JP7288665B2 - Method for producing ethylanilinotoluenesulfonic acid derivative - Google Patents

Description

The present invention relates to a method for producing ethylanilinotoluenesulfonic acid derivatives and novel intermediates produced in the production of ethylanilinotoluenesulfonic acid derivatives.

Japanese Patent No. 4200222 (Patent Document 1) describes that brilliant blue G (hereinafter referred to as BBG) is useful as a staining agent for staining the ocular membrane during surgery for treatment of eye diseases. In addition, in Non-Patent Documents 1 and 2 below, BBG and brilliant blue FCF (hereinafter referred to as BB-FCF) are effective for spinal cord injury and other inflammation-related diseases by inhibiting P2X7 receptors and pannexin 1. Something is stated. As is clear from these examples, triarylmethane compounds such as BBG and BB-FCF have the property of being applicable not only as pigments but also as pharmaceuticals. Japanese Patent Application Laid-Open No. 2017-95439 (Patent Document 2) and Chinese Patent No. 102617411 (Patent Document 3) describe production methods for obtaining BBG and BB-FCF.

However, from the viewpoint of practicality in pharmaceutical production, when these known production methods were examined, it was found that an ethylanilinotoluenesulfonic acid derivative (hereinafter referred to as compound 1) corresponding to an intermediate represented by formula (1) was obtained. It was found that each process has the following problems.

That is, since the sulfonyl chloride reaction uses an organometallic reagent, sulfur dioxide and a chlorinating agent under ultra-low temperature conditions, the work is complicated. In addition, since benzenethiol, which has a high odor, is used when introducing a benzylthio group, it is not easy to handle. Since fuming sulfuric acid and sulfuric acid are used at high temperature to introduce sulfonic acid groups, the reaction conditions are harsh and unwanted positional isomers are generated in the product. In addition, it is necessary to repeat recrystallization to remove it, which lowers the yield.

Patent No. 4200222 JP 2017-95439 Chinese Patent No. 102617411

PNAS, 2009, 106(30), 12489-12493. J. Gen. Physiol. , 2013, 141(5), 649-56.

One of the inventions described in the present specification is an inexpensive and highly pure ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a salt thereof, which is an intermediate for obtaining BBG or BB-FCF. The purpose is to provide a manufacturing method.

An object of one of the inventions described in this specification is to provide a novel intermediate for synthesizing the ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a salt thereof.

One of the inventions described herein uses the readily available 3-methylbenzenesulfonyl chloride as a starting material to form a sulfonate ester by reaction with phenol, benzylic bromination, N-ethyl-m - based on the discovery that the desired compound can be obtained very easily and in high quality by addition of toluidine or N-ethylaniline and hydrolysis under alkaline conditions.

（式（１）中，Ｒ^１は，水素原子又はメチル基を示す。） The first invention described in this specification relates to a method for producing an ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a pharmaceutically acceptable salt thereof.

(In formula (1), R ¹ represents a hydrogen atom or a methyl group.)

（式（５）中，Ｘ^１は，脱離基を示し，Ｙ^１は保護基を示す。） This method comprises reacting a compound of formula (5) with N-ethyl-m-toluidine or N-ethylaniline to obtain a compound of formula (6).

(In formula (5), X ¹ represents a leaving group and Y ¹ represents a protecting group.)

（式（６）中，Ｒ^１は，水素原子又はメチル基を示し，Ｙ^１は保護基を示す。）

(In formula (6), R ¹ represents a hydrogen atom or a methyl group, and Y ¹ represents a protecting group.)

And this method includes a step of obtaining an ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a pharmaceutically acceptable salt thereof from a compound represented by formula (6).

（式（３）中，Ｙ^１は保護基を示す。） A preferred embodiment of the above method further comprises the step of obtaining the compound of formula (5) by halogenating the compound of formula (3). In chronological order, this step is "a step of reacting a compound represented by formula (5) with N-ethyl-m-toluidine or N-ethylaniline to obtain a compound represented by formula (6)". It is a step that exists before

(In formula (3), Y ¹ represents a protecting group.)

（式（２）中，Ｘ^２は，脱離基を示す。） A preferred embodiment of the above method further comprises the step of obtaining the compound represented by formula (3) by esterifying the compound represented by formula (2). This step is a step that precedes "the step of obtaining the compound represented by the formula (5) by halogenating the compound represented by the formula (3)" chronologically.

(In formula (2), X ² represents a leaving group.)

（式（４）中，Ｘ^１及びＸ^２は，同一でも異なってもよく脱離基を示す。） A preferred embodiment of the above method further comprises the step of obtaining the compound represented by formula (5) by esterifying the compound represented by formula (4). In chronological order, this step is "a step of reacting a compound represented by formula (5) with N-ethyl-m-toluidine or N-ethylaniline to obtain a compound represented by formula (6)". It is a step that exists before

(In formula (4), X ¹ and X ² may be the same or different and represent a leaving group.)

（式（２）中，Ｘ^２は，脱離基を示す。） A preferred embodiment of the above method further comprises the step of obtaining the compound represented by formula (4) by halogenating the compound represented by formula (2). This step is a step that precedes "the step of obtaining the compound represented by the formula (5) by esterifying the compound represented by the formula (4)" chronologically.

(In formula (2), X ² represents a leaving group.)

A preferred embodiment of the above method is a method in which X ¹ represents a bromine atom and Y ¹ represents a phenyl group. Also, when ^X2 is included in the process, ^X2 is preferably a chlorine atom.

The ethylanilinotoluenesulfonic acid derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof is an intermediate in the production of BBG or BB-FCF. Thus, this specification also provides a method for producing BBG, BB-FCF, or a pharmaceutically acceptable salt thereof, comprising the steps described above. A method for producing BBG or BB-FCF using the ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a pharmaceutically acceptable salt thereof is known.

Another invention described in this specification relates to novel intermediates used in the production of ethylanilinotoluenesulfonic acid derivatives represented by formula (1) or pharmaceutically acceptable salts thereof.

An example of a specific intermediate is phenyl-3-(bromomethyl)benzene-1-sulfonic acid, or a pharmaceutically acceptable salt thereof. This is a compound or a salt thereof in which ^X1 is a bromine atom and ^Y1 is a phenyl group in the formula (5). This specification describes phenyl-3-(bromomethyl)benzene-1-sulfonic acid, or its Use of pharmaceutically acceptable salts is also provided.

Examples of specific intermediates are phenyl-3-{[ethyl(3-methylphenyl)amino]methyl}benzene-1-sulfonic acid, phenyl-3-{[ethyl(phenyl)amino]methyl}benzene-1 - is a sulfonic acid, or a pharmaceutically acceptable salt thereof. These are compounds in which R ¹ is a methyl group or a hydrogen atom and Y ¹ is a phenyl group in formula (6), or salts of any of these. This specification describes phenyl-3-{[ethyl(3-methylphenyl)amino]methyl for producing ethylanilinotoluenesulfonic acid derivatives represented by formula (1) or pharmaceutically acceptable salts thereof. }benzene-1-sulfonic acid, phenyl-3-{[ethyl(phenyl)amino]methyl}benzene-1-sulfonic acid, or a pharmaceutically acceptable salt thereof.

The present specification provides a method for producing an ethylanilinotoluenesulfonic acid derivative or a salt thereof represented by the formula (1), which is an intermediate for obtaining BBG or BB-FCF, at low cost and with high purity. is disclosed.

The present specification discloses providing novel intermediates for synthesizing ethylanilinotoluene sulfonic acid derivatives represented by formula (1) or salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments for carrying out the present invention will be described below with reference to the drawings. The present invention is not limited to the embodiments described below, and includes appropriate modifications within the scope obvious to those skilled in the art from the following embodiments. In the following description, for example, the compound represented by formula (1) is expressed as compound 1.

One of the features of the invention disclosed in this specification is the method of introducing the sulfonic acid group of compound 1. In the present invention, for example, a chlorosulfonyl group, which can be easily converted into a sulfonic acid group, is introduced in advance into a starting material at an appropriate position. As a result, conventional problems such as complicated reaction procedures, use of reagents and raw materials that are not easy to handle, harsh reaction conditions, formation and removal of positional isomers can be avoided. Furthermore, in this production method, easy-to-handle reagents are used under mild reaction conditions, so there is little work load. Therefore, this specification can provide a highly practical method for producing an ethylanilinotoluenesulfonic acid derivative (compound 1) useful as a pharmaceutical intermediate, and the production method uses compound 1 and compound 1. suitable for mass production of compounds The ethylanilinotoluene sulfonic acid derivative obtained by this production method does not contain unnecessary isomers and has high quality without repeating special purification procedures, so BBG and BB-FCF are produced at pharmaceutical grade. It can be used as an extremely useful intermediate in some cases.

（式（１）中，Ｒ^１は，水素原子又はメチル基を示す。） The first invention described in this specification relates to a method for producing an ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a pharmaceutically acceptable salt thereof.

(In formula (1), R ¹ represents a hydrogen atom or a methyl group.)

The ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a pharmaceutically acceptable salt thereof (compound 1 or a salt thereof) is ionized, for example, in an aqueous solution, and the chemical formula at that time is (1) There are also different However, those forms are self-evident for those skilled in the art, and both ionized and non-ionized forms are naturally included in compound 1 or salts thereof. In addition, Compound 1 or its salt may be a solvate (e.g. hydrate), because such a form exhibits substantially the same behavior as Compound 1 or its salt in aqueous solution. , compound 1 or a salt thereof.

Examples of pharmacologically acceptable salts include salts composed of inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic organic acids, halogen ions, etc., and intramolecular salts. Examples of inorganic bases include alkali metals (Na, K, etc.) and alkaline earth metals (Ca, Mg, etc.). Examples of organic bases include trimethylamine, triethylamine, choline, procaine, ethanolamine, and the like. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, and the like. Examples of basic organic acids include lysine, arginine, ornithine, histidine and the like.

The outline of the method for producing compound 1 is as follows.
By halogenating the benzylic position of compound 2 and compound 3 with a halogenating agent, compound 4 and compound 5 can be obtained, respectively.
Compound 2 and compound 4 are reacted with an aromatic compound to which a hydroxyl group is directly bonded, and sulfonic acid esterification is performed to obtain compound 3 and compound 5, respectively.
Compound 6 can be obtained by reacting compound 5 with N-ethyl-m-toluidine or N-ethylaniline.
By hydrolyzing or deprotecting compound 6, compound 1 can be obtained.

Below, the first scheme (scheme 1) which manufactures the compound 1 from the compound 2 is demonstrated.

Scheme 1
Scheme 1 shows a scheme obtained in the order of compound 2→compound 3→compound 5→compound 6→compound 1. Each step is optionally represented as in Scheme 1.1. It should be noted that this specification is not only the entire scheme 1, but also a combination of any number of consecutive schemes, such as a combination of schemes 1.1 and 1.2, and a combination of schemes 1.3 and 1.4. An invention is also provided. This point also applies to Scheme 2, which will be described later.

Scheme 1.1
In Scheme 1.1, for example, compound 2 is reacted with an aromatic compound to which a hydroxyl group is directly bonded (for example, a compound represented by Y ^-OH ), and sulfonic acid esterification is performed to convert compound 3 to It is a process to obtain.

In formula (2), ^X2 represents a leaving group. A known leaving group can be appropriately used as the leaving group. Examples of leaving groups are halogen atoms, p-toluenesulfonyl groups, trifluoromethanesulfonyl groups, methanesulfonyl groups and pentafluorophenyloxy groups. Examples of halogen atoms are fluorine, chlorine, bromine and iodine atoms. A preferred example of ^X2 is a chlorine atom.

Y ¹ is a protecting group. In Scheme 1.2 and Scheme 1.3, the sulfonate ester moiety is protected because a protecting group has been introduced. That is, Y ¹ is a sulfonic acid protecting group that is not deprotected in Schemes 1.2 and 1.3. Examples of Y ¹ are C ₁ -C ₄ alkyl groups, C ₂ -C ₄ alkenyl groups, C ₂ -C 4 alkynyl groups, C ₁ -C ₄ alkoxy groups, C _{1 -C 4 alkylthio} groups or fluorine atoms, chlorine A phenyl group optionally substituted with an atom, a bromine atom, and an iodine atom. Further examples of Y ¹ are 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2,2, dichloroethyl and 2,2-dichloropropyl groups.

The compound represented by Y ¹ -OH is added, for example, in the range of 1 to 3 equivalents, more preferably 1 to 1.5 equivalents, relative to compound 2. This reaction is preferably carried out in the presence of a tertiary amine such as pyridine, triethylamine, N,N-diisopropylethylamine, etc. Among them, triethylamine is preferred. The tertiary amine is added, for example, in the range of 1 to 3 equivalents, preferably 1 to 1.5 equivalents. Solvents used in the reaction include halogenated hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; aprotic polar solvents such as acetamide (DMA), dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), 1-methyl-2-pyrrolidone (NMP); ethyl ether, isopropyl ether, Ethers such as methyl tert-butyl ether (MTBE), 1,2-dimethoxyethane (DME), tetrahydrofuran (THF) and dioxane; nitriles such as acetonitrile and propionitrile; Among these, solvents such as dichloromethane, acetonitrile, and tetrahydrofuran are preferred. The reaction may be carried out, for example, at room temperature to 60° C. for 1 to 12 hours. For example, compound 3 can be obtained by washing the obtained organic layer using a known method, drying and concentrating.

Scheme 1.2
Scheme 1.2 is a step to obtain compound 5 by halogenating the benzylic position of compound 3 using, for example, a halogenating agent.
X ¹ in formula (5) represents a leaving group. A known leaving group can be appropriately used as the leaving group. This leaving group is, for example, a halogen atom derived from a halogenating agent. Other examples of leaving groups are p-toluenesulfonyl, trifluoromethanesulfonyl and methanesulfonyl groups. Examples of halogen atoms are fluorine, chlorine, bromine and iodine atoms. A preferred example of X ¹ is a bromine atom.
Examples of halogenating agents are bromine, chlorine and N-bromosuccinimide (NBS), of which NBS is preferred. The amount of the halogenating agent to be added is, for example, in the range of 1 to 10 equivalents, more preferably 1 to 3 equivalents. Heat, light, and radical initiators may be used to accelerate the reaction. It is preferable to use azobisbutyronitrile (AIBN) as a radical initiator, and AIBN is added, for example, in the range of 0.1 to 1 equivalent, and may be added in 0.1 to 0.3 equivalent. good. As the solvent used for the reaction, the solvents shown above can be appropriately used, and dichloromethane, acetonitrile and the like are preferable. The reaction may be carried out, for example, at room temperature to 100° C. for 1 to 24 hours. For example, compound 5 can be obtained by washing the obtained organic layer using a known method, drying and concentrating.

Scheme 1.3
Scheme 1.3 is a process for obtaining compound 6, for example, by reacting compound 5 with N-ethyl-m-toluidine or N-ethylaniline (aniline compound).
The aniline compound is added, for example, in the range of 1 to 3 equivalents, more preferably 1 to 1.5 equivalents. This reaction is carried out in the presence of an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate. Among these inorganic bases, potassium carbonate is preferred. The amount of inorganic base added is, for example, 1 to 10 equivalents, preferably 1 to 5 equivalents. As the solvent used for the reaction, the solvents shown above can be appropriately used, and acetonitrile, tetrahydrofuran, dimethylformamide and the like are preferable. The reaction may be carried out at room temperature to 100° C. for 1 to 12 hours. For example, compound 6 can be obtained by washing the obtained organic layer using a known method, drying and concentrating.

Scheme 1.4
Scheme 1.4 is a process for obtaining compound 1 by hydrolyzing or deprotecting compound 6, for example.
Deprotection and hydrolysis are known, and compound 1 can be obtained by appropriately neutralizing after these treatments. For example, hydrolysis and deprotection can occur by adding 1 to 50 equivalents (or 1 to 20 equivalents) of an aqueous solution of sodium hydroxide or potassium hydroxide prepared to an appropriate concentration. Examples of solvents used in this reaction are hydrophilic organic solvents. Examples of hydrophilic organic solvents are methanol and ethanol. The reaction may be carried out at room temperature to 100° C. for 1 to 12 hours. After treatment such as hydrolysis, for example, the solvent is distilled off under reduced pressure, and an appropriate amount of hydrochloric acid is added to neutralize. Compound 1 may be purified by recrystallization if necessary.

Scheme 2
Next, a second scheme (scheme 2) for producing compound 1 from compound 2 will be described. Scheme 2 shows a scheme obtained in the order of compound 2→compound 4→compound 5→compound 6→compound 1. Note that schemes 2.3 and 2.4 are the same as schemes 1.3 and 1.4, respectively, so the descriptions are cited.

Scheme 2.1
Scheme 2.1 is a process for obtaining compound 4 by, for example, halogenating the benzylic position of compound 2 using a halogenating agent. This step may be performed in the same manner as in Scheme 1.2.

Scheme 2.2
In Scheme 2.2, for example, compound 4 is reacted with an aromatic compound (for example, a compound represented by Y ¹ —OH) to which a hydroxyl group is directly bonded, and sulfonic acid esterification is performed to convert compound 5 into It is a process to obtain. This step may be performed in the same manner as in Scheme 1.1.

EXAMPLES Next, the present invention will be specifically described with reference to examples. The present invention is by no means limited to these examples, and the present invention also includes a suitable combination of known conditions and processes.

Synthesis of compound 5a via compound 3a

Phenol (247 mg, 2.62 mmol) was dissolved in dichloromethane (15 mL), triethylamine (0.55 mL, 3.97 mmol) and m-toluenesulfonyl chloride (2) (500 mg, 2.62 mmol) were added at 0°C. . The mixture was stirred at room temperature for 2 hours and ethyl acetate was added. The organic layer was washed with 0.5M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave compound 3a as an oil (635 mg). Subsequently, compound 3a (552 mg, 2.22 mmol) was dissolved in acetonitrile (11 mL), N-bromosuccinimide (594 mg, 3.33 mmol), and azobisisobutyronitrile (37 mg, 0.23 mmol) were added, and 80 C. for 16 hours, the heating was stopped, and the temperature was returned to room temperature. Subsequently, N,N-diisopropylethylamine (0.39 mL, 2.23 mmol) and diethyl phosphite (0.57 mL, 4.42 mmol) were added and stirred at room temperature for 2 hours. Ethyl acetate was added, and the organic layer was washed with a 5% potassium carbonate aqueous solution three times and with a saturated saline solution. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain compound 5a as an oil (1.17 g).

(5a) ¹ H NMR (500 MHz, CDCl ₃ ) 4.47 (s, 2H), 6.96-6.98 (m, 2H), 7.26-7.32 (m, 3H), 7.51 ( dd, 1H, J = 7.6Hz), 7.68 (d, 1H, J = 7.6Hz), 7.76 (d, J = 7.6Hz, 1H), 7.28 (s, 1H).

Synthesis of compound 5a via compound 4a

Commercially available m-toluenesulfonyl chloride (2) (5.00 g, 26.2 mmol) was dissolved in acetonitrile (100 mL), N-bromosuccinimide (5.30 g, 29.7 mmol), azobisisobutyronitrile (430 mg , 2.62 mmol) was added, and the mixture was heated and stirred at 80°C for 16 hours, then stopped heating and allowed to return to room temperature. It was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Dichloromethane (50 mL) was added to the crude product of compound 4a, and this solution was added to a prepared solution of phenol (2.46 g, 26.2 mmol) and triethylamine (3.65 mL, 26.2 mmol) in dichloromethane (50 mL). was added slowly at 0° C. and stirred at the same temperature for 1 hour. Water was added and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was decolorized through a short column (hexane/ethyl acetate=4/1) to give compound 5a as an oil (7.9 g). ¹ H NMR was consistent with that of compound 5a obtained by the method via compound 3a.

Synthesis of compound 1a

Compound 5a (1.17 g) was dissolved in acetonitrile (10 mL), N-ethyl-m-toluidine (270 mg, 2.00 mmol) and potassium carbonate (338 mg, 2.45 mmol) were added, and the mixture was heated and stirred at 80°C for 18 hours. Then, the heating was stopped and the temperature was returned to room temperature. After removing potassium carbonate by filtration, the solution was concentrated under reduced pressure. The obtained residue was subjected to a short column (hexane/ethyl acetate=4/1) for decolorization to obtain compound 6a as an oil (719 mg).

Subsequently, compound 6a (719 mg) was dissolved in methanol (10 mL), 2M aqueous sodium hydroxide solution (10 mL) was added, and the mixture was heated and stirred at 70°C for 2 hours. After concentrating under reduced pressure to remove methanol, the aqueous layer was washed with MTBE and neutralized by carefully adding 0.5 M hydrochloric acid. More toluene was added, and the water bath was set at 60° C. and concentrated under reduced pressure. Methanol was added to the resulting residue, insoluble components were removed by filtration, and the filtrate was concentrated under reduced pressure. After drying the obtained amorphous solid under reduced pressure, isopropyl alcohol (5 mL) and MTBE (5 mL) were added and stirred at 60° C. to wash the solid. After cooling at 0° C., the solid was filtered and dried under reduced pressure to obtain compound 1a as a pale brown solid (505 mg, 1.65 mmol, HPLC purity 94%).

(6a) ¹ H NMR (500 MHz, _CDCl3 ) 1.18 (t, 3H, J = 7.0 Hz), 2.27 (s, 3H), 3.43 (q, 2H, J = 7.0 Hz), 4.52 (s, 2H), 6.41 (d, 1H, J = 7.7Hz), 6.46 (s, 1H), 6.54 (d, 1H, J = 7.7Hz), 6. 91-6.93 (m, 2H), 7.07 (dd, 1H, J = 7.5Hz), 7.22-7.25 (m, 3H), 7.44 (dd, 1H, J = 7 .5Hz), 7.54 (d, 1H, J = 7.5Hz), 7.69 (d, 1H, J = 7.5Hz), 7.72 (s, 1H).

(1a) ¹ H NMR (500 MHz, D ₂ O) 1.05 (t, 3H, J = 7.0 Hz), 2.13 (s, 3H), 3.32 (q, 2H, J = 7.0 Hz), 4.46 (s, 2H), 6.50 (d, 1H, J = 8.0 Hz), 6.53 (d, 1H, J = 8.5 Hz) 6.57 (s, 1H ), 7.02 (dd, 1H, J = 9.0 Hz), 7.28 (d, 1H, J = 7.4 Hz), 7.32 (dd, 1H, J = 7.4 Hz), 7.50 (s, 1H), 7.53 (d, 1H, J = 8.5Hz).

実施例１と同様な方法でＮ－エチル－ｍ－トルイジンの代わりにＮ－エチルアニリンを用いることで化合物１ｂを白色固体として得た（２工程収率５９％，ＨＰＬＣ純度９５％）。
Synthesis of compound 1b

Compound 1b was obtained as a white solid in the same manner as in Example 1 using N-ethylaniline instead of N-ethyl-m-toluidine (2 step yield 59%, HPLC purity 95%).

(6b) ¹ H NMR (500 MHz, _CDCl3 ) 1.18 (t, 3H, J = 7.0 Hz), 3.31 (q, 2H, J = 7.0 Hz), 4.51 (s, 2H), 6.61-6.62 (m, 2H), 6.71 (dd, 1H, J = 7.0Hz), 6.90-6.92 (m, 2H), 7.17-7.26 (m , 5H), 7.44 (dd, 1H, J = 7.6Hz), 7.54 (d, 1H, J = 7.6Hz), 7.70 (d, 1H, J = 7.6Hz), 7 .71(s, 1H).

(1b) ¹ H NMR (500 MHz, _D2O ) 0.90 (t, 3H, J = 6.7 Hz), 3.16 (q, 2H, J = 6.7 Hz), 4.26 (s, 2H) , 6.52-6.56 (m, 3H), 6.99-7.02 (m, 2H), 7.09 (d, 1H, J = 7.5Hz), 7.14 (dd, 1H, J = 7.5 Hz), 7.49 (d, 1H, J = 7.5 Hz), 7.50 (s, 1H).

[Reference example]
Synthesis of compound 7 from compound 1a

Using the highly pure compound 1a obtained in Example 1, compound 7 was synthesized according to the method described in Patent Document 2, and it was found that compound 7 was obtained in high yield and high purity. . That is, it was shown that the compound 1a obtained by the production method of the present invention has sufficient quality to be used in the next step.

INDUSTRIAL APPLICABILITY The present invention relates to methods for producing ethylanilinotoluenesulfonic acid derivatives and intermediates thereof, and can be used in the chemical and pharmaceutical industries.

Claims (8)

A method for producing an ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a pharmaceutically acceptable salt thereof,

(In formula (1), R ¹ represents a hydrogen atom or a methyl group.)
a step of reacting a compound represented by formula (5) with N-ethyl-m-toluidine or N-ethylaniline to obtain a compound represented by formula (6);

(In formula (5), X ¹ represents a leaving group and Y ¹ represents a protecting group.)

(In formula (6), R ¹ represents a hydrogen atom or a methyl group, and Y ¹ represents a protecting group.)
obtaining an ethylanilinotoluenesulfonic acid derivative represented by formula (1) or a pharmaceutically acceptable salt thereof from a compound represented by formula (6);
Method. The method of claim 1, wherein
Further comprising a step of obtaining the compound represented by the formula (5) by halogenating the compound represented by the formula (3),

(In formula (3), Y ¹ represents a protecting group.)
Method. 3. The method of claim 2, further comprising the step of obtaining the compound of formula (3) by esterifying the compound of formula (2),

(In formula (2), X ² represents a leaving group.)
Method. The method of claim 1, wherein
Further comprising a step of obtaining the compound represented by the formula (5) by esterifying the compound represented by the formula (4),

(In formula (4), X ¹ and X ² may be the same or different and represent a leaving group.)
Method. 5. The method of claim 4, further comprising the step of obtaining the compound of formula (4) by halogenating the compound of formula (2).

(In formula (2), X ² represents a leaving group.)
Method. A method according to any one of claims 1 to 5, wherein X ¹ represents a bromine atom and Y ¹ represents a phenyl group. Phenyl-3-(bromomethyl)benzene-1-sulfonic acid, or a pharmaceutically acceptable salt thereof. Phenyl-3-{[ethyl(3-methylphenyl)amino]methyl}benzene-1-sulfonic acid, phenyl-3-{[ethyl(phenyl)amino]methyl}benzene-1-sulfonic acid, or the pharmaceutically acceptable salt.