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

Abstract

The invention provides a method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid, which can be safely and efficiently produced. A method for producing 2-m-hydroxyphenylacetic acid according to one embodiment of the present invention comprises: a first step for generating 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 for generating 2-(m-hydroxyphenyl) acetaldehyde by an acid hydrolysis reaction of the m-hydroxystyryl methyl ether; and a third step in which the 2-(m-hydroxyphenyl) acetaldehyde is treated using an oxidizing agent. In addition, the method for producing 2-m-hydroxyphenylacetic acid involves performing the second step and the third step in situ. The general formula (I) is H3C-O-CH = PPh3 (I).

Description

Technical Field

[0001] The present invention relates to a preparation method of 2-m-hydroxyphenylacetic acid and the 2-m-hydroxyphenylacetic acid. Background Art

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

[0003] On the other hand, 2-m-hydroxyphenylacetic acid is believed to be obtained by, for example, using a CN (cyanide) source (NaCN or KCN), converting the methyl group of m-cresol to a halogen to obtain m-hydroxyphenyl halide, converting this m-hydroxyphenyl halide to m-hydroxyphenyl cyanide, and then hydrolyzing it to obtain 2-m-hydroxyphenylacetic acid. Furthermore, TMSCN (trimethylsilyl cyanide) has been developed as another CN source and can be used as a bare CN source based on F anions (Y. Yamasaki et al. Chem Lett 1985, 1387-1390, and references cited in).

[0004] In addition, the possibility of producing 2-m-hydroxyphenylacetic acid using the Willgerodt reaction has been previously disclosed (Non-Patent Document 2). In this reaction, a sulfur (S)-based reactant is used.

[0005] Background Art Literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent No. 6550656

[0008] Patent Document 2: Japanese Patent No. 6457292

[0009] Patent Document 3: Japanese Patent No. 5082102

[0010] Non-patent literature

[0011] Non-patent document 1: J Am Chem Soc, 2008, 130, 13110

[0012] Non-patent document 2: J Am Chem Soc, 1946, 68(12), 2633-2634 Summary of the Invention

[0013] [Problems to be solved by the invention]

[0014] However, at least in Japan, where safety regulations are strict, using a CN (cyanide) source in the manufacturing process is not practical. Furthermore, even if TMSCN could be used, the high prices of TMSCN and the reaction medium would cause production cost issues in addition to safety.

[0015] Furthermore, even if the sulfur-based reactant disclosed in Non-Patent Document 2 is used, it is difficult to adopt it from an industrial perspective because equipment is required to deal with the odor of the sulfur-based gas and the number of steps required to obtain 2-m-hydroxyphenylacetic acid increases.

[0016] [Technical means to solve the problem]

[0017] Recognizing the challenges of the prior art in improving safety and reducing process steps, the present inventors conducted intensive research on methods for producing 2-m-hydroxyphenylacetic acid. Through repeated experiments, detailed analysis, and research, the present inventors concluded that using m-hydroxybenzaldehyde or an alkali metal salt of m-hydroxybenzaldehyde as a starting material and employing the Wittig reaction, among a wide variety of available reactions, could safely produce 2-m-hydroxyphenylacetic acid with a reduced number of process steps. Further research has been conducted.

[0018] However, during the inventors' research into new manufacturing methods, they encountered a significant obstacle. Specifically, when using commercially available and readily available m-hydroxybenzaldehyde as a starting material, the Wittig reaction is a non-aqueous reaction. Therefore, it is generally difficult to apply the Wittig reaction to starting materials containing derivatives containing acidic protons, such as hydroxyl groups, in their molecules.

[0019] In addition, if the m-hydroxybenzaldehyde or an alkali metal salt of the m-hydroxybenzaldehyde is used as a starting material, the following problem may arise: it is difficult to remove the reaction mixture produced by the Wittig reaction by separation filtration using a known mineral oil solvent. Specifically, when using the Wittig reaction, it has been found that if the starting material is used, it is difficult to remove the reaction mixture containing triphenylphosphine oxide (Ph3PO, triphenylphosphine oxide), which is a representative by-product of the reaction.

[0020] Therefore, the present inventors tried to react m-hydroxybenzaldehyde as a starting material with a Wittig reactant represented by the following general formula (I), a 2-methoxymethyltriphenylphosphazene derivative, in an amount far exceeding the reaction equivalent of the Wittig reaction.

[0021] [Chemistry 1]

[0022] H3C-O-CH=PPh3 (I)

[0023] The results are very interesting and may produce the following unique effects (a) and (b).

[0024] (a) A portion of the Wittig reactant may substitute a proton of a hydroxyl group of m-hydroxybenzaldehyde, which is a starting material, with a phosphine group.

[0025] (b) Another portion of the Wittig reactant reacts with the aldehyde group of the starting material to produce an enol derivative, that is, a one-carbon homologation reaction is achieved in which the number of carbon atoms is increased by one.

[0026] Here, those skilled in the art generally believe that, because the Wittig reaction is a non-aqueous reaction, starting materials containing hydroxyl groups are unsuitable. However, a notable feature of the present invention is that by introducing an amount of Wittig reactant far exceeding the reaction equivalent of the Wittig reaction, the aforementioned effect (a) is utilized, i.e., the proton of the hydroxyl group is replaced by a phosphine group from the Wittig reactant. This allows starting materials containing hydroxyl groups, which were previously considered unsuitable, to be put into practical use.

[0027] Furthermore, H3C-O-CH=PPh3 as a Wittig reaction agent is not limited to being used as a ready-made compound. For example, by reacting (methoxymethyl)triphenylphosphine chloride (H3C-O-CH 2- P + (Cl - )Ph3) and a strong base (e.g., potassium tert-butoxide) react in situ to generate a Wittig reactant H3C-O-CH=PPh3. Therefore, in this case, using H3C-O-CH=PPh3 as a Wittig reactant also includes subjecting the Wittig reactant, which can be generated from the raw material compound, to a Wittig reaction with m-hydroxybenzaldehyde as a starting material.

[0028] Furthermore, the above attempt was used in the so-called first-stage step (reaction step), which aims to obtain 2-m-hydroxyphenylacetic acid via the following chemical reaction formula (II). It is particularly noteworthy that, as described above, by reacting the Wittig reactant with the m-hydroxybenzaldehyde in an amount far exceeding the reaction equivalent of the Wittig reaction (X1 in the following chemical reaction formula (II)), the Wittig reactant can exert the aforementioned two effects. Furthermore, the following chemical reaction formula (II) is a reaction formula using H3C-O-CH=PPh3, an example of a Wittig reactant.

[0029] [Chemistry 2]

[0030]

[0031] Here, in order to accurately achieve the step X1 (chemical reaction step) of the chemical reaction formula (II), it is preferable to react the Wittig reactant with the m-hydroxybenzaldehyde 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, the residual m-hydroxybenzaldehyde will be directly oxidized to m-hydroxybenzoic acid (m-hydroxybenzoic acid) in the subsequent oxidation reaction step Z1, resulting in a mixture of m-hydroxybenzoic acid and 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 identify 2-m-hydroxyphenylacetic acid using various analyses or to isolate and extract only 2-m-hydroxyphenylacetic acid. As a result, the target 2-m-hydroxyphenylacetic acid and m-hydroxybenzoic acid are present together, leading to problems such as the reduced effectiveness of the chemical product described in the background art.

[0032] On the other hand, in order to achieve the step (reaction step) represented by X1 in the chemical reaction formula (II) with high accuracy, the upper limit of the amount of the Wittig reactant introduced is not particularly limited. In addition, from the perspectives of avoiding the economic disadvantages of introducing an unnecessary large amount, preventing or suppressing the influence of secondary reactions, and / or optimizing the accompanying purification steps, setting the amount to 3 times or less (more preferably 2.5 times or less) the reaction equivalent of the Wittig reactant is a preferred embodiment.

[0033] Furthermore, during the course of the present inventors' continued research, they found that they needed to overcome new obstacles in order to accurately carry out the steps (reaction steps) represented by Y1 and Z1 in the chemical reaction formula (II), namely, the steps of obtaining 2-m-hydroxyphenylacetic acid by acid hydrolysis of the generated enol derivative.

[0034] Specifically, the enol derivative is easily hydrolyzed under acidic conditions. Therefore, 2-(m-hydroxyphenyl)acetaldehyde, which has one additional carbon atom, can be generated from the starting material m-hydroxybenzaldehyde. However, it has been confirmed that 2-(m-hydroxyphenyl)acetaldehyde is an unstable compound that is difficult to isolate.

[0035] Therefore, the present inventors have further studied and analyzed, and as a result, have found that 2-(m-hydroxyphenyl)acetaldehyde can be produced by performing an oxidation reaction in situ in the reaction medium of the acid hydrolysis reaction without isolating the 2-(m-hydroxyphenyl)acetaldehyde.

[0036] As a result, the present inventors discovered that 2-m-hydroxyphenylacetic acid can be efficiently produced safely and without multiple steps from commercially available starting materials, completely eliminating the use of toxic CN-source reactants or sulfur-based reactants requiring odor control. One of the present inventions was created based on this perspective and background.

[0037] One method for producing 2-m-hydroxyphenylacetic acid of the present invention comprises: a first step of reacting m-hydroxybenzaldehyde with a Wittig reactant represented by general formula (I) in an amount of 2 or more molar equivalents relative to the m-hydroxybenzaldehyde to produce m-hydroxystyryl methyl ether; a second step of acid hydrolyzing the m-hydroxystyryl methyl ether to produce 2-(m-hydroxyphenyl)acetaldehyde; and a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent. Furthermore, this method for producing 2-m-hydroxyphenylacetic acid comprises performing the second and third steps in situ.

[0038] General formula (I)

[0039] [Chemistry 3]

[0040] H3C-O-CH=PPh3 (I)

[0041] According to this method for producing 2-m-hydroxyphenylacetic acid, by reacting m-hydroxybenzaldehyde, the starting material, with 2 molar equivalents or more of the Wittig reactant in the first step (corresponding to the reaction step X1 in the chemical reaction formula (II)), m-hydroxyphenylmethyl ether can be accurately produced from the starting material. In other words, the amount of the starting material remaining after the first step can be accurately reduced. Furthermore, by performing the second step (corresponding to the reaction step Y1 in the chemical reaction formula (II)) and the third step (corresponding to the reaction step Z1 in the chemical reaction formula (II)) in this production method in situ, 2-m-hydroxyphenylacetic acid can be produced with high accuracy. Furthermore, compared to another method for producing 2-m-hydroxyphenylacetic acid described below using an alkali metal salt of m-hydroxybenzaldehyde as the starting material, this method eliminates the need for pre-preparation of an alkali metal salt of m-hydroxybenzaldehyde. Therefore, specialized materials are no longer required, simplifying the production process.

[0042] Furthermore, the present inventors have attempted to use an alkali metal salt of m-hydroxybenzaldehyde as a starting material instead of the m-hydroxybenzaldehyde used as a starting material in Step 1. As a result, it was found that the amount of the Wittig reactant represented by the general formula (I) used could be reduced.

[0043] The following chemical reaction formula (III) is a reaction formula for the case of using sodium (Na) salt of m-hydroxybenzaldehyde, which is an example of an alkali metal salt of m-hydroxybenzaldehyde. As shown in chemical reaction formula (III), when the sodium (Na) salt of m-hydroxybenzaldehyde is used as the starting material, the Wittig reactant does not substantially need to perform the (a) of the two functions (a) and (b). Therefore, the present inventors have discovered that by introducing the Wittig reactant in an amount sufficient to perform the (b) function, in other words, to perform the carburization reaction, the same effect as the first step in the method for producing 2-m-hydroxyphenylacetic acid using m-hydroxybenzaldehyde as the starting material can be achieved.

[0044] [Chemistry 4]

[0045]

[0046] In the above description, the sodium (Na) salt of m-hydroxybenzaldehyde is used as an example of an alkali metal salt of m-hydroxybenzaldehyde. However, 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 may also achieve the same results as the sodium (Na) salt.

[0047] Therefore, the amount of the Wittig reactant introduced for accurately achieving the step (reaction step) represented by X2 of the chemical reaction formula (III) can be at least the reaction equivalent relative to the alkali metal salt of m-hydroxybenzaldehyde. In addition, the upper limit of the amount introduced is not particularly limited. However, from the perspective of economic disadvantages of introducing an unnecessary large amount, preventing or suppressing the influence of secondary reactions, and / or optimizing the accompanying purification step, it is a preferred embodiment to set it to less than 2 times (more preferably 1.5 times or less) the reaction equivalent of the Wittig reactant.

[0048] The present inventors have also learned that the technical problems of the steps (reaction steps) represented by Y2 and Z2 in the chemical reaction formula (III) are the same as those in the case of using m-hydroxybenzaldehyde as the starting material, and that these problems can be overcome by adopting the same solution as described above.

[0049] As a result, the present inventors discovered 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 toxic CN-source reactants or sulfur-based reactants requiring odor control. Another aspect of the present invention was created based on this perspective and background.

[0050] Another aspect of the present invention is a method for producing 2-m-hydroxyphenylacetic acid, comprising: a first step of reacting an alkali metal salt of m-hydroxybenzaldehyde with a Wittig reactant represented by general formula (I) in an amount equivalent to or greater than the alkali metal salt to produce m-hydroxyphenylmethyl ether; a second step of acid hydrolyzing the m-hydroxyphenylmethyl ether to produce 2-(m-hydroxyphenyl)acetaldehyde; and a third step of treating the 2-(m-hydroxyphenyl)acetaldehyde with an oxidizing agent. Furthermore, this method for producing 2-m-hydroxyphenylacetic acid comprises performing the second and third steps in situ.

[0051] General formula (I)

[0052] [Chemistry 5]

[0053] H3C-O-CH=PPh3 (I)

[0054] 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 represented by the general formula (I) when reacting the alkali metal salt with the Wittig reactant is sufficient as long as it is at least a reaction equivalent. In other words, the amount of the Wittig reactant can be kept low, i.e., lower than the amount used when using m-hydroxybenzaldehyde as the starting material. Furthermore, by performing the second step (corresponding to the reaction step Y2 in the chemical reaction formula (III)) and the third step (corresponding to the reaction step Z2 in the chemical reaction formula (III)) of this production method in situ, 2-m-hydroxyphenylacetic acid can be produced with high accuracy.

[0055] In addition, in the 2-m-hydroxyphenylacetic acid composition of the present invention, the 2-m-hydroxyphenylacetic acid composition contains less than 0.1 wt % of m-hydroxybenzaldehyde.

[0056] According to this 2-m-hydroxyphenylacetic acid composition, by employing the aforementioned method for producing 2-m-hydroxyphenylacetic acid, high-purity 2-m-hydroxyphenylacetic acid can be achieved. Specifically, the content of m-hydroxybenzaldehyde, the starting material, or in other words, the residual m-hydroxybenzaldehyde content, can be 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 requiring odor control.

[0057] In the present case, a "2-m-hydroxyphenylacetic acid composition" refers to a composition that, in addition to 2-m-hydroxyphenylacetic acid, may also contain other substances (e.g., m-hydroxybenzaldehyde or an alkali metal salt of m-hydroxybenzaldehyde as a starting material, or a by-product generated during the production process of 2-m-hydroxyphenylacetic acid). The composition of the "2-m-hydroxyphenylacetic acid composition" is not particularly limited.

[0058] [Effects of the Invention]

[0059] According to one method for producing 2-m-hydroxyphenylacetic acid of the present invention, m-hydroxystyryl methyl ether can be produced from starting materials with high accuracy. Furthermore, by performing the second step (equivalent to the acid hydrolysis step) and the third step (equivalent to the oxidation step) of this production method in situ, 2-m-hydroxyphenylacetic acid can be produced with high accuracy after undergoing a carburization reaction from the starting materials. Furthermore, this production method allows for safe and efficient production of 2-m-hydroxyphenylacetic acid without the use of toxic CN source reactants or sulfur-based reactants requiring odor control.

[0060] Furthermore, the 2-m-hydroxyphenylacetic acid composition according to one aspect of the present invention can produce high-purity 2-m-hydroxyphenylacetic acid. Specifically, the content of m-hydroxybenzaldehyde, the starting material, is reduced to less than 0.1 wt %. In other words, the residual m-hydroxybenzaldehyde content is reduced to less than 0.1 wt %. Furthermore, the 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 This is an HPLC (high performance liquid chromatography) chart of the mid-stage of the first step in Example 1, which was performed immediately after the dropwise addition of m-hydroxybenzaldehyde as a starting material to the reaction mixture under predetermined temperature conditions after the Wittig reactant was adjusted.

[0062] Figure 2 This is an HPLC chart after the first step (Wittig reaction) in Example 1.

[0063] Figure 3 This is an HPLC chart after the second step (acid hydrolysis reaction) in Example 1.

[0064] Figure 4 This is an HPLC chart after the third step (oxidation reaction) in Example 1.

[0065] Figure 5 The proton nuclear magnetic resonance (NMR) of the purified product obtained after the third step (oxidation reaction) in Example 1 is 1 H NMR) spectrum.

[0066] Figure 6 The C-13 NMR spectra of the purified product obtained after the third step (oxidation reaction) in Example 1 are shown in FIG. 13 C NMR) spectrum.

[0067] Figure 7 This is an IR spectrum (infrared absorption spectrum) of the purified product obtained after the third step (oxidation reaction) in Example 1. DETAILED DESCRIPTION

[0068] <First embodiment>

[0069] Hereinafter, the method for producing 2-m-hydroxyphenylacetic acid and the 2-m-hydroxyphenylacetic acid in the present embodiment will be described.

[0070] <Method for producing 2-m-hydroxyphenylacetic acid>

[0071] In this embodiment, a method for producing 2-m-hydroxyphenylacetic acid using m-hydroxybenzaldehyde as a starting material will be described.

[0072] In this embodiment, the following reaction steps (A) and (B) are carried out in a solvent commonly used in Wittig reactions (e.g., toluene or tetrahydrofuran) to allow H3C-O-CH=PPh3, a Wittig reactant, and m-hydroxybenzaldehyde, a starting material, to undergo a Wittig reaction. Therefore, the reaction steps (A) and (B) are so-called carried out in situ.

[0073] (A) The commercially available raw material compound (methoxymethyl) triphenylphosphine chloride (H3C-O-CH 2- P + (Cl - )Ph3) and a strong base (such as potassium tert-butoxide) to react to produce the Wittig reactant

[0074] (B) Following the reaction in (A), a step of generating m-hydroxyphenylmethyl ether by subjecting m-hydroxybenzaldehyde to a Wittig reaction with the Wittig reactant.

[0075] More specifically, after the reaction step (A), i.e., the step of generating the Wittig reactant, m-hydroxybenzaldehyde, a starting material, is introduced into a container (e.g., a flask) containing the Wittig reactant, thereby generating m-hydroxystyryl methyl ether through an in situ Wittig reaction. As shown in this embodiment, by performing the reaction steps (A) and (B) in situ, commercially available starting compounds can be used, and there is no need to specifically isolate the Wittig reactant. Therefore, m-hydroxystyryl methyl ether can be generated very efficiently and with minimal waste in terms of yield.

[0076] Here, from the perspective of highly accurate production of the reaction step (B), a preferred embodiment is that the amount of the Wittig reactant produced in the reaction step (A) should be significantly greater than the amount of the starting material in the Wittig reaction, more specifically, at least 2 molar equivalents, or the amounts of the starting compound and the strong base should be adjusted to achieve such an amount. As described above, minimizing the amount of the starting material (m-hydroxybenzaldehyde) remaining after the reaction step (B) can accurately prevent the formation of m-hydroxybenzoic acid, a useless and difficult-to-isolate byproduct, after the third step described below.

[0077] Furthermore, from the viewpoint of more accurately preventing the formation of by-product m-hydroxybenzoic acid, a more preferred embodiment is to react m-hydroxybenzaldehyde as a starting material with the Wittig reactant in an amount exceeding 2 molar equivalents (more preferably 2.1 molar equivalents or more) relative to the m-hydroxybenzaldehyde.

[0078] In addition, the reaction step (A) and the reaction step (B) are preferably reacted while cooling and stirring. In addition, the reaction step (B) becomes the first step in this embodiment (equivalent to the reaction step of X1 in the chemical reaction formula (II) described above).

[0079] Subsequently, in this embodiment, the following organic layer is used, which is obtained by separating the reaction mixture containing m-hydroxyphenylvinyl methyl ether obtained by the first step (including unreacted compounds) with hydrochloric acid water having a concentration of several wt%. After separating the organic layer with hydrochloric acid water and water, the solvent of the first step is distilled off under reduced pressure, an ester solution such as ethyl acetate is added and stirred, and the solid precipitated under cooling is filtered out. Subsequently, the ester solution 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-hydroxyphenylvinyl methyl ether. In addition, in this embodiment, the aforementioned viscous solid is a mixture (i.e., a viscous mixture) of the crude product of m-hydroxyphenylvinyl methyl ether and a portion of the by-products of the Wittig reaction generated by the first step.

[0080] Thereafter, in this embodiment, the second step (corresponding to the reaction step of Y1 in the chemical reaction formula (II) described above) is performed.

[0081] As a specific example, the second step is a step in which the viscous mixture containing m-hydroxystyryl methyl ether obtained in the first step is diluted with an organic solvent (e.g., acetonitrile), and then hydrochloric acid is added to the container containing the mixture to cause an acid hydrolysis reaction. In this embodiment, hydrochloric acid is used for the acid hydrolysis reaction, but at least some of the effects of this embodiment can be achieved by using dilute sulfuric acid, methanesulfonic acid, or p-toluenesulfonic acid instead of hydrochloric acid.

[0082] In this embodiment, after a sufficient time for the acid hydrolysis reaction to produce m-hydroxyphenylmethyl ether, the reaction mixture (representatively 2-(m-hydroxyphenyl)acetaldehyde) is not removed, that is, the subsequent third step (corresponding to the reaction step Z1 of the chemical reaction formula (II) described above) is carried out in situ.

[0083] As a specific example, the third step is a step in which an oxidizing agent is added to the reaction system having undergone the second step under appropriate temperature control, and 2-(m-hydroxyphenyl)acetaldehyde is oxidized by the oxidizing agent to obtain a reaction mixture containing 2-m-hydroxyphenylacetic acid.

[0084] In this embodiment, the solid is filtered from the reaction mixture to obtain a filtrate. After the organic solvent is distilled off under reduced pressure from the filtrate, an ester solution such as ethyl acetate and sodium hydroxide (NaOH) are added and stirred to separate the mixture, thereby obtaining an alkaline aqueous solution. This embodiment uses the organic layer obtained by adding the ester solution and concentrated hydrochloric acid to the aqueous solution for separation. The ester solution is distilled off under reduced pressure from the organic layer to obtain a crude product of 2-m-hydroxyphenylacetic acid as a viscous solid.

[0085] Furthermore, to purify the crude product, for example, a large amount of an organic solvent (e.g., toluene) is used to heat the crude product under reflux, followed by filtration, and the resulting filtrate is cooled to precipitate a light brown solid. This light brown solid is purified 2-m-hydroxyphenylacetic acid.

[0086] Furthermore, the third step of treating with an oxidizing agent is preferably performed at a temperature of -10°C to 10°C. If the third step is performed at a temperature below -10°C, the in-situ conversion of the generated 2-(m-hydroxyphenyl)acetaldehyde to the target 2-m-hydroxyphenylacetic acid is extremely slow, making it industrially impractical. If the third step is performed at a temperature exceeding 10°C, oxygen radicals attack the methylene carbon of the carbon-added carbon, causing a cleavage reaction followed by an oxidation reaction, potentially leading to the formation of m-hydroxybenzoic acid (the same compound as the oxidation product of the starting material).

[0087] Furthermore, the type of the oxidizing agent capable of achieving the reaction in the third step is not limited as long as it satisfies the following requirements (x) and (y).

[0088] (x) an oxidizing agent capable of introducing the aldehyde group in 2-(m-hydroxyphenyl)acetaldehyde into a carboxyl group

[0089] (y) an oxidizing agent that is unlikely to produce a side reaction with a functional group other than the aldehyde group

[0090] From this perspective, a preferred aspect of this embodiment is that the oxidizing agent used in the third step is at least one selected from the group consisting of peroxides including hydrogen peroxide and Oxone (registered trademark) (2KHSO5·KHSO4·K2SO4). Furthermore, among the two oxidizing agents described above, using Oxone (registered trademark) as the oxidizing agent is particularly preferred because it produces the effects of this embodiment with the highest accuracy.

[0091] By employing the method for producing 2-m-hydroxyphenylacetic acid according to this embodiment, m-hydroxystyryl methyl ether can be produced with high accuracy from m-hydroxybenzaldehyde, the starting material. In other words, the residual amount of this starting material 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. Furthermore, it is particularly noteworthy that by employing the method for producing 2-m-hydroxyphenylacetic acid according to this embodiment, 2-m-hydroxyphenylacetic acid can be produced efficiently and safely without the use of toxic CN source reactants or sulfur-based reactants requiring odor control, without requiring multiple steps.

[0092] Furthermore, by employing the method for producing 2-m-hydroxyphenylacetic acid according to this embodiment, the residual amount of the starting material can be reduced with high accuracy, as described above. Consequently, the amount of m-hydroxybenzaldehyde contained in the 2-m-hydroxyphenylacetic acid composition produced by this method can be reduced to less than 0.1 wt%.

[0093] <Second embodiment>

[0094] Hereinafter, a method for producing 2-m-hydroxyphenylacetic acid which is different from the first embodiment in the present embodiment will be described.

[0095] <Method for producing 2-m-hydroxyphenylacetic acid>

[0096] In this embodiment, a method for producing 2-m-hydroxyphenylacetic acid using an alkali metal salt of m-hydroxybenzaldehyde as a starting material is described.

[0097] As previously explained, chemical reaction formula (III) is a reaction formula using the sodium (Na) salt of m-hydroxybenzaldehyde as an example of an alkali metal salt of m-hydroxybenzaldehyde. Alternatively, a readily available alkali metal salt of m-hydroxybenzaldehyde can be used as a starting material, or generating the alkali metal salt of m-hydroxybenzaldehyde from a raw material compound of the alkali metal salt of m-hydroxybenzaldehyde is another possible embodiment.

[0098] <Synthesis process of starting materials>

[0099] As described above, in this embodiment, an alkali metal salt of m-hydroxybenzaldehyde is used as a starting material. The following is an example of synthesizing a sodium salt of m-hydroxybenzaldehyde as a representative example of an alkali metal salt of m-hydroxybenzaldehyde from m-hydroxybenzaldehyde as a starting compound.

[0100] The raw material compound, m-hydroxybenzaldehyde (Mw = 122.12, 204.7 mmol), was added to 100 mL of methanol and stirred at 0°C to 5°C. Simultaneously, 39.5 g of a 28 wt% methanol solution of sodium methoxide (Mw = 54.01, 204.7 mmol) was added dropwise. This step yielded a reaction mixture.

[0101] The methanol solvent was then distilled off under reduced pressure from the reaction mixture, which had returned to room temperature. This resulted in a solid, which was then dried under reduced pressure at 50°C for approximately 12 hours to obtain a light yellow crystalline sodium (Na) salt of m-hydroxybenzaldehyde (Mw = 144.1, 29.49 g), which serves as the starting material of this embodiment.

[0102] <Synthesis process of starting materials>

[0103] The sodium (Na) salt of m-hydroxybenzaldehyde synthesized in the above manner reacts with the Wittig reactant H3C-O-CH=PPh3 (Wittig reaction) to produce m-hydroxystyryl methyl ether (the first step in this embodiment) in the same manner as in the first embodiment.

[0104] Furthermore, in this embodiment, unlike the first embodiment, the amount of the Wittig reactant introduced only needs to be at least the reaction equivalent relative to the m-hydroxybenzaldehyde alkali metal salt (sodium salt in the aforementioned example). This is because, in the starting material of this embodiment, the protons of the hydroxyl groups have been replaced with sodium groups, and therefore, the influence of these hydroxyl groups is substantially eliminated during the Wittig reaction.

[0105] The subsequent second step in this embodiment (corresponding to the acid hydrolysis reaction step of Y2 in the chemical reaction formula (III) described above) is the same as the second step in the first embodiment (corresponding to the acid hydrolysis reaction step of Y1 in the chemical reaction formula (II) described above). In addition, the subsequent third step in this embodiment (corresponding to the oxidation reaction step of Z2 in the chemical reaction formula (III) described above) is the same as the third step in the first embodiment (corresponding to the acid hydrolysis reaction step of Z1 in the chemical reaction formula (II) described above).

[0106] As described above, even when an alkali metal salt of m-hydroxybenzaldehyde is used as the starting material, 2-m-hydroxyphenylacetic acid can be produced with high accuracy by performing the second and third steps in situ, as in the first embodiment. Furthermore, it is particularly noteworthy that, by employing the method for producing 2-m-hydroxyphenylacetic acid of this embodiment, as in the first embodiment, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without requiring multiple steps, without using any toxic CN source reactants or sulfur-based reactants requiring odor control.

[0107] <Example>

[0108] The embodiment will be described in detail with reference to the following examples, but the scope of the present invention and the embodiment is not limited to the description of the examples.

[0109] (Example 1)

[0110] [Regarding the method for producing 2-m-hydroxyphenylacetic acid using m-hydroxybenzaldehyde as a starting material]

[0111] (Generation of the Wittig reactant used in the first step)

[0112] In this example, 206 g (0.6 mol) of the raw material (methoxymethyl)triphenylphosphine 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 nitrogen was purged and the temperature within the reaction system was controlled to below 5°C. As a result, H3C-O-CH=PPh3, a Wittig reactant, was produced.

[0113] (Step 1)

[0114] Subsequently, 30.6 g (0.251 mol) of m-hydroxybenzaldehyde was added to the reaction system in which the Wittig reactant had been generated, with the temperature within the reaction system controlled to be below 20°C, and the mixture was stirred at room temperature. In this example, the amount of Wittig reactant generated in the Wittig reactant generation step was approximately 2.4 molar equivalents of the m-hydroxybenzaldehyde as the starting material.

[0115] The first reaction mixture (including unreacted compounds) from the first step was then cooled to approximately 10°C, and the organic layer was separated using 100 g of ice and 200 g of 5% aqueous hydrochloric acid. The organic layer was then further separated using aqueous hydrochloric acid and water, and the toluene solvent was distilled off under reduced pressure. 100 mL of ethyl acetate was added, and the mixture was stirred at approximately 0°C. This yielded a viscous mixture (first mixture) containing crude m-hydroxystyryl methyl ether and a by-product of the Wittig reaction.

[0116] Figure 1 This is an HPLC (High Performance Liquid Chromatography) chart of the mid-stage of the first step in this example, which was performed immediately after the dropwise addition of m-hydroxybenzaldehyde as a starting material to the reaction mixture under predetermined temperature conditions after the Wittig reactant was adjusted. Figure 2 This is an HPLC chart after the first step (Wittig reaction) in this example. Here, P1 in the figure is the Wittig reactant, Q1 is the starting material (m-hydroxybenzaldehyde). In addition, R1 is the by-product of the Wittig reaction, S1 is the product of the Wittig reaction, namely m-hydroxyphenylmethyl ether. In addition, T1 is toluene as a solvent. In addition, Figure 1 In the HPLC diagrams other than those shown, common compounds are denoted by common symbols unless otherwise specified.

[0117] like Figure 1 and Figure 2 As shown, the peak Q1 representing the starting material gradually decreases as the Wittig reaction proceeds. After the first step in this example, the peak height of Q1 has decreased to a level that is almost undetectable. Therefore, as described above, by reacting the starting material with 2 molar equivalents or more of the Wittig reactant (e.g., approximately 2.4 molar equivalents) relative to the starting material m-hydroxybenzaldehyde in the Wittig reaction, the residual amount of the starting material can be reduced with high accuracy.

[0118] (Step 2)

[0119] Thereafter, the first mixture was diluted with 300 ml of acetonitrile, and hydrochloric acid prepared by adding 5 g of water to 5 g of concentrated hydrochloric acid was added to the container containing the first mixture, and the mixture was stirred at room temperature, thereby causing an acid hydrolysis reaction (equivalent to the reaction step Y1 of the chemical reaction formula (II) described above).

[0120] Figure 3 This is an HPLC chart after the second step (acid hydrolysis reaction) in this example. In the figure, U1 represents 2-(m-hydroxyphenyl)acetaldehyde, and V1 represents residual ethyl acetate.

[0121] Here, in this embodiment, after a sufficient time (e.g., 12 hours) has passed before the completion of the second step, the reaction mixture (second mixture) containing 2-(m-hydroxyphenyl)acetaldehyde is not removed, that is, the subsequent third step (equivalent to the reaction step Z1 of the chemical reaction formula (II) described above) is carried out in situ.

[0122] (Step 3)

[0123] As described above, 153.7 g of the oxidizing agent Oxone (registered trademark) (2KHSO5·KHSO4·K2SO4) was added to the container containing the second mixture under in-situ conditions at a temperature of 0°C to 5°C, and stirred to obtain a reaction mixture containing 2-m-hydroxyphenylacetic acid (third mixture).

[0124] The solid was filtered out from the third mixture to obtain a filtrate. The acetonitrile was distilled off under reduced pressure from the filtrate, and then 240 mL of ethyl acetate and a 10 wt % aqueous sodium hydroxide (NaOH) solution were added and stirred to obtain an alkaline aqueous solution through liquid separation.

[0125] Thereafter, 300 mL of ethyl acetate and approximately 80 g of concentrated hydrochloric acid were added to the aqueous solution and stirred, followed by separation to obtain an organic layer, from which ethyl acetate was distilled off under reduced pressure to obtain a crude product of 2-m-hydroxyphenylacetic acid as a viscous solid.

[0126] To further purify the crude product, approximately 10 volumes of toluene and a small amount of activated carbon were added to the container containing the crude product. The mixture was heated under reflux and then filtered. In this example, the filtrate obtained by filtration was cooled to obtain 19.65 g of 2-m-hydroxyphenylacetic acid as a light brown solid. The yield in this example was approximately 51.6%.

[0127] Figure 4 This is an HPLC chart of the purified light brown solid material after the third step (oxidation reaction) in this example. In addition, W1 in the figure is 2-m-hydroxyphenylacetic acid.

[0128] like Figure 4 As shown in FIG1 , when the by-product (R1) of the Wittig reaction is removed, only the peak (W1) of 2-m-hydroxyphenylacetic acid is observed. Therefore, it is known that other compounds remain only in very small amounts.

[0129] in addition, Figure 5 This is the proton nuclear magnetic resonance (NMR) of the purified product obtained after the third step (oxidation reaction) in this example. 1 H NMR) spectrum. In addition, Figure 6This is the C-13 NMR spectra of the purified product obtained after the third step (oxidation reaction) in this example. 13 C NMR) spectrum. In addition, Figure 7 This is an IR spectrum (infrared absorption spectrum) of the purified product obtained after the third step (oxidation reaction) in this example.

[0130] like Figures 5 to 7 As shown in FIG. 1 , the purified 2-m-hydroxyphenylacetic acid contains almost no m-hydroxybenzaldehyde as a starting material. More specifically, it is found that the 2-m-hydroxyphenylacetic acid composition contains less than 0.1 wt % of m-hydroxybenzaldehyde as a starting material.

[0131] (Example 2)

[0132] [Regarding the method for producing 2-m-hydroxyphenylacetic acid using an alkali metal salt of m-hydroxybenzaldehyde as a starting material]

[0133] First, in a flask containing 120 mL of an organic solvent (toluene) (approximately 40% by volume relative to Example 1), 37.8 g (0.11 mol) of the raw material (methoxymethyl)triphenylphosphine chloride and 13.5 g (0.12 mol) of potassium tert-butoxide were reacted while nitrogen was purged, with the temperature within the reaction system controlled at 5°C or below, to produce H3C-O-CH=PPh3, a Wittig reactant. Since an alkali metal salt of m-hydroxybenzaldehyde was used as the starting material, the amounts of the raw material compound and potassium tert-butoxide were both approximately 20% by mole relative to Example 1.

[0134] (Step 1)

[0135] Subsequently, in this embodiment, in the reaction system in which the Wittig reactant was generated, 14.4 g (0.10 mol) of sodium (Na) salt of m-hydroxybenzaldehyde as a starting material described in the second embodiment was added while the temperature in the reaction system was controlled to be below 20° C., and the mixture was stirred at room temperature.

[0136] In addition, the amount of the starting material in this example is about 40% by 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, which is at least a reaction equivalent relative to the m-hydroxybenzaldehyde alkali metal salt (more specifically, the introduced amount is a slight excess of the reaction equivalent. A representative example is about 1.2 equivalents).

[0137] In the subsequent second and third steps, the amounts of the compounds used in each step were adjusted to approximately 40% of the amount of the compounds in Example 1, and the operations were carried out according to the various treatments (including purification) described in the second embodiment. As a result, 7.76 g of 2-m-hydroxyphenylacetic acid as a light brown solid was obtained by carrying out the same reaction as described in Example 1. The yield in this example was approximately 51.0%. In addition, various HPLC analyses and proton nuclear magnetic resonance (NMR) were carried out in the same manner as in Example 1. 1 H NMR) spectral analysis, C-13 nuclear magnetic resonance ( 13 CNMR) spectral analysis and IR spectral analysis showed the same results as in Example 1.

[0138] The present invention is not limited in any way by the above-described embodiments and examples, and modifications within the scope of the present invention including other combinations of the above-described embodiments and examples are also encompassed by the claims.

[0139] [Industrial Applicability]

[0140] 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 material for various applications (for example, functional materials used in various pharmaceuticals and cosmetics, or intermediates thereof) as a useful chemical substance or a useful production method.

Claims

1. A method for producing 2-m-hydroxyphenylacetic acid, comprising: In the first step, m-hydroxybenzaldehyde is reacted with a Wittig reactant represented by the general formula (I) in an amount of 2 or more molar equivalents relative to the m-hydroxybenzaldehyde to produce m-hydroxystyryl methyl ether; In the second step, 2-(m-hydroxyphenyl)acetaldehyde is produced by acid hydrolysis of the m-hydroxyphenylmethyl ether; and In the third step, the 2-(m-hydroxyphenyl)acetaldehyde is treated with an oxidizing agent; and The second step and the third step are performed in situ, General formula (I) [Chemistry 1] H3C-O-CH=PPh3 (I).

2. A method for producing 2-m-hydroxyphenylacetic acid, comprising: In the first step, an alkali metal salt of m-hydroxybenzaldehyde is reacted with a Wittig reactant represented by the general formula (I) in an amount equivalent to or greater than the alkali metal salt to produce m-hydroxystyryl methyl ether. In the second step, 2-(m-hydroxyphenyl)acetaldehyde is produced by acid hydrolysis of the m-hydroxyphenylmethyl ether; and In the third step, the 2-(m-hydroxyphenyl)acetaldehyde is treated with an oxidizing agent; and The second step and the third step are performed in situ, General formula (I) [Chemistry 2] H3C-O-CH=PPh3 (I). 3 . The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 , wherein the m-hydroxybenzaldehyde is reacted with the Wittig reactant in an amount exceeding 2 molar equivalents relative to the m-hydroxybenzaldehyde. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 or 2, wherein the third step is performed at a temperature of -10°C to 10°C. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 or 2, wherein the oxidizing agent is at least one selected from the group consisting of peroxides including hydrogen peroxide and Oxone (registered trademark) (2KHSO5·KHSO4·K2SO4).

6. 2-m-hydroxyphenylacetic acid, wherein the 2-m-hydroxyphenylacetic acid composition comprises less than 0.1 wt% of m-hydroxybenzaldehyde.

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