JP2008074837A - Method for producing 2-(4-carboxymethylphenoxy methyl)benzoic acid compound and dibenzooxepinacetic acid compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing an intermediate for producing a dibenzooxepinacetic acid compound useful as an intermediate for pharmaceutical products on an industrial scale at a low cost. <P>SOLUTION: A method for producing 2-(4-methoxycarbonylmethylphenoxymethyl)benzoic acid methyl ester represented by formula (3) comprises reacting 2-chloromethylbenzoic acid methyl ester and 4-hydroxyphenylacetic acid methyl ester represented by formula (2). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention provides intermediate production of 11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-yl) acetic acid (hereinafter also referred to as dibenzooxepin acetic acid compound) useful as an intermediate for pharmaceuticals. Body and a method for producing a dibenzooxepin acetic acid compound.

  Olopatadine, which is a dibenzooxepin acetic acid derivative, is a useful drug as an antiallergic drug. For example, Patent Document 1 discloses a reaction process as shown in the following scheme from a dibenzooxepin acetic acid compound as a method for producing olopatadine. Discloses a method for producing olopatadine.

  The dibenzooxepin acetic acid compound is 2- (4-carboxymethylphenoxymethyl) benzoic acid or 2- (4-ethoxycarbonylmethylphenoxymethyl) benzoic acid ethyl ester produced from phthalide or 2-methylbenzoic acid ethyl ester. The raw material is produced by a ring closure reaction. For example, Patent Document 1 and Patent Document 2 disclose the production method.

That is, in Patent Document 1, 1.62 times the amount of phthalide is used in Reference Example 1 with respect to 4-hydroxybenzoic acid methyl ester, and further reacted at a high temperature of 150 ° C. for 6 hours. It is described that-(4-methoxycarbonylphenoxymethyl) benzoic acid is obtained, and methyl 11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-carboxylate is obtained by subjecting this to a ring-closing reaction. In Reference Example 2, it is described that a dibenzooxepin acetic acid compound can be obtained by using p-hydroxyphenylacetic acid instead of 4-hydroxybenzoic acid methyl ester. The latter reaction can be expressed by the following equation.

  However, this method is not an economical method because phthalide is excessively used. Moreover, since a high temperature of 150 ° C. is necessary, it is difficult and disadvantageous to use a steam line as a heat source when considering industrial production.

  On the other hand, in Patent Document 2, as shown in the following scheme, 2-methylbenzoic acid ethyl ester is brominated with N-bromosuccinimide in carbon tetrachloride and benzoyl peroxide as a catalyst. -Bromomethylbenzoic acid ethyl ester and 4-hydroxyphenylacetic acid ethyl ester were reacted in the presence of potassium carbonate and potassium iodide for 16 hours to give 2- (4-ethoxycarbonylmethylphenoxymethyl) benzoic acid ethyl ester, It is described that a dibenzooxepin acetic acid compound can be obtained by hydrocyclizing and ring-closing reaction.

  However, even in this method, the solvent to be used, peroxide, expensive halogenating agent, and the like become restrictions in industrial implementation and have many problems.

Japanese Patent Publication No.7-116174 US4082850

  An object of the present invention is to efficiently and inexpensively produce a production intermediate of a dibenzooxepin acetic acid compound useful as a pharmaceutical intermediate in view of the above-described problems of the prior art. It is an object of the present invention to provide an industrially advantageous method for producing a dibenzooxepin acetic acid compound.

  As a result of intensive studies to solve the above problems, the present inventors have reacted phthalide with thionyl chloride, and then reacted with methanol to obtain methyl 2-chloromethylbenzoate in high yield. The present inventors have found that a novel production intermediate can be obtained economically and efficiently by reacting an approximately equimolar amount of 4-hydroxyphenylacetic acid ester.

で表される２−クロルメチル安息香酸メチルエステルと、下記式（２）：

で表される４−ヒドロキシフェニル酢酸メチルエステルとを反応させることを特徴とする下記式（３）：

で表される２−（４−メトキシカルボニルメチルフェノキシメチル）安息香酸メチルエステルの製造方法、
[２] 以下の工程１〜３を包含してなることを特徴とする、２−（４−メトキシカルボニルメチルフェノキシメチル）安息香酸メチルエステルの製造方法：
[工程１]フタライドと塩化チオニルとを反応させて２−クロルメチルベンゾイルクロリドを製造する工程；
[工程２]２−クロルメチルベンゾイルクロリドとメタノールとを反応させて下記式（１）で表される２−クロルメチル安息香酸メチルエステルを製造する工程；

[工程３]２−クロルメチル安息香酸メチルエステルと下記式（２）で表される４−ヒドロキシフェニル酢酸メチルエステルとを反応させて、下記式（３）で表される２−（４−メトキシカルボニルメチルフェノキシメチル）安息香酸メチルエステルを製造する工程、

[３] 式（３）：

で表される２−（４−メトキシカルボニルメチルフェノキシメチル）安息香酸メチルエステル、および
[４] ２−（４−メトキシカルボニルメチルフェノキシメチル）安息香酸メチルエステルを加水分解して、式（４）：

で表される２−（４−カルボキシメチルフェノキシメチル）安息香酸を製造し、次いでこれを環化反応させることを特徴とする、式（５）：

で表されるジベンゾオキセピン酢酸化合物の製造方法
に関する。 That is, the present invention
[1] The following formula (1):

2-chloromethylbenzoic acid methyl ester represented by the following formula (2):

The following formula (3) characterized by reacting with 4-hydroxyphenylacetic acid methyl ester represented by:

A process for producing 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester represented by:
[2] A process for producing 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester, comprising the following steps 1 to 3:
[Step 1] A step of producing 2-chloromethylbenzoyl chloride by reacting phthalide with thionyl chloride;
[Step 2] A step of producing 2-chloromethylbenzoic acid methyl ester represented by the following formula (1) by reacting 2-chloromethylbenzoyl chloride with methanol;

[Step 3] 2-Chloromethylbenzoic acid methyl ester is reacted with 4-hydroxyphenylacetic acid methyl ester represented by the following formula (2) to give 2- (4-methoxycarbonyl represented by the following formula (3) Methylphenoxymethyl) benzoic acid methyl ester,

[3] Formula (3):

2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester represented by:
[4] Hydrolysis of 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester gives the formula (4):

2- (4-carboxymethylphenoxymethyl) benzoic acid represented by the following formula (5):

The manufacturing method of the dibenzo oxepin acetic acid compound represented by these.

  According to the present invention, problems of conventional production (for example, use of solvents and reagents difficult to industrially use) are solved, and 2- (4-carboxymethylphenoxy) is efficiently and inexpensively produced on an industrial scale. (Methyl) benzoic acid can be produced, which is advantageous in the production of a dibenzooxepin acetic acid compound. In the production method of the present invention, since a series of reactions can be performed at a temperature of less than 140 ° C., it is easy to use steam heating, which is advantageous for energy saving.

で表される２−クロルメチル安息香酸メチルエステルと、式（２）：

で表される４−ヒドロキシフェニル酢酸メチルエステルとを反応させることにより、式（３）：

で表される２−（４−メトキシカルボニルメチルフェノキシメチル）安息香酸メチルエステルを製造する。 In the present invention, the formula (1):

2-chloromethylbenzoic acid methyl ester represented by formula (2):

Is reacted with 4-hydroxyphenylacetic acid methyl ester represented by the formula (3):

2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester represented by

  The 2-chloromethylbenzoic acid methyl ester represented by the formula (1) can be produced by, for example, Step 1 and Step 2 described below. Steps 1 and 2 can be produced according to the method described in Japanese Patent No. 3433319.

[Step 1] A step of producing 2-chloromethylbenzoyl chloride by reacting phthalide with thionyl chloride. This step is usually carried out in a solvent. For example, phthalide can be reacted with thionyl chloride by adding thionyl chloride to a solution heated in the presence of a catalyst, using phthalide in a suitable solvent. Examples of the solvent for reacting phthalide with thionyl chloride include aromatic hydrocarbons such as xylene and toluene, and halogenated hydrocarbons such as chlorobenzene, and xylene is preferred. The catalyst is preferably a BF ₃ -ether complex.
As a usage-amount of a solvent, 100-1000 mass parts is preferable with respect to 100 mass parts of a phthalide.
The amount of the catalyst used is preferably about 0.01 to 0.2 mol with respect to 1 mol of phthalide.

  The solution preferably contains a quaternary ammonium salt (such as benzyltriethylammonium chloride) and the like in order to promote the reaction. The content is preferably about 0.01 to 0.2 mol with respect to 1 mol of phthalide.

  The amount of thionyl chloride used is preferably about 1 to 2 moles per mole of phthalide. In adding thionyl chloride to the phthalide solution, the temperature of the solution is preferably 80 to 130 ° C. Moreover, as a method of adding thionyl chloride, it is preferable to dripping over about 0.5 to 2 hours. After thionyl chloride is added dropwise as described above, it is preferable to stir at a temperature of about 120 to 135 ° C. for about 1 to 5 hours in order to carry out the reaction more reliably.

  After completion of the reaction, excess thionyl chloride and the solvent are removed. As a method for this, it is preferable to distill off the thionyl chloride at normal pressure and then distill off the solvent under reduced pressure. In this way, 2-chloromethylbenzoyl chloride is obtained as a residue.

[Step 2] A step of producing 2-chloromethylbenzoic acid methyl ester represented by the formula (1) by reacting 2-chloromethylbenzoyl chloride with methanol;

  In this step, 2-chloromethylbenzoyl chloride obtained in step 1 is reacted with methanol. For example, methanol is added dropwise to 2-chloromethylbenzoyl chloride over a period of about 0.5 to 2 hours and stirred at 30 to 60 ° C. for about 0.5 to 1 hour. Methanol can be diluted with an appropriate solvent and added dropwise. Alternatively, 2-chloromethylbenzoyl chloride may be added dropwise to a mixture of methanol and a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as chlorobenzene, and the amount of methanol used is 1 to 3 mol with respect to 1 mol of 2-chloromethylbenzoyl chloride. Is preferred.

  Since the reaction solution thus reacted contains hydrogen chloride produced by the reaction, it is preferably neutralized with an alkali. For example, the reaction solution may be dropped at 0 to 50 ° C. into an aqueous solution in which a predetermined amount of potassium carbonate is dissolved. After neutralization, after washing with a saline solution having a concentration of about 15 to 35% by mass, the organic layer is concentrated under reduced pressure to give 2-chloromethylbenzoic acid methyl ester represented by the formula (1). It can be obtained as a residue.

  2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid represented by the formula (3) is performed by performing the step 3 described below using the 2-chloromethylbenzoic acid methyl ester obtained as described above. Acid methyl esters can be produced.

[Step 3] 2-Chloromethylbenzoic acid methyl ester is reacted with 4-hydroxyphenylacetic acid methyl ester represented by the following formula (2) to give 2- (4-methoxycarbonyl represented by the following formula (3) (Methylphenoxymethyl) benzoic acid methyl ester.

  The 2-chloromethylbenzoic acid methyl ester used in this step can be obtained as described above. On the other hand, 4-hydroxyphenylacetic acid methyl ester is obtained by reacting 4-hydroxyphenylacetic acid directly with methanol in the presence of an acid catalyst (for example, sulfuric acid, hydrochloric acid, P-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.). Can be obtained.

This step is usually performed in a solvent in the presence of a base under heating conditions of about 50 to 120 ° C. Examples of the base used include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, and examples of the solvent include acid amides such as dimethylacetamide, Aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as chlorobenzene, etc. may be mentioned.
Specifically, for example, about 0.5 to 1.5 mol of potassium carbonate with respect to 1 mol of 2-chloromethylbenzoic acid methyl ester and 100 to 100 parts by mass of 4-hydroxyphenylacetic acid methyl ester. After adding a predetermined amount of 4-hydroxyphenylacetic acid methyl ester to a solution heated to about 50 to 120 ° C. by adding about 500 parts by mass of dimethylacetamide, stirring is performed at the same temperature for about 1 to 12 hours. Can do. Here, the amount of 4-hydroxyphenylacetic acid methyl ester used can be substantially stoichiometric (equal molar amount), and such an amount of 4-hydroxyphenylacetic acid methyl ester is added over about 0.5 to 2 hours. It is preferable to add it dropwise to the heated solution. In addition, methyl 4-hydroxyphenyl acetate is previously reacted with a base such as an alkali metal carbonate such as potassium carbonate or sodium carbonate, an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, and then a potassium salt or sodium salt. It is also possible to react methyl 2-chloromethylbenzoate with methyl 4-hydroxyphenylacetate.

  After the above reaction, the target product may be separated by a known method. For example, the reaction solution is poured into water, an organic solvent (for example, toluene) is added, the organic layer is separated, and further washed with water, and then the organic solvent is distilled off to obtain the target formula (3). The 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester represented is obtained.

  As described above, 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester represented by the formula (3) can be produced. This 2- (4-methoxycarbonylmethylphenoxymethyl) can be produced. ) Benzoic acid methyl ester is a novel compound, and such a novel compound is also one aspect of the present invention.

で表される２−（４−カルボキシメチルフェノキシメチル）安息香酸を製造することができ、次いでこれを環化反応させることにより、式（５）：

で表されるジベンゾオキセピン酢酸化合物を製造することができる。したがって、そのようなジベンゾオキセピン酢酸化合物の製造方法も本発明のひとつである。 Also, by hydrolyzing this 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester, the formula (4):

2- (4-carboxymethylphenoxymethyl) benzoic acid represented by the following formula (5):

The dibenzooxepin acetic acid compound represented by these can be manufactured. Therefore, the manufacturing method of such a dibenzooxepin acetic acid compound is also one of this invention.

The method for hydrolyzing 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester may be carried out in accordance with a method for hydrolyzing a known ester with an acid or an alkali. For example, methyl 2- (4-methoxycarbonylmethylphenoxymethyl) benzoate is dissolved in an alcohol solvent such as methanol or ethanol, and a basic aqueous solution such as potassium hydroxide or sodium hydroxide, or an acidic aqueous solution such as hydrochloric acid or sulfuric acid. To process. The base or acid used is usually in a proportion of 1 mol to a large excess, preferably about 1 mol to 5 mol, per 1 mol of methyl 2- (4-methoxycarbonylmethylphenoxymethyl) benzoate. The reaction temperature is usually about 20-80 ° C.
Further, the cyclization reaction of 2- (4-carboxymethylphenoxymethyl) benzoic acid may be performed under the conditions of a normal dehydration condensation reaction. For example, the cyclization reaction can be performed by reacting 2- (4-carboxymethylphenoxymethyl) benzoic acid with a dehydrating agent such as trifluoroacetic anhydride, polyphosphoric acid, or phosphorus pentoxide. When trifluoroacetic anhydride is used, a solvent such as a halogenated hydrocarbon such as chlorobenzene is usually used, and a catalyst such as a BF ₃ -ether complex is preferably used. The reaction temperature is usually about -20 to 50 ° C.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, it goes without saying that the present invention is not limited to the following examples.

[Example 1]: Method for producing 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester via production of 2-chloromethylbenzoic acid methyl ester, step 1
In a 1 L four-necked flask, 643 ml of xylene, 134.1 g (1.0 mol) of phthalide, 18.2 g (0.08 mol) of benzyltriethylammonium chloride and 9.9 g (0.07 mol) of BF ₃ -ether complex And heated to 100 ° C. Next, 142.8 g (1.2 mol) of thionyl chloride was added dropwise over 1 hour, and the mixture was further stirred at 125 to 132 ° C. for 2 hours. Xylene and excess thionyl chloride (about 350 ml) were distilled off under normal pressure until the internal temperature reached 135 ° C., and xylene (about 350 ml) was distilled off under reduced pressure.

・ Process 2
Methanol 80.1g (2.5mol) was dripped at the concentration residue obtained at the said process 1 in 1 hour. At this time, since heat generation and generation of hydrogen chloride were accompanied, the internal temperature was kept at 60 ° C. or lower by cooling with a water bath. Then, it stirred at 50 degreeC for 1 hour, and cooled to 25 degreeC.
Next, a solution obtained by adding 300 ml of toluene to this reaction solution was dropped into a solution obtained by dissolving 70.0 g (0.51 mol) of potassium carbonate in 300 ml of water over 30 minutes. The toluene layer was separated, washed with 130 g of 30% brine, and concentrated under reduced pressure to obtain 189.2 g of 2-chloromethylbenzoic acid methyl ester. The apparent yield was 102.5%.
(Physical property data)
MS (m / z) 184 (M ^<+> )

・ Process 3
In a 500 ml four-necked flask, 30.4 g (0.20 mol) of 4-hydroxyphenylacetic acid and 300 ml of methanol were added, 0.1 g of sulfuric acid was added, and the mixture was stirred for 1 hour under heating and reflux. Subsequently, most of methanol was distilled off under reduced pressure. Then, 100 ml of methanol was added and methanol was distilled off again to obtain 4-hydroxyphenylacetic acid methyl ester.
A 1 L four-necked flask was charged with 38.8 g (0.21 mol) of 2-chloromethylbenzoic acid methyl ester obtained in Step 2 above, 30.4 g (0.22 mol) of potassium carbonate and 100 ml of dimethylacetamide. Heated to 90 ° C.
To this solution, the entire amount of 4-hydroxyphenylacetic acid methyl ester obtained above was added dropwise over 1 hour, and then stirred at 90 ° C. for 7 hours. The reaction solution was poured into 400 ml of water, 200 ml of toluene was then added, and the toluene layer was separated. The obtained toluene layer was washed with 200 ml of water, and then toluene was distilled off to obtain 64.3 g (0.2045 mol) of 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester. The apparent yield was 102.2%.
(Physical property data)
¹ H NMR (400 MHz, CDCl ₃ )
δ 3.57 (s, 2H), 3.68 (s, 3H), 3.90 (s, 3H), 5.49 (s, 2H), 6.95 (d, J = 8.8 Hz, 2H) ), 7.19 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 7.6, 1H), 8.02 (D, J = 8.0, 1H)

Example 2 Production of (11-oxo-6,11-dihydrodibenz [b, e] oxepin-2-yl) acetic acid 2- (4-methoxycarbonylmethylphenoxy obtained in Example 1 above A total amount of methyl) benzoic acid methyl ester was charged into a four-necked flask, a solution of 17.0 g of sodium hydroxide dissolved in 100 ml of water and 150 ml of methanol were added, and the mixture was stirred at 65 ° C. for 2 hours.
Then, after cooling to room temperature (about 25 ° C.), dilute with 200 ml of water, add 2.0 g of activated carbon, stir at room temperature for 1 hour, filter with a Buchner funnel to separate the activated carbon, Washed with 100 ml of water on the funnel. A solution prepared by dissolving 26.5 g of acetic acid in 50 ml of water was added dropwise over 2 hours to a mixture of the filtered mother liquor and the washing solution and heated to 60 ° C., and crystals were precipitated at the same temperature. Next, after cooling to 10 ° C., the crystals were collected by filtration through a Buchner funnel and further washed with 200 ml of water. The crystal after washing was dried under reduced pressure to obtain 46.5 g (0.1624 mol) of 2- (4-carboxymethylphenoxymethyl) benzoic acid. The yield (yield from 4-hydroxyphenylacetic acid in Example 1) was 81.2%.
(Physical property data)
¹ H NMR (400 MHz, DMSOd ₆ )
δ 3.47 (s, 2H), 5.45 (s, 2H), 6.90 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7 .47 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.57 (d, J = 7.2, 1H), 7.86 (d, J = 7.6, 1H)

Charge the total amount of 2- (4-carboxymethylphenoxymethyl) benzoic acid obtained above and 200 ml of chlorobenzene into a 500 ml four-necked flask, and add 75.0 g (0.3753 mol) of trifluoroacetic anhydride. , And stirred at about 20 ° C. for 4 hours. Next, 2.3 g (0.0162 mol) of BF ₃ -ether complex was added dropwise at −10 to 0 ° C. over 10 minutes, and the mixture was further stirred for 30 minutes and then separated, and the organic layer was washed with 200 ml of water. . The organic layer after washing was added to a solution obtained by dissolving 7.2 g of sodium hydroxide in 300 ml of water, stirred for 30 minutes, and then separated. The separated aqueous layer was added with 2.0 g of activated carbon, stirred for 30 minutes, filtered through a Buchner funnel to separate the activated carbon, and further washed with 10 ml of water on the Buchner funnel. A mixture of the filtrate and the washing solution was kept at about 40 ° C., and a mixed solution of 11.3 g (0.1876 mol) of acetic acid and 50 ml of water was added dropwise thereto over 30 minutes. After completion of dropping, the mixture was cooled to 0 to 10 ° C., filtered through a Buchner funnel to collect the precipitated crystals, and further washed with 200 ml of water. The crystal after washing was dried under reduced pressure to obtain 42.0 g of the title compound. The yield (yield from 2- (4-carboxymethylphenoxymethyl) benzoic acid) was 96.4%, and the purity measured by HPLC was 99.9%.
(HPLC conditions)
Column: Inertsil ODS-5 μm (4.6 mm ID × 15 cm)
Mobile phase: 0.02% trifluoroacetic acid aqueous solution / acetonitrile = 5/5 → 3/7 (30 minutes)
Detection wavelength: UV254nm
(Physical property data)
¹ H NMR (400 MHz, DMSOd ₆ )
δ 3.63 (s, 2H), 5.30 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 3.6 Hz, 1H), 7 .55 (dd, J = 7.9 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.97 ( d, J = 2.0Hz, 1H)

Claims (4)

Following formula (1):

2-chloromethylbenzoic acid methyl ester represented by the following formula (2):

The following formula (3) characterized by reacting with 4-hydroxyphenylacetic acid methyl ester represented by:

The manufacturing method of 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester represented by these. A process for producing 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester, comprising the following steps 1 to 3:
[Step 1] A step of producing 2-chloromethylbenzoyl chloride by reacting phthalide with thionyl chloride;
[Step 2] A step of producing 2-chloromethylbenzoic acid methyl ester represented by the following formula (1) by reacting 2-chloromethylbenzoyl chloride with methanol;

[Step 3] 2-Chloromethylbenzoic acid methyl ester is reacted with 4-hydroxyphenylacetic acid methyl ester represented by the following formula (2) to give 2- (4-methoxycarbonyl represented by the following formula (3) (Methylphenoxymethyl) benzoic acid methyl ester.

Formula (3):

2- (4-Methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester represented by Hydrolysis of 2- (4-methoxycarbonylmethylphenoxymethyl) benzoic acid methyl ester gives the formula (4):

2- (4-carboxymethylphenoxymethyl) benzoic acid represented by the following formula (5):

The manufacturing method of the dibenzo oxepin acetic acid compound represented by these.