JP2006028139A - Method for producing 2,4,5-trialkoxybenzoic acid and benzoic acid ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for stably producing a 2,4,5-trialkoxybenzoic acid and a benzoic acid ester each in high yield. <P>SOLUTION: A 2,4,5-trialkoxybenzoic acid ester expressed by formula (2) (R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R are each independently an alkyl) is produced by reacting a compound expressed by formula (1) (R<SP>1</SP>and R<SP>2</SP>are each independently an alkyl) with carbon dioxide in the presence of a base to introduce a carboxyl group and alkylating phenolic hydroxyl group. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing 2,4,5-trialkoxybenzoic acid and benzoic acid ester with high yield.

Various methods for producing 2,4,5-trialkoxybenzoic acid have been studied. As a typical production method, in recent years, after bromination of the 6-position of 3,4-dialkoxybenzoic acid, A method of introducing (Patent Document 1) and a method of oxidizing 2,4,5-trialkoxybenzalkyd with sodium chlorite (Patent Document 2) are disclosed.
However, the former has a problem that the isolation yield is low and the load of wastewater treatment of the bromine-containing aqueous solution is large. In the latter case, there are problems that the reproducibility of the reaction is low, and that the yield varies greatly depending on the manufacturer of sodium chlorite used, and that it is difficult to produce stably.
JP 2003-252826 A JP 2003-277313 A

  The object of the present invention is to produce 2,4,5-trialkoxybenzoic acid and benzoic acid ester stably in high yield.

The object of the present invention has been achieved by the following means.
[1] The compound represented by the general formula (1) is reacted with carbon dioxide in the presence of a base to introduce a carboxyl group, and then the phenolic hydroxyl group is alkylated to represent the general formula (2). A production method for obtaining 2,4,5-trialkoxybenzoic acid ester.
General formula (1)

(In the formula, R ¹ and R ² each independently represents an alkyl group.)
General formula (2)

(In the formula, R ¹ , R ² , R ³ and R each independently represents an alkyl group.)
[2] 2,4,5-trialkoxybenzoic acid ester represented by the general formula (2) obtained by the production method according to the above [1] is hydrolyzed to represent 2,4,5-trialkoxybenzoic acid ester represented by the general formula (3). A method for producing 4,5-trialkoxybenzoic acid.
General formula (3)

[3] The method according to the above [1] or [2], wherein R ¹ , R ² , R ³ and R in the general formula (2) are all methyl groups.

  By using the production method of the present invention, 2,4,5-trialkoxybenzoic acid and benzoic acid ester can be produced in high yield.

First, the general formula (1) which is a raw material of the present invention will be described in detail.
In general formula (1), R ¹ and R ² each independently represents an alkyl group.
The alkyl group represented by R ¹ and R ² may be linear or branched, and may further have a substituent. If possible, they may be connected to each other to form a ring.
R ¹ and R ² are preferably an alkyl group having 1 to 20 carbon atoms, more preferably an alkyl group having 1 to 12 carbon atoms, and still more preferably an alkyl group having 1 to 8 carbon atoms (for example, 2 -Ethylhexyl group, n-hexyl group, n-butyl group, n-propyl group, ethyl group, methyl group, benzyl group, methoxyethoxymethyl group and the like), particularly preferably an alkyl group having 1 to 4 carbon atoms. And most preferably a methyl group.

Next, the general formula (2) which is the target compound of the present invention will be described in detail. In general formula (2), R ¹ and R ² each independently represent an alkyl group, and have the same meaning as those in general formula (1). In addition, the preferable range is also the same.
In general formula (2), the alkyl group represented by R ³ or R may be linear or branched, and may further have a substituent. If possible, they may be connected to each other to form a ring. R ³ and R are preferably an alkyl group having 1 to 20 carbon atoms, more preferably an alkyl group having 1 to 12 carbon atoms, still more preferably an alkyl group having 1 to 8 carbon atoms, and particularly preferably carbon. It is a C1-C4 alkyl group, Most preferably, it is a methyl group.

Examples of the substituent for R ¹ , R ² , R ³ and R include the substituent T described later, preferably an alkenyl group, an alkynyl group, an aryl group, an alkoxy group and an aryloxy group, more preferably an aryl group. It is.

Hereinafter, the substituent T will be described in detail.
Examples of the substituent T include an alkyl group (preferably having 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms, particularly preferably 1 to 8 carbon atoms, such as methyl, ethyl, iso-propyl, tert-butyl. , N-octyl, n-decyl, n-hexadecyl, cyclopropyl, cyclopentyl, cyclohexyl, etc.), an alkenyl group (preferably having 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, particularly preferably carbon atoms). 2 to 8, for example, vinyl, allyl, 2-butenyl, 3-pentenyl, etc.), an alkynyl group (preferably having 2 to 20 carbon atoms, more preferably having 2 to 12 carbon atoms, particularly preferably carbon). 2 to 8, and examples thereof include propargyl and 3-pentynyl).

  An aryl group (preferably having 6 to 30 carbon atoms, more preferably 6 to 20 carbon atoms, and particularly preferably 6 to 12 carbon atoms, such as phenyl, p-methylphenyl, naphthyl, etc.), substituted or not Substituted amino group (preferably having 0 to 20 carbon atoms, more preferably 0 to 10 carbon atoms, particularly preferably 0 to 6 carbon atoms, such as amino, methylamino, dimethylamino, diethylamino, dibenzylamino, etc. An alkoxy group (preferably having 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms, particularly preferably 1 to 8 carbon atoms, such as methoxy, ethoxy, butoxy, etc.), aryloxy Group (preferably having 6 to 20 carbon atoms, more preferably 6 to 16 carbon atoms, particularly preferably 6 to 12 carbon atoms, Oxy, 2-naphthyloxy, etc.), acyl groups (preferably having 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, particularly preferably 1 to 12 carbon atoms, such as acetyl, benzoyl, formyl , Pivaloyl, etc.)

  An alkoxycarbonyl group (preferably having 2 to 20 carbon atoms, more preferably 2 to 16 carbon atoms, particularly preferably 2 to 12 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, etc.), an aryloxycarbonyl group ( Preferably it has 7 to 20 carbon atoms, more preferably 7 to 16 carbon atoms, particularly preferably 7 to 10 carbon atoms, and examples thereof include phenyloxycarbonyl, etc.), an acyloxy group (preferably 2 to 20 carbon atoms, More preferably, it has 2 to 16 carbon atoms, particularly preferably 2 to 10 carbon atoms, and examples thereof include acetoxy, benzoyloxy, etc.), an acylamino group (preferably 2 to 20 carbon atoms, more preferably 2 to 2 carbon atoms). 16, particularly preferably 2 to 10 carbon atoms, such as acetylamino, benzoylamino An alkoxycarbonylamino group (preferably having 2 to 20 carbon atoms, more preferably 2 to 16 carbon atoms, particularly preferably 2 to 12 carbon atoms, such as methoxycarbonylamino). An aryloxycarbonylamino group (preferably having 7 to 20 carbon atoms, more preferably 7 to 16 carbon atoms, particularly preferably 7 to 12 carbon atoms, such as phenyloxycarbonylamino);

  A sulfonylamino group (preferably having 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, particularly preferably 1 to 12 carbon atoms, such as methanesulfonylamino, benzenesulfonylamino, etc.), a sulfamoyl group ( Preferably it is C0-20, More preferably, it is C0-16, Most preferably, it is C0-12, For example, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, phenylsulfamoyl etc. are mentioned. ), A carbamoyl group (preferably having 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, particularly preferably 1 to 12 carbon atoms, and examples thereof include carbamoyl, methylcarbamoyl, diethylcarbamoyl, and phenylcarbamoyl). An alkylthio group (preferably having 1 to 20 carbon atoms) Preferably it is C1-C16, Most preferably, it is C1-C12, for example, methylthio, ethylthio etc. are mentioned, for example, An arylthio group (Preferably C6-C20, More preferably C6-C16, Particularly preferably, it has 6 to 12 carbon atoms, and examples thereof include phenylthio, etc.), an alkylsulfonyl group or an arylsulfonyl group (preferably 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, particularly preferably carbon numbers). 1 to 12, for example, mesyl, tosyl, etc.)

  Alkylsulfinyl group or arylsulfinyl group (preferably having 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, particularly preferably 1 to 12 carbon atoms, such as methanesulfinyl, benzenesulfinyl, etc.), ureido A group (preferably having 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, and particularly preferably 1 to 12 carbon atoms, such as ureido, methylureido, phenylureido, etc.), phosphoric acid amide group ( Preferably it has 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, particularly preferably 1 to 12 carbon atoms, and examples thereof include diethyl phosphoric acid amide and phenyl phosphoric acid amide.), Hydroxy group, mercapto group , Halogen atoms (eg fluorine atom, chlorine atom, bromine atom, iodine atom), cyano group, Rufo group, carboxyl group, nitro group, hydroxamic acid group, sulfino group, hydrazino group, imino group, heterocyclic group (preferably having 1 to 30 carbon atoms, more preferably 1 to 12 carbon atoms. An atom, an oxygen atom, a sulfur atom, specifically, for example, imidazolyl, pyridyl, quinolyl, furyl, piperidyl, morpholino, benzoxazolyl, benzimidazolyl, benzthiazolyl, etc., a silyl group (preferably having 3 carbon atoms) To 40, more preferably 3 to 30 carbon atoms, particularly preferably 3 to 24 carbon atoms, and examples thereof include trimethylsilyl and triphenylsilyl). These substituents may be further substituted.

Next, the method for producing the compound represented by the general formula (2) of the present invention will be described in detail.
First, the compound represented by the general formula (1) is reacted with carbon dioxide in the presence of a base to introduce a carboxyl group to produce the following general formula (1-A) in detail.

(In the formula, R ¹ , R ² and R ³ each independently represents an alkyl group.)

  The 3,4-dialkoxyphenol represented by the general formula (1) as a raw material is obtained by using, for example, 3,4-dialkoxybenzaldehyde with a peracid (peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc.). It can be produced by a method in which an aldehyde group is converted into a formyl ester by a Bayer-Billiger reaction and the formyl ester is hydrolyzed to a phenolic hydroxyl group.

Next, the process for producing the general formula (1-A) from the raw material represented by the general formula (1) will be described. The base used in the step of producing the general formula (1-A) may be an organic base or an inorganic base, but is preferably an inorganic base. Among inorganic bases, potassium carbonate, t-butoxypotassium, and t-butoxysodium are preferable, and t-butoxysodium is more preferable from the viewpoint of solubility in a solvent.
The molar ratio of t-butoxy sodium to the compound represented by the general formula (1) is 1 to 10, preferably 1 to 6. Further, potassium carbonate may be added to t-butoxy sodium and used as a mixed base. In this case, the molar ratio of potassium carbonate to t-butoxy sodium is 0.1 to 10, preferably 0.1 to 2.

The organic solvent used in the step of producing the general formula (1-A) may be any organic solvent, but is preferably an aprotic organic solvent. Examples of the aprotic polar solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N, N′-dimethylimidazolidone, and these are used alone or as a mixed solvent. N, N-dimethylacetamide or N-methylpyrrolidone is preferred.
The amount of the organic solvent to be used is not particularly limited, and it is sufficient that at least an amount capable of sufficiently dissolving the reaction raw material is present. Preferably, the mass ratio of the compound represented by the general formula (1) is 1 time or more. Preferably, it is 2 to 10 times.

  The preferable reaction temperature of the reaction in the step of producing the general formula (1-A) is 20 ° C to 200 ° C, more preferably 20 ° C to 150 ° C. A preferable carbon dioxide pressure for the reaction between the compound represented by the general formula (1) and carbon dioxide is 50 kPa to 5 MPa, and more preferably 0.5 MPa to 2 MPa. The preferred reaction time for the reaction between the compound represented by the general formula (1) and carbon dioxide is 1 hour to 12 hours, preferably 1 hour to 6 hours.

  As a reaction procedure in the step of producing the general formula (1-A), the compound represented by the general formula (1) is heated and stirred in a nitrogen atmosphere, in an organic solvent, in the presence of a base, and after heating, carbon dioxide and You may make it react, or it heats and stirs in a carbon dioxide atmosphere, and may pressurize carbon dioxide after temperature rising, or may heat-heat-temperature under carbon dioxide pressurization. Preferably, the compound represented by the general formula (1) is heated and stirred in a nitrogen atmosphere, in an organic solvent, in the presence of a base, and reacted with carbon dioxide after heating.

Next, the step of alkylating a phenolic hydroxyl group (the step of producing a compound represented by the general formula (1-B)) will be described in detail.
The compound represented by the general formula (1-A) obtained by reacting the compound represented by the general formula (1) with carbon dioxide to introduce a carboxyl group is reacted with an alkylating agent in the presence of a base. , Can be converted to an ester form (1-B).
The base used in the step of producing the compound represented by the general formula (1-B) may be an organic base or an inorganic base. Examples of the organic base include triethylamine, diisopropylethylamine, DBU (1,8 diazabicyclo [5,4, 0] undec-7-ene) is preferable, and if it is an inorganic base, metal alkoxide (sodium methoxide, t-butoxy potassium, t-butoxy sodium, etc.), potassium carbonate and the like are preferable.

As the alkylating agent used in the step of producing the compound represented by the general formula (1-B), any alkylating agent can be used as long as it can alkylate a phenolic hydroxyl group. Alkyl halide, dialkyl sulfuric acid, p-toluene sulfone may be used. Examples thereof include alkyl halides, diazomethanes, and the like, preferably alkyl halides, dialkyl sulfates, alkyl p-toluenesulfonates, specifically iodomethane, benzyl bromide, dimethyl sulfate, diethyl sulfate, methyl p-toluenesulfonate, p- Examples include ethyl toluenesulfonate.
1-5 are preferable, as for the molar ratio with respect to the phenol of the raw material of an alkylating agent, More preferably, it is 2-3, More preferably, it is 2.2-3.0.

The kind of the solvent used in the step of producing the compound represented by the general formula (1-B) is not particularly limited, such as hydrocarbon, halogenated hydrocarbon, alcohol, ketone, ester, ether, amide, and the like. May be used as a mixture of two or more thereof, or may be a mixed solvent with water. The amount of the solvent used is not particularly limited, and it is sufficient that at least an amount capable of sufficiently dissolving the raw material is present. However, the mass ratio is preferably 0.5 or more, more preferably 1 or more.
When an alkyl halide is used as the alkylating agent, acetone, dimethylformamide or the like is preferable. When dialkyl sulfuric acid is used, acetone is preferable, and when alkyl p-toluenesulfonate is used, alcohol is preferable.
The reaction temperature in the step of producing the compound represented by the general formula (1-B) is preferably 0 ° C to 200 ° C, more preferably 0 ° C to 150 ° C, still more preferably 0 ° C to 100 ° C, particularly preferably. Is from 10 ° C to 80 ° C.

Next, the process of obtaining the benzoic acid represented by General formula (2) by hydrolyzing the benzoic acid ester of the compound represented by General formula (1-B) is demonstrated in detail.
Although acid hydrolysis or alkali hydrolysis may be used in the presence of water using the general formula (1-B) as a raw material, alkali hydrolysis is preferred.
The alkali used in the step of obtaining the benzoic acid represented by the general formula (2) is not particularly limited as long as the aqueous solution exhibits an alkalinity of pH 10 or more, and preferably sodium hydroxide or potassium hydroxide.
The solvent used in the step of obtaining the benzoic acid represented by the general formula (2) may be any solvent as long as it does not inhibit hydrolysis, but is preferably an organic solvent miscible with water by 50% or more, more preferably an alcohol. More preferred are methanol, ethanol, and isopropanol. The amount of the solvent used is not particularly limited, and there may be no organic solvent in some cases. The mass ratio of the solvent to be used to the general formula (1-B) is preferably 0 to 10, and more preferably 0 to 5.
0-100 degreeC is preferable, as for the reaction temperature in the process of obtaining the benzoic acid represented by General formula (2), More preferably, it is 10-90 degreeC, More preferably, it is 15-85 degreeC.

  EXAMPLES Next, although this invention is demonstrated further in detail based on an Example, this invention is not limited at all by the following Example.

[Example 1: Synthesis of 2,4,5-trimethoxybenzoic acid]
<1-1: Synthesis of 3,4-dimethoxyphenol>
After dissolving 8.3 g (50 mmol) of 3,4-dimethoxybenzaldehyde (Bellatoraldehyde, manufactured by Tokyo Chemical Industry) in 16.6 mL of acetonitrile and heating to 40 ° C., m-chloroperbenzoic acid (purity manufactured by Wako Pure Chemical Industries, Ltd.) was previously prepared. A solution in which 16.3 g (75 mmol) of acetonitrile was dissolved in 83 mL of acetonitrile was added dropwise for 20 minutes, followed by stirring at 40 ° C. for 10 hours. Thereafter, 95 g (75 mmol) of 10% aqueous sodium sulfite solution was added dropwise and stirred at 40 ° C. for 1 hour, and 84 g (150 mmol) of 10% aqueous potassium hydroxide solution was added dropwise and stirred at 40 ° C. to room temperature for 3 hours. Thereafter, 4.4 mL of concentrated hydrochloric acid was added to adjust the pH to 6.5, 100 mL of ethyl acetate was added, liquid separation operation was performed, and the organic phase was recovered. Sodium sulfate was added to the collected organic phase to remove water, and then sodium sulfate was removed by filtration. The obtained solution was concentrated under reduced pressure to obtain 6.8 g (yield 88%) of the target compound as brown crystals.

<1-2: Synthesis of 2-hydroxy-4,5-dimethoxybenzoic acid>
After adding 15.4 g (0.1 mol) of 3,4-dimethoxyphenol, 115 mL of N-methylpyrrolidone and 28.8 g (0.3 mol) of tert-butoxy sodium to a 500 mL autoclave, carbon dioxide gas was added at room temperature. After adding until the pressure reached 3.5 MPa, the mixture was heated to 120 ° C. and stirred for 8 hours. The reaction solution was cooled to room temperature, and carbon dioxide gas was expelled from the autoclave. Ice water was added to the reaction solution, and 31 mL of concentrated hydrochloric acid was added with stirring. The obtained crystals were filtered and washed with water. The obtained crystals were sufficiently dried to obtain 19.0 g (yield 96%) of the target compound as a white powder.

<1-3: Synthesis of 2,4,5-trimethoxybenzoic acid>
Stir 4.95 g (25 mmol) of 2-hydroxy-4,5-dimethoxybenzoic acid, 10.36 g (75 mmol) of potassium carbonate and 80 mL of acetone at room temperature, and then add 9.46 g (75 mmol) of dimethyl sulfate over 10 minutes. The solution was heated and refluxed for 10 hours. Thereafter, the reaction solution was cooled to room temperature, ethyl acetate 80 mL, 1 mol / L dilute hydrochloric acid 60 mL was added, liquid separation operation was performed, and the organic phase was washed with saturated brine 20 mL. Thereafter, the organic phase was recovered and concentrated under reduced pressure to obtain 5.54 g (yield 98%) of methyl 2,4,5-trimethoxybenzoate. Next, 42 mL of 10% potassium hydroxide aqueous solution and 42 mL of methanol were added, and the mixture was heated to reflux at 80 ° C. for 1 hour. Thereafter, the mixture was cooled to room temperature, 80 mL of 1 mol / L dilute hydrochloric acid was added, and the mixture was cooled to 10 ° C. The precipitated crystals were collected by filtration and dried to obtain 4.80 g (yield 90%) of the target compound as white crystals. It was. The isolated yield from 3,4-dimethoxybenzaldehyde was 75%.
The structure was confirmed by ¹ H-NMR.
¹ H-NMR (CDCl ₃ ) δ 3.90 (s, 3H), 3.97 (s, 3H), 4.07 (s, 3H), 6.55 (s, 1H), 7.65 (s, 1H), 10.70 (br, 1H)

[Comparative Example 1: Synthesis of 2,4,5-trimethoxybenzoic acid]
According to Japanese Patent Laid-Open No. 2003-277313, 19.6 g (0.10 mol) of 2,4,5-trimethoxybenzaldehyde was dissolved in 90 g of toluene, 50 g of water and 55 g of N, N-dimethylformamide were added, and then the temperature was increased to 5 ° C. After cooling, 19.4 g (0.20 mol) of aminosulfuric acid (sulfamic acid) was added, and 12.4 g (0.22 mol) of sodium chlorite having a purity of 80% manufactured by Wako Pure Chemical Industries, Ltd. was dissolved in 45 mL of water. The aqueous solution was dripped over 2 hours due to intense heat generation. After dropping, the mixture was stirred at 5 ° C. or lower for 3 hours. Thereafter, 12.6 g (0.20 mol) of sodium sulfite was dissolved in 45 mL of water and added dropwise, and then 12.5 g of 50% aqueous sodium hydroxide solution was added dropwise. Thereafter, the mixture was heated to 50 ° C. and separated to recover the aqueous phase. The aqueous phase was washed with toluene. Next, 200 mL of water was added, 8.6 g of 98% sulfuric acid was added, and the mixture was cooled to 10 ° C. and stirred for 1 hour. The resulting crystals were collected by filtration and dried to obtain 12.0 g of the target compound as a white solid. (57%) was obtained.
As a result of carrying out the reaction on a 1.96 kg scale with 2,4,5-trimethoxybenzaldehyde in this formulation, the exotherm during dripping of sodium chlorite was very large, and it took 8 hours for dripping. Except that, the same operation was performed, but only 601 g (yield 28%) of the target compound could be obtained.

Thus, it can be seen that in the synthesis method of Comparative Example 1, the exotherm during dripping of sodium chlorite is very large, and the reproducibility of the reaction is poor depending on the scale.
In contrast, when the synthesis method of the present invention is used, 2,4,5-trimethoxybenzoic acid of the present invention and its methyl ester can be stably produced without great heat generation.
It can also be seen that 2,4,5-trimethoxybenzoic acid can be obtained in a high yield even when compared with Comparative Example 1.

[Example 2: Synthesis of 2,5-dimethoxy-4-benzyloxybenzoic acid]
<2-1: Synthesis of 3-benzyloxy-4-methoxyphenol>
After dissolving 12.1 g (50 mmol) of 3-benzyloxy-4-methoxybenzaldehyde in 16.3 mL of acetonitrile and heating to 40 ° C., m-chloroperbenzoic acid (purity of about 70%, manufactured by Wako Pure Chemical Industries) was previously added. A solution dissolved in 80 mL of 16.3 g (75 mmol) of acetonitrile was added dropwise for 45 minutes, followed by stirring at 40 ° C. for 5 hours.
Thereafter, 95 g (75 mmol) of 10% aqueous sodium sulfite solution was added dropwise over 30 minutes. After the addition, the mixture was stirred for 30 minutes at 40 ° C., and 42 g (75 mmol) of 10% aqueous potassium hydroxide solution was added dropwise over 30 minutes. Stir at room temperature for 1 hour. Then, 100 mL of ethyl acetate was added, liquid separation operation was performed, and the organic phase was recovered. After washing the organic phase with saturated sodium bicarbonate, 100 mL of toluene and 60 mL of a 1 mol / L aqueous sodium hydroxide solution were added to the recovered organic phase, and a liquid separation operation was performed to recover the aqueous phase. After the aqueous phase was washed again with 100 mL of toluene, the aqueous phase was recovered and adjusted to pH 3 or less with 1 mol / L dilute hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried to obtain 9.9 g (yield 86%) of the target compound as brown crystals.

<2-2: Synthesis of 4-benzyloxy-2-hydroxy-5-methoxybenzoic acid>
After adding 11.5 g (50 mmol) of 3-benzyloxy-4-methoxyphenol, 72 mL of N-methylpyrrolidone and 14.4 g (50 mmol) of tert-butoxy sodium to a 200 mL autoclave, 4 carbon dioxide gas was added at room temperature. After adding 0.0 MPa, the mixture was heated to 120 ° C. and stirred for 8 hours. The reaction solution was cooled to room temperature, and carbon dioxide gas was expelled from the autoclave. 70 mL of water was added to the reaction solution, and the reaction solution was transferred from the autoclave to a 1 L beaker. Concentrated hydrochloric acid was added to pH 4 while cooling the reaction solution with ice water, and then 500 mL of ethyl acetate was added to carry out a liquid separation operation. The obtained organic phase was recovered, washed with 200 mL of saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was recovered. Concentrated hydrochloric acid was added to the obtained aqueous phase with stirring until pH 4 was reached, the mixture was cooled to 10 ° C. or lower, and the precipitated crystals were collected. The obtained crystals were added to 500 mL of methanol, heated and stirred for 20 minutes, cooled to 10 ° C. or lower, and the precipitated crystals were collected by filtration and dried to obtain 10 g (74%) of the target compound as white crystals.

<2-3: Synthesis of 2,5-dimethoxy-4-benzyloxybenzoic acid>
4-Benzyloxy-2-hydroxy-5-methoxybenzoic acid 10.0 g (36 mmol), potassium carbonate 18.8 g (136 mmol) and acetone 250 mL were stirred at room temperature, and dimethyl sulfate 17.1 g (136 mmol) was stirred. After dropwise addition over 10 minutes, the mixture was heated to reflux at 50 ° C. for 10 hours. Thereafter, the reaction solution is cooled to room temperature, 500 mL of ethyl acetate and 1 mol / L dilute hydrochloric acid are added, and a liquid separation operation is performed. The organic phase is recovered and concentrated under reduced pressure, and 60 mL of 10% potassium hydroxide aqueous solution and 60 mL of methanol are added. The mixture was heated to reflux at 1 ° C. for 1 hour. Then, it cooled to room temperature, 120 mL of 1 mol / L dilute hydrochloric acid was added, it cooled to 10 degreeC, and the depositing crystal | crystallization was collect | recovered by filtration. The obtained crystals were further heated with 150 mL of methanol and cooled to 10 ° C., and the precipitated crystals were collected by filtration and dried to obtain 9.0 g (yield 86%) of the target compound as white crystals. The isolated yield from 3-benzyloxy-4-methoxybenzaldehyde was 55%.
The structure was confirmed by ¹ H-NMR.
¹ H-NMR (CDCl ₃ ) δ 3.92 (s, 3H), 3.95 (s, 3H), 5.25 (s, 2H) 6.57 (s, 1H), 7.32-7.45 (M, 5H), 7.65 (s, 1H), 10.69 (br, 1H)

  As described above, compounds other than 2,4,5-trimethoxybenzoic acid can be synthesized by the same synthesis method.

Claims (3)

The compound represented by the general formula (1) is reacted with carbon dioxide in the presence of a base to introduce a carboxyl group, and then alkylated with a phenolic hydroxyl group to produce 2,4 represented by the general formula (2). , 5-Trialkoxybenzoic acid ester production method.
General formula (1)

(In the formula, R ¹ and R ² each independently represents an alkyl group.)
General formula (2)

(In the formula, R ¹ , R ² , R ³ and R each independently represents an alkyl group.) The 2,4,5-trialkoxybenzoic acid ester represented by the general formula (2) obtained by the production method according to claim 1 is hydrolyzed to 2,4,4, represented by the general formula (3). A method for producing 5-trialkoxybenzoic acid.
General formula (3)

(In the formula, R ¹ , R ² and R ³ have the same meanings as those in the general formula (2).) The production method according to claim 1 or 2, wherein R ¹ , R ² , R ³ , and R in the general formula (2) are all methyl groups.