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CN120476101A - Method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid - Google Patents

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

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Publication number
CN120476101A
CN120476101A CN202480006888.1A CN202480006888A CN120476101A CN 120476101 A CN120476101 A CN 120476101A CN 202480006888 A CN202480006888 A CN 202480006888A CN 120476101 A CN120476101 A CN 120476101A
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CN
China
Prior art keywords
reaction
hydroxybenzaldehyde
hydroxyphenylacetic acid
producing
starting material
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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CN202480006888.1A
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Chinese (zh)
Inventor
山崎康宽
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Osaka Pharmaceutical Co Ltd
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Osaka Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C47/27—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供一种2‑间羟基苯乙酸的制造方法及2‑间羟基苯乙酸，能够安全且高效生产。本发明之一的2‑间羟基苯乙酸的制造方法包括：第1工序，通过使间羟基苯甲醛和相对于该间羟基苯甲醛为2摩尔当量以上的通式(I)所表示的维蒂希反应剂进行反应而生成间羟基苯乙烯基甲醚；第2工序，通过该间羟基苯乙烯基甲醚的酸水解反应而生成2‑(间羟基苯基)乙醛；及第3工序，使用氧化剂对该2‑(间羟基苯基)乙醛进行处理。此外，该2‑间羟基苯乙酸的制造方法是在原位进行前述第2工序和前述第3工序。通式(I)H3C‑O‑CH＝PPh3 (I)。

The present invention provides a method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid, which can be produced safely and efficiently. The method for producing 2-m-hydroxyphenylacetic acid according to one embodiment 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-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, the method for producing 2-m-hydroxyphenylacetic acid comprises performing the second and third steps in situ. General formula (I): H 3 C-O-CH=PPh 3 (I).

Description

Method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid
Technical Field
The invention relates to a method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid.
Background
2-M-hydroxyphenylacetic acid is a chemical, and is found to be at least useful as a preparation for preventing or treating allergic inflammatory skin diseases or skin barrier dysfunction (patent document 1), a chemical for plant preservation and/or plant growth promotion (patent document 2), and an activity as a GGT inhibitor (patent document 3), and is also useful as a starting material for an anti-aging agent added to cosmetics and the like, namely, carboxymethyl amino carboxypropyl methyl phosphonate (also referred to as Nahlsgen (registered trademark)).
On the other hand, 2-m-hydroxyphenylacetic acid is considered to be a substance obtained by converting a methyl group of m-cresol into a halogen to obtain a m-hydroxyphenylhalide, converting the m-hydroxyphenylhalide into m-hydroxyphenylcyanide, and hydrolyzing the m-hydroxyphenylhalide to obtain 2-m-hydroxyphenylacetic acid, if a source of CN (cyanide) (NaCN or KCN) is used, for example. In addition, TMSCN (trimethylcyanosilane) was developed as another CN source, and thus can be used as a bare source of CN based on F anions (Y. Yamasaki ET AL CHEM LETT 1985,1387-1390,and the references citedin).
In addition, a method for producing 2-m-hydroxyphenylacetic acid by using the Wilgmotel (Willgerodt) reaction has been disclosed in the past (non-patent document 2). In this reaction, a sulfur (S) -based reactant is used.
Background art literature
Patent literature
Patent document 1 Japanese patent No. 6550656
Patent document 2 Japanese patent No. 6457292
Patent document 3 Japanese patent No. 5082102
Non-patent literature
Non-patent document 1:J Am Chem Soc,2008,130,13110
Non-patent document 2:J Am Chem Soc,1946,68 (12), 2633-2634
Disclosure of Invention
[ Problem to be solved by the invention ]
However, it is not practical to use CN (cyanide) sources in manufacturing processes, at least in japan where regulations for safety are strict. In addition, even if TMSCN is available, the high price of TMSCN and reaction medium can cause production cost problems outside of safety.
In addition, even if the sulfur-based reactant disclosed in non-patent document 2 is used, it is difficult to use it from an industrial point of view because equipment for coping with the odor of sulfur-based gas is required and the number of steps before obtaining 2-m-hydroxyphenylacetic acid becomes large.
[ Means of solving the problems ]
The present inventors have made intensive studies on a method for producing 2-m-hydroxyphenylacetic acid, based on the awareness of the problems such as improvement of safety and reduction of the steps of the known technology. The present inventors have conducted repeated experiments and detailed analyses and studies, and as a result, have thought that it is possible to obtain 2-m-hydroxyphenylacetic acid safely and in a small number of steps, using m-hydroxybenzaldehyde or an alkali metal salt of the m-hydroxybenzaldehyde as a starting material, and using Wittig (Wittig) reaction from among a number of possible reactions, and further conducted studies.
However, the present inventors have presented a significant obstacle in the course of studying new manufacturing methods. Specifically, when a commercially available and readily available m-hydroxybenzaldehyde is used as a starting material, the wittig reaction is a nonaqueous reaction, and therefore it is generally difficult to apply the wittig reaction to a starting material of a derivative having an acidic proton such as a hydroxyl group in a molecule.
In addition, if the m-hydroxybenzaldehyde or an alkali metal salt of the m-hydroxybenzaldehyde is used as a starting material, there is a problem that it is difficult to remove the reaction mixture generated by the wittig reaction by separation filtration using a known mineral oily solvent. In detail, when using the wittig reaction, it was found that if the starting material was employed, it was difficult to remove the reaction mixture containing triphenylphosphine oxide (Ph 3 PO, triphenylphosphine oxide), which is a representative by-product of the reaction.
Accordingly, the present inventors have attempted to react 2-methoxymethyltriphenylphosphine derivatives, which are wittig reactants represented by the following general formula (I), in an amount far exceeding the reaction equivalent of the wittig reaction, with a starting material of m-hydroxybenzaldehyde.
[ Chemical 1]
H3C-O-CH＝PPh3 (I)
As a result, it is very interesting that the following characteristic effects (a) and (b) may be produced.
(A) A part of the wittig reagent may replace the proton of the hydroxyl group of the m-hydroxybenzaldehyde as a starting material with a phosphine group.
(B) The other part of the wittig reagent reacts with the aldehyde group of the starting material, whereby an enol derivative can be produced, i.e., a carburisation reaction (One-carbon Homologation Reaction) is achieved which increases the carbon number by 1.
Here, it is generally considered by those skilled in the art that the use of a starting material having a hydroxyl group is not suitable because the wittig reaction is a nonaqueous reaction. However, one of the remarkable characteristics of the above-described attempts is that the effect (a) is utilized by introducing a wittig reagent in an amount of the reaction equivalent of the far-reaching wittig reaction, that is, replacing the proton of the hydroxyl group with the phosphine group derived from the wittig reagent, whereby it can be said that a starting material having a hydroxyl group which has been considered unsuitable in the past can be put into practical use.
In addition, H 3C-O-CH＝PPh3 as a Wittig reagent is not limited to use as a ready-made compound. For example, wittig reagent H 3C-O-CH＝PPh3 can be produced by reacting (methoxymethyl) triphenylphosphine chloride (H 3C-O-CH2-P+(Cl-)Ph3) with a strong base (e.g., potassium t-butoxide) in situ in a solvent commonly used in wittig reactions (e.g., toluene or tetrahydrofuran). Thus, in this case, the use of H 3C-O-CH＝PPh3 as a Wittig reagent further includes subjecting the Wittig reagent, which can be formed from the starting compounds, and m-hydroxybenzaldehyde as a starting material to the Wittig reaction.
The above-described attempt was applied to a step (reaction step) of the 1 st stage, which is intended to obtain 2-m-hydroxyphenylacetic acid by the following chemical reaction formula (II). In particular, as described above, the wittig reagent can exert the 2 actions by reacting the m-hydroxybenzaldehyde with the wittig reagent in an amount far exceeding the reaction equivalent of the wittig reaction (X 1 of the following chemical formula (II)). The following chemical reaction formula (II) is a reaction formula in which H 3C-Ο-CH＝PPh3 is used as an example of the wittig reagent.
[ Chemical 2]
Here, in order to realize the step (chemical reaction step) represented by X 1 of the chemical reaction formula (II) with high accuracy, it is a preferred mode to react the m-hydroxybenzaldehyde with the wittig reagent in an amount of 2 times or more (more preferably more than 2 times, still more preferably 2.1 times or more) the reaction equivalent of the wittig reaction. This is because, if m-hydroxybenzaldehyde as a starting material remains in the reaction system, this remaining m-hydroxybenzaldehyde is directly oxidized to produce m-hydroxybenzoic acid (m-hydroxybenzoic acid) in the subsequent step shown by Z 1, i.e., oxidation reaction, to produce a mixture with 2-m-hydroxyphenylacetic acid. Since the m-hydroxybenzoic acid and 2-m-hydroxyphenylacetic acid differ by only one methylene chain, it can be said that it is substantially impossible to identify 2-m-hydroxyphenylacetic acid by various analyses or to isolate only 2-m-hydroxyphenylacetic acid. As a result, the target 2-m-hydroxyphenylacetic acid and m-hydroxybenzoic acid are mixed, and thus, there arises a problem such as a decrease in the utility of the chemicals described in the background art.
On the other hand, in order to realize the process (reaction process) represented by X 1 of the chemical reaction formula (II) with high accuracy, the upper limit of the amount of the wittig reagent to be introduced is not particularly limited. In addition, from the viewpoints of introducing an unnecessarily large amount of the catalyst, preventing or suppressing the influence of the secondary reaction, and/or optimizing the accompanying purification step, it is preferable to set the reaction equivalent of the wittig reagent to 3 times or less (more preferably 2.5 times or less).
In addition, in the course of the present inventors, in order to realize each step (reaction step) shown by Y 1 and Z 1 in the chemical reaction formula shown in (II) with high accuracy, that is, a step of obtaining 2-m-hydroxyphenylacetic acid from the produced enol derivative by acid hydrolysis, the present inventors have demanded to overcome new obstacles.
In particular, the enol derivatives are readily hydrolyzed under acidic conditions. Thus, 2- (m-hydroxyphenyl) acetaldehyde having 1 carbon added thereto can be produced from m-hydroxybenzaldehyde as a starting material. However, it was confirmed that this 2- (m-hydroxyphenyl) acetaldehyde was unstable and was hardly isolated.
Accordingly, as a result of further repeated studies and analyses, the present inventors have found that 2-m-hydroxyphenylacetic acid can be produced by performing an oxidation reaction in situ in a reaction medium of an acid hydrolysis reaction, without isolating the 2- (m-hydroxyphenyl) acetaldehyde.
As a result, the present inventors have found that 2-m-hydroxyphenylacetic acid can be produced from commercially available starting materials safely and efficiently without going through a plurality of steps without using a toxic CN-source reactant or a sulfur-based reactant requiring odor control at all. One of the inventions is created on the basis of the viewing angle and the background.
A process for producing 2-m-hydroxyphenylacetic acid, which comprises the steps of (1) reacting m-hydroxybenzaldehyde with a wittig reagent represented by the general formula (I) in an amount of not less than 2 molar equivalents relative to the m-hydroxybenzaldehyde to produce m-hydroxystyryl methyl ether, (2) producing 2- (m-hydroxyphenyl) acetaldehyde by acid hydrolysis of the m-hydroxystyryl methyl ether, and (3) treating the 2- (m-hydroxyphenyl) acetaldehyde with an oxidizing agent. The process for producing 2-m-hydroxyphenylacetic acid is carried out in situ by the steps 2 and 3.
General formula (I)
[ Chemical 3]
H3C-O-CH＝PPh3 (I)
According to the method for producing 2-m-hydroxyphenylacetic acid, m-hydroxystyryl methyl ether can be produced from a starting material with high accuracy by reacting m-hydroxybenzaldehyde as the starting material with 2 molar equivalents or more of the wittig reagent in step 1 (a reaction step corresponding to X 1 of the chemical reaction formula (II)). In other words, the residual amount of the starting material after the 1 st step can be reduced with high accuracy. In addition, 2-m-hydroxyphenylacetic acid can be produced with high accuracy by performing the 2 nd step (the reaction step corresponding to Y 1 of the chemical formula (II)) and the 3 rd step (the reaction step corresponding to Z 1 of the chemical formula (II)) in situ in the production method. Further, if this production method is adopted, there is no need to adjust the alkali metal salt of m-hydroxybenzaldehyde in advance as compared with another production method of 2-m-hydroxyphenylacetic acid using the alkali metal salt of m-hydroxybenzaldehyde as a starting material described below, and therefore, from this point of view, it is possible to eliminate the need for a special material and to simplify the production process.
In addition, the present inventors have tried to replace the m-hydroxybenzaldehyde as a starting material in the step 1, with an alkali metal salt of m-hydroxybenzaldehyde as a starting material in the course of continuous studies. As a result, it was found that the amount of the wittig reagent represented by the general formula (I) used can be reduced.
The following chemical formula (III) is a reaction formula when a sodium (Na) salt of m-hydroxybenzaldehyde, which is an example of an alkali metal salt of m-hydroxybenzaldehyde, is used. As shown in the chemical reaction formula (III), in the case of using sodium (Na) salt of m-hydroxybenzaldehyde as a starting material, the wittig reagent does not substantially need to exert the 2 actions, i.e., (a) action among the actions of (a) and (b). Accordingly, the present inventors have found that the same effect as the step 1 in the above-mentioned process for producing 2-m-hydroxyphenylacetic acid using m-hydroxybenzaldehyde as a starting material can be obtained by introducing the wittig reagent in an amount necessary for the action of (b), in other words, for carrying out the carburetion reaction.
[ Chemical 4]
In the above description, 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 sodium (Na) salt of m-hydroxybenzaldehyde. The potassium (K) salt of m-hydroxybenzaldehyde may also achieve the same trend of the result as the sodium (Na) salt.
Accordingly, the amount of the wittig reagent to be introduced for realizing the step (reaction step) shown by X 2 of the chemical formula (III) with high accuracy is not less than the reaction equivalent to the alkali metal salt of m-hydroxybenzaldehyde. The upper limit of the amount to be introduced is not particularly limited. However, from the viewpoints of introducing an unnecessarily large amount of the catalyst, preventing or suppressing the influence of the secondary reaction, and/or optimizing the accompanying purification step, it is preferable to set the reaction equivalent of the reactants to be 2 times (more preferably 1.5 times or less) smaller than Yu Weidi.
The present inventors have found that the technical problems of the steps (reaction steps) shown by Y 2 and Z 2 in the chemical reaction formula shown in (III) are the same as those of the case where m-hydroxybenzaldehyde is used as the starting material, and that the problems can be overcome by adopting the same solutions as those described above.
As a result, the present inventors have found that 2-m-hydroxyphenylacetic acid can be produced safely and efficiently by using an alkali metal salt of m-hydroxybenzaldehyde as a starting material without using a toxic CN source reactant at all or a sulfur type reactant requiring odor control. Another aspect of the invention is created based on the viewing angle and the background.
The other method for producing 2-m-hydroxyphenylacetic acid according to the present invention comprises a1 st step of reacting an alkali metal salt of m-hydroxyphenylformaldehyde with a wittig reagent represented by the general formula (I) in a reaction equivalent or more to the alkali metal salt to produce m-hydroxystyryl methyl ether, a 2 nd step of producing 2- (m-hydroxyphenyl) acetaldehyde by an acid hydrolysis reaction of the m-hydroxystyryl methyl ether, and a 3 rd step of treating the 2- (m-hydroxyphenyl) acetaldehyde with an oxidizing agent. The process for producing 2-m-hydroxyphenylacetic acid is carried out in situ by the steps 2 and 3.
General formula (I)
[ Chemical 5]
H3C-O-CH＝PPh3 (I)
According to this production method, in step 1, the alkali metal salt of m-hydroxybenzaldehyde is used as a starting material, so that the amount of the wittig reagent in the reaction of the alkali metal salt with the wittig reagent represented by the general formula (I) is sufficient as long as the amount is equal to or more than the reaction equivalent. In other words, the amount of the wittig reagent can be suppressed to be low, that is, lower than when m-hydroxybenzaldehyde is used as a starting material. In addition, 2-m-hydroxyphenylacetic acid can be produced with high accuracy by performing the 2 nd step (the reaction step corresponding to Y 2 of the chemical formula (III)) and the 3 rd step (the reaction step corresponding to Z 2 of the chemical formula (III)) in the production method in situ.
In addition, in the 2-m-hydroxyphenylacetic acid composition of the present invention, the 2-m-hydroxyphenylacetic acid composition includes less than 0.1wt% of m-hydroxybenzaldehyde.
According to the 2-m-hydroxyphenylacetic acid composition, by adopting the described method for producing 2-m-hydroxyphenylacetic acid, it is possible to achieve high purity of 2-m-hydroxyphenylacetic acid, that is, the content of m-hydroxybenzaldehyde as a starting material, in other words, the residual amount of m-hydroxybenzaldehyde is reduced to less than 0.1wt%. In addition, the 2-m-hydroxyphenylacetic acid composition does not contain a toxic CN source reactant or a sulfur-based reactant requiring odor control, and thus has high safety.
In the present application, the term "2-m-hydroxyphenylacetic acid composition" refers to a composition which may contain other substances (for example, m-hydroxybenzaldehyde as a starting material or an alkali metal salt of m-hydroxybenzaldehyde, or a by-product generated in the production process of 2-m-hydroxyphenylacetic acid) in addition to 2-m-hydroxyphenylacetic acid, and the composition of the "2-m-hydroxyphenylacetic acid composition" is not particularly limited.
[ Effect of the invention ]
According to the method for producing 2-m-hydroxyphenylacetic acid of one of the present invention, m-hydroxystyryl methyl ether can be produced from a starting material with high accuracy. In addition, by performing the 2 nd step (corresponding to the acid hydrolysis step) and the 3 rd step (corresponding to the oxidation step) in the production method in situ, 2-m-hydroxyphenylacetic acid obtained by the carburetion reaction of the starting material can be produced with high accuracy. 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 sulfur type reactant that requires odor control.
In addition, according to the 2-m-hydroxyphenylacetic acid composition of one aspect of the present invention, it is possible to achieve high purity of 2-m-hydroxyphenylacetic acid, i.e., the content of m-hydroxybenzaldehyde as a starting material, in other words, the residual amount of m-hydroxybenzaldehyde is reduced to less than 0.1wt%. In addition, the 2-m-hydroxyphenylacetic acid composition does not contain a toxic CN source reactant or a sulfur-based reactant requiring odor control, and thus has high safety.
Drawings
FIG. 1 is a HPLC (high Performance liquid chromatography) diagram showing a stage in the middle of the 1 st step immediately after the completion of the dropwise addition of m-hydroxybenzaldehyde as a starting material to the reaction mixture under a predetermined temperature condition after the adjustment of the Wittig reagent in example 1.
FIG. 2 is an HPLC chart after the 1 st step (Wittig reaction) in example 1.
FIG. 3 is an HPLC chart after the 2 nd step (acid hydrolysis reaction) in example 1.
Fig. 4 is an HPLC diagram after the 3 rd step (oxidation reaction) in example 1.
FIG. 5 is a proton nuclear magnetic resonance (1 H NMR) spectrum of the purified product obtained after the 3 rd step (oxidation reaction) in example 1.
FIG. 6 is a C-13 nuclear magnetic resonance (13 C NMR) spectrum of the purified product obtained after the 3 rd step (oxidation reaction) in example 1.
FIG. 7 is an IR spectrum (infrared absorption spectrum) of a purified product obtained after the 3 rd step (oxidation reaction) in example 1.
Detailed Description
< Embodiment 1 >
Hereinafter, a method for producing 2-m-hydroxyphenylacetic acid and the 2-m-hydroxyphenylacetic acid according to this embodiment will be described.
< Method for producing 2-m-hydroxyphenylacetic acid >
In this embodiment, a method for producing 2-m-hydroxyphenylacetic acid using m-hydroxybenzaldehyde as a starting material will be described.
In this embodiment, the following reaction steps (a) and (B) are performed in a solvent (e.g., toluene or tetrahydrofuran) commonly used in the wittig reaction to cause the wittig reaction to proceed with H 3C-O-CH＝PPh3 as a wittig reagent and m-hydroxybenzaldehyde as a starting material. Therefore, the reaction step (a) and the reaction step (B) are performed so-called in-situ.
(A) A step of reacting a commercially available starting compound (methoxymethyl) triphenylphosphine chloride (H 3C-O-CH2-P+(Cl-)Ph3) with a strong base (e.g., potassium t-butoxide) to produce the wittig reagent
(B) A step of producing m-hydroxystyryl methyl ether by subjecting m-hydroxybenzaldehyde and the wittig reagent to wittig reaction after the reaction of (A)
More specifically, after the reaction step (a), that is, the step of producing the wittig reagent, m-hydroxybenzaldehyde as a starting material is introduced into a container (for example, a flask) containing the wittig reagent, whereby m-hydroxystyryl methyl ether can be produced by the in-situ wittig reaction. As shown in the present embodiment, by performing the reaction step (a) and the reaction step (B) in situ, it is possible to use commercially available raw material compounds and without intentionally separating the wittig reagent, and thus it is possible to produce m-hydroxystyryl methyl ether in a very efficient and less wasteful manner in terms of yield.
Here, from the viewpoint of producing the reaction step (B) with high accuracy, it is preferable that the amount of the wittig reagent produced in the reaction step (a) should be far beyond the amount of the reaction equivalent in the wittig reaction with respect to the starting material, more specifically, should be 2 molar equivalents or more, or the amounts of the raw material compound and the strong base should be adjusted to reach such an amount. As described above, minimizing the residual amount of the starting material (m-hydroxybenzaldehyde) after the reaction step (B) can prevent the formation of m-hydroxybenzoic acid, a by-product which is useless and difficult to be isolated, after the following step 3 with high accuracy.
In addition, from the viewpoint of preventing the formation of m-hydroxybenzoic acid as a by-product with further high accuracy, it is a more preferable form to react m-hydroxybenzaldehyde as a starting material with the wittig reagent in an amount exceeding 2 molar equivalents (more preferably 2.1 molar equivalents or more) with respect to the m-hydroxybenzaldehyde.
In addition, it is preferable that the reaction step (A) and the reaction step (B) are both carried out while cooling and stirring. The reaction step (B) is the 1 st step (corresponding to the reaction step of X 1 in the chemical reaction formula (II) described above) in the present embodiment.
Thereafter, in this embodiment, an organic layer obtained by separating a reaction mixture containing m-hydroxystyryl methyl ether obtained in step 1 (containing an unreacted compound) or the like with hydrochloric acid water having a concentration of several wt% is used. After the organic layer was separated into aqueous hydrochloric acid and water, the solvent in step 1 was distilled off under reduced pressure, and an ester solution such as ethyl acetate was added thereto and stirred, whereby solids precipitated under cooling were filtered. Thereafter, the ester solution such as ethyl acetate was distilled off under reduced pressure from the obtained organic layer to obtain a viscous solid, which was a crude product of m-hydroxystyryl methyl ether. In the present embodiment, the viscous solid is a mixture (i.e., a viscous mixture) of the crude product of m-hydroxystyryl methyl ether and a part of the by-products of the wittig reaction generated in the step 1.
Thereafter, in this embodiment, the step 2 (corresponding to the reaction step of Y 1 in the chemical reaction formula (II) described above) is performed.
As a specific example, the 2 nd step is a step of diluting the viscous mixture containing m-hydroxystyryl methyl ether obtained in the 1 st step with an organic solvent (for example, acetonitrile) and then adding hydrochloric acid to a container for holding the mixture to generate an acid hydrolysis reaction. In the present embodiment, hydrochloric acid is used for the acid hydrolysis reaction, but dilute sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, or the like may be used instead of hydrochloric acid, so that at least a part of the effects of the present embodiment may be exhibited.
In this embodiment, after a time sufficient for the acid hydrolysis reaction to produce m-hydroxystyryl methyl ether, the reaction mixture (typically 2- (m-hydroxyphenyl) acetaldehyde) is not withdrawn, i.e., the subsequent step 3 (corresponding to the reaction step of Z 1 of the chemical formula (II) described above) is performed in situ.
As a specific example, the 3 rd step is a step of adding an oxidizing agent to the reaction system in which the 2 nd step has been performed under an appropriate temperature control. By the oxidation reaction of 2- (m-hydroxyphenyl) acetaldehyde using the oxidizing agent, a reaction mixture containing 2-m-hydroxyphenylacetic acid is obtained.
In the present embodiment, the solid is filtered from the reaction mixture to obtain a filtrate, the organic solvent is distilled off from the filtrate under reduced pressure, and then an ester solution such as ethyl acetate and sodium hydroxide (NaOH) are added thereto and stirred, whereby an alkaline aqueous solution is obtained by separation. The present embodiment employs an organic layer obtained by subsequently adding the ester solution and concentrated hydrochloric acid to the aqueous solution to separate the liquid. The organic layer was distilled off under reduced pressure to obtain a crude product of 2-m-hydroxyphenylacetic acid as a viscous solid.
Further, in order to purify the crude product, for example, the crude product is subjected to a heat reflux treatment using a large amount of an organic solvent (e.g., toluene), and then is subjected to a filtration treatment, and the obtained filtrate is cooled, whereby a light brown solid substance is precipitated. The light brown solid material was purified 2-m-hydroxyphenylacetic acid.
The 3 rd step of the treatment with the oxidizing agent is preferably performed at a temperature of-10 ℃ or higher and 10 ℃ or lower. If this 3 rd step is performed at a temperature of less than-10 ℃, the process of in-situ conversion of the generated 2- (m-hydroxyphenyl) acetaldehyde into the target 2-m-hydroxyphenylacetic acid is extremely slow, and is not industrially practical, and if this 3 rd step is performed at a temperature of more than 10 ℃, oxygen radicals attack the methylene carbon which is a carburised carbon, thereby causing oxidation reaction to be provided after cleavage reaction, and thus there is a possibility that a problem of formation of m-hydroxybenzoic acid (the same compound as the oxidation product of the starting material) occurs.
The type of the oxidizing agent capable of performing the reaction in the 3 rd step is not limited as long as the oxidizing agent satisfies the following requirements (x) and (y).
(X) Oxidizing agent capable of realizing reaction of introducing aldehyde group in 2- (m-hydroxyphenyl) acetaldehyde into carboxyl group
(Y) an oxidizing agent which is difficult to cause side reaction with a functional group other than the aldehyde group
From the above point of view, a preferred embodiment of the present embodiment is that the oxidizing agent used in the 3 rd step is at least 1 selected from the group consisting of peroxides including hydrogen peroxide and Oxone (registered trademark) (2 KHSO 5·KHSO4·K2SO4). Among the examples of the 2 kinds of oxidizing agents, particularly, oxone (registered trademark) is preferable because the effect of the present embodiment is most accurately produced.
By adopting 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 as a starting material. In other words, the residual amount of the starting material after the 1 st step can be reduced with high accuracy. In addition, by performing the 2 nd and 3 rd steps in the production method in situ, 2-m-hydroxyphenylacetic acid can be produced with high accuracy. In addition, it is particularly noted that by adopting the method for producing 2-m-hydroxyphenylacetic acid according to the present embodiment, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without using a toxic CN source reactant or a sulfur-based reactant requiring odor control.
Further, by adopting the method for producing 2-m-hydroxyphenylacetic acid according to this embodiment, as described above, the residual amount of the starting material can be reduced with high accuracy. Therefore, the amount of m-hydroxybenzaldehyde contained in the 2-m-hydroxyphenylacetic acid composition produced by the production method can be reduced to less than 0.1wt%.
< Embodiment 2>
The following describes a method for producing 2-m-hydroxyphenylacetic acid, which is different from embodiment 1 of the present embodiment.
< Method for producing 2-m-hydroxyphenylacetic acid >
In this embodiment, a method for producing 2-m-hydroxyphenylacetic acid using an alkali metal salt of m-hydroxybenzaldehyde as a starting material will be described.
As described above, the chemical formula (III) is a formula in which sodium (Na) salt of m-hydroxybenzaldehyde is used as an example of an alkali metal salt of m-hydroxybenzaldehyde. In addition, an alkali metal salt of m-hydroxybenzaldehyde can be used as a starting material, but the formation of an alkali metal salt of m-hydroxybenzaldehyde from a starting compound of an alkali metal salt of m-hydroxybenzaldehyde is also one form that can be used.
< Procedure for synthesizing starting Material >
As described above, in the present embodiment, an alkali metal salt of m-hydroxybenzaldehyde is used as a starting material. The synthesis of sodium salt of m-hydroxybenzaldehyde as an example of representative alkali metal salt of m-hydroxybenzaldehyde from m-hydroxybenzaldehyde as a raw material compound is shown below, for example.
M-hydroxybenzaldehyde (mw=122.12, 204.7 mmol) as a raw material compound was put into 100mL (mL) of methanol, and stirred at a temperature of 0 ℃ to 5 ℃ while 39.5g (mw=54.01, 204.7 mmol) of 28wt% methanol solution of sodium methoxide was added dropwise. This step produces a reaction mixture.
Thereafter, the solvent methanol was distilled off from the reaction mixture recovered to room temperature under reduced pressure. As a result, a solid was obtained, and the obtained solid was dried under reduced pressure at 50 ℃ for about 12 hours, whereby a pale yellow crystalline sodium m-hydroxybenzaldehyde (Na) salt (mw=144.1, 29.49 g) as the starting material of the present embodiment was able to be obtained.
< Procedure for synthesizing starting Material >
The sodium (Na) salt of m-hydroxybenzaldehyde synthesized in the manner described above is reacted with the wittig reagent H 3C-O-CH＝PPh3 (wittig reaction) to produce m-hydroxystyryl methyl ether (step 1 in the present embodiment) similarly to the step 1.
In this embodiment, unlike embodiment 1, the amount of the wittig reagent to be introduced is not less than the reaction equivalent to the alkali metal salt of m-hydroxybenzaldehyde (sodium salt in the above example). This is because, in the starting material of the present embodiment, the proton of the hydroxyl group has been substituted with a sodium group, and therefore, the effect of the hydroxyl group has virtually disappeared when the wittig reaction is performed.
The following step 2 (the acid hydrolysis step corresponding to Y 2 of the chemical formula (III)) in this embodiment is the same as the step 2 (the acid hydrolysis step corresponding to Y 1 of the chemical formula (II)) in the following embodiment. The following step 3 (the oxidation reaction step corresponding to Z 2 of the chemical formula (III)) in this embodiment is the same as the step 3 (the acid hydrolysis reaction step corresponding to Z 1 of the chemical formula (II)) in embodiment 1.
As described above, even when an alkali metal salt of m-hydroxybenzaldehyde is used as a starting material, 2-m-hydroxyphenylacetic acid can be produced with high accuracy by performing the 2 nd step and the 3 rd step in situ as in embodiment 1. In addition, it is particularly noted that by using the method for producing 2-m-hydroxyphenylacetic acid of the present embodiment, as in embodiment 1, 2-m-hydroxyphenylacetic acid can be produced safely and efficiently without using a toxic CN source reactant or a sulfur-based reactant requiring odor control.
< Example >
The embodiments are specifically described by the following examples, but the scope of the present invention and the embodiments are not limited by the description of the examples.
Example 1
[ Method for producing 2-m-hydroxyphenylacetic acid Using m-hydroxybenzaldehyde as starting Material ]
(Production of the wittig reagent used in step 1)
In this example, 206g (0.6 mol) of a raw material compound (methoxymethyl) triphenylphosphine chloride and 74.1g (0.66 mol) of potassium tert-butoxide were reacted in a flask containing 300mL of an organic solvent (toluene) while introducing nitrogen gas, at a temperature of 5℃or lower in a reaction system. As a result, H 3C-O-CH＝PPh3 was produced as a Wittig reagent.
(Step 1)
Thereafter, 30.6g (0.251 mol) of m-hydroxybenzaldehyde was added to the reaction system in which the wittig reagent was formed, and the mixture was stirred at room temperature while the temperature in the reaction system was controlled to 20 ℃ or lower. In this example, the amount of the wittig reagent produced in the wittig reagent production step was about 2.4 molar equivalents of the m-hydroxybenzaldehyde as the starting material.
Thereafter, the 1 st reaction mixture (containing unreacted compounds) in the 1 st step was cooled to about 10℃and the organic layer was separated by using 100g of ice and 200g of 5% hydrochloric acid water. Subsequently, after the organic layer was further distilled off with hydrochloric acid water and a water solution, toluene as an organic solvent was distilled off under reduced pressure, 100mL of ethyl acetate was added thereto, and stirring was performed at a temperature of about 0 ℃. As a result, a viscous mixture (mixture 1) containing a crude product of m-hydroxystyryl methyl ether and a by-product of the Wittig reaction was obtained.
FIG. 1 is a HPLC (high Performance liquid chromatography) diagram showing a stage in the middle of the 1 st step immediately after the completion of the dropwise addition of m-hydroxybenzaldehyde as a starting material to the reaction mixture under a predetermined temperature condition after the adjustment of the Wittig reagent in this example. Fig. 2 is an HPLC diagram after step 1 (wittig reaction) in this example. Here, P1 in the figure is a wittig reagent, and Q1 is a starting material (m-hydroxybenzaldehyde). R1 is a by-product of the Wittig reaction, and S1 is m-hydroxystyryl methyl ether which is a product of the Wittig reaction. In addition, T1 is toluene as a solvent. In the HPLC diagrams other than fig. 1, common symbols are given to common compounds unless otherwise indicated.
As shown in fig. 1 and 2, as the wittig reaction proceeds, the peak of Q1 representing the starting material gradually becomes smaller, and after step 1 in this example, the peak height of Q1 becomes smaller to such an extent that it is hardly confirmed. Therefore, as described above, by reacting the wittig reagent (for example, about 2.4 molar equivalents) with the starting material in the wittig reaction in an amount of 2 molar equivalents or more with respect to the m-hydroxybenzaldehyde as the starting material, the residual amount of the starting material can be reduced with high accuracy.
(Step 2)
Thereafter, the 1 st mixture was diluted with 300ml of acetonitrile, and then 5g of water was added to 5g of concentrated hydrochloric acid to prepare hydrochloric acid in a container containing the 1 st mixture, followed by stirring at room temperature, whereby an acid hydrolysis reaction (corresponding to the reaction step of Y 1 in the chemical reaction formula (II) described above) was generated.
Fig. 3 is an HPLC diagram after step 2 (acid hydrolysis) in this example. In the figure, U1 is 2- (m-hydroxyphenyl) acetaldehyde, and V1 is residual ethyl acetate.
In this example, after a sufficient time (for example, 12 hours) has elapsed before the completion of the step2, the reaction mixture (step 2) containing 2- (m-hydroxyphenyl) acetaldehyde is not taken out, that is, the subsequent step 3 (corresponding to the reaction step of Z 1 of the chemical formula (II) described above) is performed in situ.
(Step 3)
As described above, 153.7g of an oxidizing agent Oxone (registered trademark) (2 KHSO 5·KHSO4·K2SO4) was added to the vessel containing the 2 nd mixture under in-situ conditions and at a temperature of 0℃to 5℃and below, and stirred, to obtain a reaction mixture (3 rd mixture) containing 2-m-hydroxyphenylacetic acid.
The solid was filtered from the 3 rd mixture to obtain a filtrate, from which the acetonitrile was distilled off under reduced pressure, and 240mL of ethyl acetate and a 10wt% aqueous sodium hydroxide (NaOH) solution were added and stirred, whereby an alkaline aqueous solution was obtained by separation.
Thereafter, 300mL of ethyl acetate and about 80g of concentrated hydrochloric acid were added again to the aqueous solution and stirred, followed by separation to obtain an organic layer, and ethyl acetate was distilled off under reduced pressure from the obtained organic layer. As a result, a crude product of 2-m-hydroxyphenylacetic acid was obtained as a viscous solid.
Thereafter, in order to further purify the crude product, about 10 times by volume of toluene and a small amount of activated carbon of the crude product were added to a vessel containing the crude product, and after heat refluxing treatment, filtration treatment was performed. In this example, the filtrate obtained by this filtration treatment was cooled, whereby 19.65g of 2-m-hydroxyphenylacetic acid, which was a light brown solid, was obtained. The yield of this example was about 51.6%.
Fig. 4 is an HPLC diagram of the light brown solid material purified after the 3 rd step (oxidation reaction) in this example. In the figure, W1 is 2-m-hydroxyphenylacetic acid.
As shown in FIG. 4, if the by-product (R1) of the Wittig reaction is removed, only the peak (W1) of 2-m-hydroxyphenylacetic acid can be observed. Therefore, it is found that other compounds remain only in a very small amount.
FIG. 5 is a proton nuclear magnetic resonance (1 H NMR) spectrum of the purified product obtained after the 3 rd step (oxidation reaction) in this example. FIG. 6 is a C-13 nuclear magnetic resonance (13 C NMR) spectrum of the purified product obtained after the 3 rd step (oxidation reaction) in this example. Further, FIG. 7 is an IR spectrum (infrared absorption spectrum) of a purified product obtained after the 3 rd step (oxidation reaction) in this example.
As shown in fig. 5 to 7, the purified 2-m-hydroxyphenylacetic acid hardly contains m-hydroxybenzaldehyde as a starting material. More specifically, it is found that the starting material, i.e., m-hydroxybenzaldehyde, contained in the 2-m-hydroxyphenylacetic acid composition is less than 0.1wt%.
Example 2
[ Method for producing 2-m-hydroxyphenylacetic acid Using an alkali metal salt of m-hydroxybenzaldehyde as a starting material ]
First, in the same manner as in example 1, a flask containing 120mL of an organic solvent (toluene) (an amount of about 40% by volume based on example 1) was charged with nitrogen gas, and 37.8g (0.11 mol) of a raw material compound (methoxymethyl) triphenylphosphine chloride and 13.5g (0.12 mol) of potassium tert-butoxide were reacted with each other in a reaction system at a temperature of 5 ℃ or less to produce H 3C-O-CH＝PPh3 as a wittig reagent. Further, since an alkali metal salt of m-hydroxybenzaldehyde was used as a starting material, the amounts of the starting compound and the potassium t-butoxide were each about 20% in terms of a molar ratio relative to example 1.
(Step 1)
Thereafter, in this example, 14.4g (0.10 mol) of sodium m-hydroxybenzaldehyde (Na) salt as a starting material described in embodiment 2 was added to the reaction system in which the wittig reagent was formed in a state in which the temperature in the reaction system was controlled to 20 ℃ or less, and stirred at room temperature.
Further, the amount of the starting material of this example was about 40% in terms of a molar ratio with respect to example 1. Therefore, in this example, as described above, the amount of the wittig reagent introduced is a relatively small amount of the reaction equivalent or more (more specifically, the amount introduced is a slight excess of the reaction equivalent, and a representative example is about 1.2 equivalents) relative to the alkali metal salt of m-hydroxybenzaldehyde.
In the following steps 2 and 3, the amounts of the compounds used in these steps were adjusted to about 40% relative to the compound of example 1, and then the operations were performed according to the processes (including purification processes) described in embodiment 2. As a result, by carrying out the same reaction as that described in example 1, 7.76g of 2-m-hydroxyphenylacetic acid as a pale 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 analyses, C-13 nuclear magnetic resonance (13 C NMR) spectroscopic analyses, and IR spectroscopic analyses were also performed in the same manner as in example 1, and as a result, the same results as in example 1 were obtained.
The present invention is not limited to the embodiments and examples. Variations that exist within the scope of the invention including other combinations of the described embodiments and examples are also encompassed by the claims.
[ Industrial applicability ]
The method for producing 2-m-hydroxyphenylacetic acid of the present invention, and the method for producing 2-m-hydroxyphenylacetic acid of the present invention can be widely used as a useful chemical substance or a useful production method for materials for various applications (for example, functional materials or intermediates for various pharmaceuticals, cosmetics, and the like).

Claims (6)

1. A process for producing 2-m-hydroxyphenylacetic acid, which comprises the first step of reacting m-hydroxybenzaldehyde with a wittig reagent represented by the general formula (I) in an amount of not less than 2 molar equivalents relative to the m-hydroxybenzaldehyde to produce m-hydroxystyryl methyl ether;
A step 2 of generating 2- (m-hydroxyphenyl) acetaldehyde by the acid hydrolysis of m-hydroxystyryl methyl ether, and
A step 3 of treating the 2- (m-hydroxyphenyl) acetaldehyde with an oxidizing agent, and
The 2 nd and 3 rd steps are performed in situ,
General formula (I)
[ Chemical 1]
H3C-O-CH＝PPh3 (I)。
2. A process for producing 2-m-hydroxyphenylacetic acid, which comprises the first step of reacting an alkali metal salt of m-hydroxyphenylaldehyde with a wittig reagent represented by the general formula (I) having a reaction equivalent or more with respect to the alkali metal salt to produce m-hydroxystyryl methyl ether;
A step 2 of generating 2- (m-hydroxyphenyl) acetaldehyde by the acid hydrolysis of m-hydroxystyryl methyl ether, and
A step 3 of treating the 2- (m-hydroxyphenyl) acetaldehyde with an oxidizing agent, and
The 2 nd and 3 rd steps are performed in situ,
General formula (I)
[ Chemical 2]
H3C-O-CH＝PPh3 (I)。
3. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1, wherein the m-hydroxybenzaldehyde and the wittig reagent are reacted in an amount exceeding 2 molar equivalents with respect to the m-hydroxybenzaldehyde.
4. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 or 2, wherein the 3 rd step is performed at a temperature of not less than-10 ℃ and not more than 10 ℃.
5. The method for producing 2-m-hydroxyphenylacetic acid according to claim 1 or 2, wherein the oxidizing agent is at least 1 selected from the group consisting of a peroxide containing hydrogen peroxide and Oxone (registered trademark) (2 KHSO 5·KHSO4·K2SO4).
6. 2-M-hydroxyphenylacetic acid, wherein the 2-m-hydroxyphenylacetic acid composition comprises less than 0.1wt% of m-hydroxybenzaldehyde.
CN202480006888.1A 2023-06-14 2024-06-10 Method for producing 2-m-hydroxyphenylacetic acid and 2-m-hydroxyphenylacetic acid Pending CN120476101A (en)

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PCT/JP2024/020996 WO2024257715A1 (en) 2023-06-14 2024-06-10 Method for producing 2-m-hydroxyphenylacetic acid, and 2-m-hydroxyphenylacetic acid

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