphosphonium chloride and 13.5 g (0.12 mol) of potassium tert-butoxide are reacted under a condition in which the temperature of the reaction system is controlled to 5° C. or less while flowing nitrogen gas in order to produce the Wittig reactant H3C-O-CH=PPh3 in a flask containing 120 mL of organic solvent (toluene) (about 40% by volume relative to Example 1). Note that, since the starting material is an alkali metal salt of m-hydroxybenzaldehyde, the amounts of the raw material compound and the potassium tert-butoxide are both about 20% by molar ratio relative to Example 1.

[0092] (1st step) In this embodiment, thereafter, in the reaction system in which the Wittig reactant was produced, 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 reactant was produced, with the temperature of the reaction system being controlled to 20° C. or less, and the mixture was stirred at room temperature.

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

[0094] In the second and third steps carried out thereafter, the amount of the compound used in each step was adjusted to about 40% of the amount of the 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 this example, various HPLC analyses, proton nuclear magnetic resonance ( 1 H NMR) spectroscopic analysis, C-13 nuclear magnetic resonance ( 13 As a result of carrying out C NMR spectroscopy and IR spectroscopy, 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. [Industrial Applicability]

[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 (e.g., functional materials or intermediates thereof used in various pharmaceuticals or cosmetics, etc.).

Claims

1. 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 acid hydrolysis of the m-hydroxystyryl methyl ether; a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent; The second step and the third step are carried out in situ. Method for the preparation of 2-m-hydroxyphenylacetic acid. General formula (I) 【Chemistry 1】

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

3. The oxidizing agent is a peroxide, including hydroperoxide, and Oxone (2KHSO 5 .KHSO 4 .K 2 SO 4 At least one selected from the group consisting of The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 or 2.

Images