HK1263035B - Method for producing 5-(bromomethyl)-1-benzothiophene - Google Patents

Description

Preparation method of 5-bromomethyl-1-benzothiophene

Technical Field

The present invention relates to a method for preparing 5-bromomethyl-1-benzothiophene which is used as a preparation intermediate for medicines.

Background Art

1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol is a compound useful as a therapeutic agent for central and peripheral nervous system diseases. This compound is prepared, for example, from 1-benzothiophene-5-acetic acid (Patent Document 1). 1-Benzothiophene-5-acetic acid is also prepared, for example, from 5-bromomethyl-1-benzothiophene (hereinafter sometimes referred to as "Compound A") (Non-Patent Document 1).

Compound A is a compound useful as a pharmaceutical intermediate.

On the other hand, as a method for producing Compound A, a method of brominating 5-methyl-1-benzothiophene (hereinafter sometimes referred to as "Compound B") is known (Patent Documents 2 to 4).

Prior art literature

Patent Literature

Patent Document 1: International Publication No. WO2006/104088

Patent Document 2: International Publication No. WO2008/073142

Patent Document 3: Japanese Patent Application Laid-Open No. 2006-111553

Patent Document 4: International Publication No. WO2005/092885

Non-patent literature

Non-patent document 1: J. Med. Chem., 1997, Vol. 40, pp. 1049-1062

Summary of the Invention

Problems to be solved by the invention

The methods for preparing Compound A described in Patent Documents 2 to 4 have the following disadvantages: (1) Carbon tetrachloride is toxic. (2) Therefore, its use is prohibited. (3) 5-dibromomethyl-1-benzothiophene is produced as a by-product. (4) Therefore, a complex purification process is required.

The object of the present invention is to provide a simple industrial production method of Compound A that has no adverse effects on the human body.

Means of solving problems

Under such circumstances, the present inventors conducted intensive studies and found that by converting the conventional batch reaction to a flow reaction in the bromination step of compound B, compound A can be produced with a simple operation, thereby completing the present invention.

The present invention provides the following contents.

[1] A method for preparing 5-bromomethyl-1-benzothiophene, comprising:

(1) a step of introducing 5-methyl-1-benzothiophene, a brominating agent and a solvent into a reaction apparatus,

(2) irradiating the reaction device with light having a wavelength range of 200 to 780 nm, and

(3) a step of recovering 5-bromomethyl-1-benzothiophene from the reaction apparatus;

in,

The reaction device is a flow-type photochemical reaction device, and

The solvent is one or more selected from esters and halogenated hydrocarbons.

[2] The method according to [1], wherein the brominating agent is one or more selected from the group consisting of bromine, N-bromocaprolactam, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, a bromine-pyridine complex, and copper (II) bromide.

[3] The method according to [1], wherein the brominating agent is one or two selected from N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin.

[4] The method according to [1], wherein the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin.

[5] The method according to any one of [1] to [4], wherein the solvent is one or more selected from esters.

[6] The method according to any one of [1] to [4], wherein the solvent is one or two selected from methyl acetate and ethyl acetate.

[7] The method according to any one of [1] to [6], wherein the reaction temperature is 5-70°C.

Effects of the Invention

The preparation method of the present invention is a method for preparing compound A from compound B using a simple operation. The preparation method of the present invention has the following advantages: (1) carbon tetrachloride is not used. (2) Therefore, it is safe for the human body. (3) 5-dibromomethyl-1-benzothiophene is not easily produced as a by-product. (4) Therefore, a complicated purification process is not required. (5) The yield is high. (6) The purity of compound A is high.

The preparation method of the present invention can be used as an industrial production method for compound A.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a diagram showing one embodiment of the flow-type photochemical reaction apparatus of the present invention.

FIG2 is a diagram showing another embodiment of the flow-type photochemical reaction device of the present invention.

Explanation of symbols

1 outer cylinder

2 inner tube

3 Light Source

4. Import section

5. Recycling Department

6 reaction tubes

7 tubes

DETAILED DESCRIPTION

The present invention is described in detail below.

Unless otherwise specified, "%" used in this specification means mass %.

The term "halogenated hydrocarbon" refers to, for example, dichloromethane, chloroform, dichloroethane, trichloroethylene, tetrachloroethylene, and the like.

The term "esters" refers to, for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isoamyl acetate, and the like.

Next, the production method of the present invention will be described.

[Preparation method 1]

Compound A can be prepared by reacting a brominating agent with compound B under light irradiation.

The reaction is carried out using a flow-type photochemical reaction apparatus. The preparation method of the present invention includes the following three steps.

<Step 1> Step of introducing compound B, brominating agent and solvent into the reaction apparatus

This step is a step of introducing compound B, a brominating agent, and a solvent into a reaction apparatus.

Examples of this step include:

(Step 1A) A step of introducing a mixture containing compound B and a solvent, and a mixture containing a brominating agent and a solvent, into a reaction apparatus, respectively, and mixing them in the reaction apparatus.

(Step 1B) A step of preparing a mixture containing compound B, a brominating agent, and a solvent, and then introducing the mixture into a reaction apparatus.

As a preferred step, (Step 1B) can be mentioned.

As a more preferred process, a process including the following steps can be mentioned:

(a) a step of preparing a mixture containing compound B and a solvent,

(b) a step of preparing a mixture containing a brominating agent and a solvent,

(c) a step of mixing the mixture obtained in (a) and (b),

(d) A step of introducing the mixture obtained in (c) into a reaction apparatus.

The mixture containing compound B and a solvent is preferably a solution containing compound B and a solvent.

The mixture containing the brominating agent and the solvent is preferably a solution containing the brominating agent and the solvent.

The mixture containing compound B, a brominating agent, and a solvent is preferably a solution containing compound B, a brominating agent, and a solvent.

The mixture obtained in (a) is preferably the solution obtained in (a), and the mixture obtained in (b) is preferably the solution obtained in (b).

The mixture obtained in (c) is preferably the solution obtained in (c).

The step (c) is preferably performed immediately before the step (d).

The solvent used in the reaction is not particularly limited as long as it does not affect the reaction. Preferred solvents include one or more selected from esters and halogenated hydrocarbons, more preferably one or more selected from esters, and even more preferably one or two selected from methyl acetate and ethyl acetate.

The amount of the solvent used is not particularly limited, and may be 1 to 200 times (v/w) the amount of compound B, preferably 1 to 5 times (v/w).

Compound B preferably dissolves.

Examples of the brominating agent used in this reaction include one or more selected from the group consisting of bromine, N-bromocaprolactam, N-bromosuccinimide (hereinafter sometimes referred to as "NBS"), 1,3-dibromo-5,5-dimethylhydantoin (hereinafter sometimes referred to as "DBH"), N-bromoacetamide, N-bromophthalimide, N-bromomaleimide, N-bromobenzenesulfonamide, bromine-pyridine complexes, and copper (II) bromide. Preferably, one or two selected from the group consisting of N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin are used, and more preferably, 1,3-dibromo-5,5-dimethylhydantoin is used.

The amount of the brominating agent used varies depending on the type of the brominating agent.

For example, when NBS is used, the amount of NBS used relative to compound B may be 0.7 to 1.3 equivalents (eq), preferably 0.8 to 1.2 eq, more preferably 0.9 to 1.2 eq, and further preferably 1.0 to 1.2 eq.

For example, when DBH is used, the amount of DBH used relative to compound B may be 0.35 to 0.65 equivalents, preferably 0.40 to 0.60 equivalents, more preferably 0.45 to 0.60 equivalents, and further preferably 0.50 to 0.60 equivalents.

When a mixture containing a brominating agent and a solvent is prepared, preferred solvents are the same as described above.

The amount of the solvent used is not particularly limited, and may be 5 to 200 times (v/w), preferably 10 to 50 times (v/w), the amount of the brominating agent.

The brominating agent is preferably dissolved.

In order to set the amount of the brominating agent used relative to compound B within the above range, it is preferred to adjust the concentration of the brominating agent.

<Step 2> Step of irradiating the reaction device with light having a wavelength range of 200 to 780 nm

This step is a step of reacting the brominating agent with the compound B introduced into the reaction apparatus under light irradiation.

The mixture containing compound B and the brominating agent is irradiated with light. For the light irradiation, a light source is preferably used.

Examples of the light source include xenon lamps, sunlight, ultrahigh-pressure mercury lamps, high-pressure mercury lamps, low-pressure mercury lamps, metal halide lamps, and LEDs (light-emitting diodes). Preferred are high-pressure mercury lamps, metal halide lamps, and LEDs.

The irradiated light may be light having a wavelength in the range of 200 to 780 nm, preferably light having a wavelength in the range of 250 to 500 nm, and more preferably light having a wavelength in the range of 300 to 450 nm.

The reaction temperature may be 5 to 70°C, preferably 20 to 60°C.

The reaction time can be 0.5 to 30 minutes, preferably 0.7 to 15 minutes, and more preferably 1 to 5 minutes. Since the reaction is carried out using a flow-type photochemical reactor, the reaction time refers to the time it takes to pass through the reactor. To set the reaction time within the above range, it is preferable to adjust the introduction rate.

The reaction time can be determined, for example, from the spatial volume in which the reaction proceeds and the introduction rate.

<Step 3> Step of recovering compound A from the reaction apparatus

This step is a step of recovering compound A produced by the reaction from the reaction apparatus.

Compound A can be isolated from a mixture containing Compound A by conventional methods such as concentration, distillation, extraction, crystallization and/or column chromatography.

When compound A is used for further subsequent reactions, compound A may be isolated or directly used in the subsequent steps without isolation.

The preparation method of the present invention is carried out using a flow-type photochemical reaction device.

One embodiment of the flow-type photochemical reaction apparatus used in the present invention is shown in FIG1 .

The flow-type photochemical reaction device used in the present invention includes, for example, an outer cylinder, an inner cylinder, and a light source.

The outer cylinder is preferably cylindrical and includes an introduction portion and a recovery portion.

The inner cylinder is preferably a transparent cylindrical shape that can transmit light, and has a light source inside.

The gap defined by the outer cylinder and the inner cylinder is closed, and the reaction proceeds in the closed gap.

A mixture containing compound B and a brominating agent is introduced into the reaction apparatus through the introduction portion of the outer cylinder, irradiated with light to cause the reaction to proceed, and the mixture containing compound A is recovered from the recovery portion. To effectively promote the reaction with light irradiated from the light source, the outer cylinder can be made of a material with high light reflection efficiency (e.g., aluminum). Alternatively, a light-reflecting material can be provided on the outside of the outer cylinder.

The dimensions of the outer cylinder and the inner cylinder are not particularly limited and can be set in consideration of the reaction temperature, reaction time, and introduction rate.

Another embodiment of the flow-type photochemical reaction device used in the present invention is shown in FIG2 .

The flow-type photochemical reaction device used in the present invention includes, for example, a reaction tube, a cartridge, and a light source.

The reaction tube is a tube wound around a drum and is preferably transparent to allow light to pass through. One end of the reaction tube is the introduction part, and the other end is the recovery part.

In order to allow light to pass through, the tube is preferably a transparent cylindrical tube with a light source inside.

A mixture containing compound B and a brominating agent is introduced into a reaction tube, and the reaction is carried out by irradiation with light, and a mixture containing compound A is recovered.

The dimensions of the reaction tube and the cylinder are not particularly limited and can be set in consideration of the reaction temperature, reaction time, introduction rate, etc.

Another embodiment of the flow-type photochemical reaction apparatus used in the present invention is, for example, a microreactor.

Next, the production method of the present invention will be described with reference to Test Examples, Reference Examples, Examples, Comparative Examples, and Production Examples, but the present invention is not limited thereto.

The abbreviations have the following meanings.

Ac：Acetyl

AcOEt: ethyl acetate

AcOMe: methyl acetate

DBH: 1,3-dibromo-5,5-dimethylhydantoin

eq: equivalent

Et: ethyl

FEP: Tetrafluoroethylene-hexafluoropropylene copolymer

HPLC: High Performance Liquid Chromatography

LED: Light Emitting Diode

Me：methyl

NBS: N-bromosuccinimide

THF: Tetrahydrofuran

Unless otherwise specified, the HPLC assay conditions are as follows.

Detector: UV absorbance photometer

Measurement wavelength: 230nm

Column: Symmetry C18 5μm, inner diameter 4.6×length 150mm

Column temperature: 40°C

Mobile phase: 50% acetonitrile buffer solution (0.05 mol/L phosphate buffer solution (pH 7.0))

Flow rate: 1 mL/min

The NMR spectrum was measured using JNM-AL400 (manufactured by JEOL) using tetramethylsilane as an internal standard, and all obtained δ values were expressed in ppm.

Test Example 1

Compound A was prepared from Compound B using a batch reaction. The reaction mixture was analyzed by HPLC to determine the peak area ratio of each compound. The results are shown below.

[Table 1]

Comparative Examples 1 to 3 were batch reactions using 2,2′-azobis(2-methylpropionitrile) as a radical generator and without using light.

Comparative Example 4 is a batch reaction using a high-pressure mercury lamp.

When benzene was used as the reaction solvent (Comparative Example 1), a large amount of Compound C was produced.

When acetonitrile was used as the reaction solvent (Comparative Example 2), a large amount of Compound D was produced.

When ethyl acetate was used as the reaction solvent (Comparative Example 3), the peak area ratio of Compound A was 78%, and the amount of by-products was small.

In the case of a batch reaction using ethyl acetate as the reaction solvent and a high-pressure mercury lamp (Comparative Example 4), a radical generator is not required and the reaction temperature can be lowered. In addition, the peak area ratio of Compound A is 71%, indicating a low amount of by-products.

Until now, carbon tetrachloride has been used as the reaction solvent in methods for preparing Compound A. However, it has been discovered that esters can also be used to facilitate the reaction. Furthermore, it has been discovered that when a high-pressure mercury lamp is used, a free radical generator is not required, the reaction temperature can be lowered, and by-products are reduced.

Test Example 2

Compound A was prepared from Compound B using a flow reaction. The reaction mixture was analyzed by HPLC to determine the peak area ratio of each compound. The results are shown below.

[Table 2]

Example 1 is a reaction using ethyl acetate as a reaction solvent and NBS as a brominating agent.

Examples 2-7 are reactions using ethyl acetate or methyl acetate as a reaction solvent and DBH as a brominating agent.

Comparative Example 5 is a reaction using THF as a reaction solvent and DBH as a brominating agent.

All of these reactions are flow-type photochemical reactions using a high-pressure mercury lamp.

When THF was used as the reaction solvent (Comparative Example 5), the reaction did not proceed.

On the other hand, in the reactions of Examples 1 to 7, the peak area ratio of Compound A was 80% or more, and the amount of by-products was small. In addition, the reaction temperature could be lowered and the reaction time could be significantly shortened compared to the batch reaction (Comparative Examples 1 to 4).

Flow photochemical reaction is an excellent method for industrial production of compound A.

Test Example 3

Compound A was prepared from Compound B using a flow reaction. The reaction mixture was analyzed by HPLC to determine the peak area ratio of each compound. The results are shown below.

[Table 3]

Examples 8 to 10 are flow-type photochemical reactions using LED as a light source.

In all of Examples 8 to 10, the peak area ratio of Compound A was 79% or more, and the amount of by-products was small.

Flow photochemical reaction is an excellent method for industrial production of compound A.

Example 1

A solution of 1.1 g of 5-methyl-1-benzothiophene (Compound B) in 3.3 mL of ethyl acetate (Solution I) was prepared. Separately, a solution of 0.66 g of NBS in 25 mL of ethyl acetate was prepared (Solution II). Solution I and Solution II were each delivered to an inline mixer connected to an FEP tube having an inner diameter of 0.5 mm by a syringe pump, wherein the flow rates of Solution I and Solution II were adjusted so that the amount of NBS was 1.1 equivalents relative to Compound B. After mixing Solution I and Solution II in the inline mixer, the FEP tube was irradiated with a high-pressure mercury lamp (UM-102, manufactured by Ushio Electric Co., Ltd.). It should be noted that the average residence time of the solution through the high-pressure mercury lamp irradiation interval was set to 2 minutes. Furthermore, these inline mixers and the high-pressure mercury lamp wound with the reaction tube were immersed in a water bath, and the water temperature was maintained at 30°C. The reaction solution obtained was measured by HPLC, and the peak area ratio of Compound A was 90%. The peak area ratios of Compound B, Compound C, and Compound D are shown in Table 2.

Example 2

Prepare a solution (Solution I) of 2.00g 5-methyl-1-benzothiophene (Compound B) in 6mL ethyl acetate. In addition, prepare a solution (Solution II) of 3.18g DBH in 90mL ethyl acetate. Solution I and Solution II are respectively transported to an online mixer connected to an FEP tube with an inner diameter of 0.5mm by a syringe pump, wherein the flow rate of Solution I and Solution II is adjusted so that the amount of DBH is 0.55 equivalents relative to Compound B. After mixing Solution I and Solution II in the online mixer, the FEP tube is irradiated with a high-pressure mercury lamp (UM-102, manufactured by Ushio Electric Co., Ltd.). It is to be noted that the average residence time of the solution through the high-pressure mercury lamp irradiation interval is set to 1 minute. In addition, these online mixers and the high-pressure mercury lamp wrapped with the reaction tube are immersed in a water bath, and the water temperature is maintained at 10°C. The reaction solution obtained by HPLC was measured, and the peak area ratio of Compound A was 80%. The peak area ratios of Compound B, Compound C and Compound D are shown in Table 2.

Example 3

The reaction was carried out in the same manner as in Example 2 except that the average residence time was set to 2 minutes and the water temperature of the water bath was maintained at 30°C.

The obtained reaction solution was measured by HPLC, and the peak area ratio of Compound A was 88%. The peak area ratios of Compound B, Compound C, and Compound D are shown in Table 2.

Example 4

The reaction was carried out in the same manner as in Example 2 except that the water temperature of the water bath was maintained at 40°C.

The obtained reaction solution was measured by HPLC, and the peak area ratio of Compound A was 86%. The peak area ratios of Compound B, Compound C, and Compound D are shown in Table 2.

Example 5

A solution (Solution I) of 3.00 g of 5-methyl-1-benzothiophene (Compound B) in 4.5 mL of ethyl acetate was prepared. Separately, a solution (Solution II) of 1.06 g of DBH in 14 mL of methyl acetate was prepared. Solution I and Solution II were respectively delivered to an online mixer connected to an FEP tube having an inner diameter of 0.5 mm by syringe pumps, wherein the flow rates of Solution I and Solution II were adjusted so that the amount of DBH was 0.55 equivalents relative to Compound B. After mixing Solution I and Solution II in the online mixer, the FEP tube was irradiated with a high-pressure mercury lamp (UM-102, manufactured by Ushio Electric Co., Ltd.). It should be noted that the average residence time of the solution through the high-pressure mercury lamp irradiation interval was set to 2 minutes. Furthermore, these online mixers and the high-pressure mercury lamp wound with the reaction tube were immersed in a water bath, and the water temperature was maintained at 30° C. The reaction solution obtained was measured by HPLC, and the peak area ratio of Compound A was 85%. The peak area ratios of Compound B, Compound C, and Compound D are shown in Table 2.

Example 6

The reaction was carried out in the same manner as in Example 5 except that the average residence time was set to 1 minute and the water temperature of the water bath was maintained at 40°C.

The obtained reaction solution was measured by HPLC, and the peak area ratio of Compound A was 85%. The peak area ratios of Compound B, Compound C, and Compound D are shown in Table 2.

Example 7

A solution (Solution I) of 0.50 g of 5-methyl-1-benzothiophene (Compound B) in 1.5 mL of dichloromethane was prepared. In addition, a solution (Solution II) of 0.53 g of DBH in 15 mL of dichloromethane was prepared. Solution I and Solution II were respectively transported to an online mixer connected to an FEP tube having an inner diameter of 0.5 mm by a syringe pump, wherein the flow rates of Solution I and Solution II were adjusted so that the amount of DBH was 0.55 equivalents relative to Compound B. After Solution I and Solution II were mixed in the online mixer, the FEP tube was irradiated with a high-pressure mercury lamp (UM-102, manufactured by Ushio Electric Co., Ltd.). It should be noted that the average residence time of the solution through the high-pressure mercury lamp irradiation interval was set to 1 minute. In addition, these online mixers and the high-pressure mercury lamp wound with the reaction tube were immersed in a water bath, and the water temperature was maintained at 30 ° C. The reaction solution obtained was measured by HPLC, and the peak area ratio of Compound A was 81%. Table 2 shows the peak area ratios of Compound B, Compound C, and Compound D.

Example 8

Prepare a solution of 0.40g 5-methyl-1-benzothiophene and 0.42g DBH in 13mL ethyl acetate. The resulting solution was transported to a quartz flow path plate having a rectangular flow path with a depth of 1.0mm and a width of 1.0mm by a syringe pump. At room temperature, an LED lamp (300nm LED3×3 arrangement manufactured by Nikki) was used to irradiate the quartz flow path plate with a wavelength of 300nm. It should be noted that the average residence time of the solution through the LED lamp irradiation interval was set to 1 minute. The obtained reaction solution was measured by HPLC, and the peak area ratio of compound A was 79%. The peak area ratios of compound B, compound C, and compound D are shown in Table 3.

Example 9

The reaction was carried out in the same manner as in Example 8, except that an LED lamp (MZeroLED manufactured by Integration Technology Co., Ltd.) was used as a light source and light having a wavelength of 365 nm was irradiated.

The obtained reaction solution was measured by HPLC, and the peak area ratio of Compound A was 84%. The peak area ratios of Compound B, Compound C, and Compound D are shown in Table 3.

Example 10

The reaction was carried out in the same manner as in Example 8 except that an LED lamp (233A manufactured by Matsuo Sangyo) was used as a light source and light having a wavelength of 405 nm was irradiated.

The obtained reaction solution was measured by HPLC, and the peak area ratio of Compound A was 86%. The peak area ratios of Compound B, Compound C, and Compound D are shown in Table 3.

Comparative Example 1

To a mixture of 2.04 g of NBS and 22 mg of 2,2'-azobis(2-methylpropionitrile) in 15 mL of benzene was added dropwise a solution of 1.00 g of 5-methyl-1-benzothiophene and 22 mg of 2,2'-azobis(2-methylpropionitrile) in 9 mL of benzene at 80°C over 30 minutes. The resulting mixture was stirred at the same temperature for 30 minutes. HPLC analysis of the resulting reaction solution revealed a peak area ratio of 60% for compound A. The peak area ratios for compounds B, C, and D are shown in Table 1.

Comparative Example 2

To a mixture of 410 mg of NBS and 4 mg of 2,2'-azobis(2-methylpropionitrile) in 3 mL of acetonitrile was added dropwise a solution of 200 mg of 5-methyl-1-benzothiophene and 4 mg of 2,2'-azobis(2-methylpropionitrile) in 3.6 mL of acetonitrile at 80°C over 30 minutes. The resulting mixture was stirred at the same temperature for 30 minutes. HPLC analysis of the resulting reaction solution revealed a peak area ratio of 0.2% for Compound A. The peak area ratios for Compounds B, C, and D are shown in Table 1.

Comparative Example 3

To a mixture of 200 mg of 5-methyl-1-benzothiophene and 410 mg of NBS in 10 mL of ethyl acetate was added 9 mg of 2,2'-azobis(2-methylpropionitrile). The resulting mixture was stirred under reflux for 30 minutes. HPLC analysis of the resulting reaction solution revealed a peak area ratio of 78% for Compound A. The peak area ratios for Compounds B, C, and D are shown in Table 1.

Comparative Example 4

A mixture of 100 mg of 5-methyl-1-benzothiophene and 200 mg of NBS in 10 mL of ethyl acetate was stirred at 40-45°C for 60 minutes while being irradiated with a high-pressure mercury lamp (UM-102, manufactured by Ushio Electric Co., Ltd.). HPLC analysis of the resulting reaction solution revealed a peak area ratio of 71% for Compound A. The peak area ratios for Compounds B, C, and D are shown in Table 1.

Comparative Example 5

A solution of 600 mg of 5-methyl-1-benzothiophene and 640 mg of DBH in 6 mL of THF was prepared. The resulting solution was transferred to a FEP tube with an inner diameter of 0.5 mm by a syringe pump and irradiated with a high-pressure mercury lamp (UM-102, manufactured by Ushio Electric Co., Ltd.). It should be noted that the average residence time of the solution in the high-pressure mercury lamp irradiation zone was set to 1 minute. In addition, the high-pressure mercury lamp wrapped with the reaction tube was immersed in a water bath, and the water temperature was maintained at 15-20°C. The obtained reaction solution was measured by HPLC, and the peak area ratio of compound A was 2%. The peak area ratios of compound B, compound C, and compound D are shown in Table 2.

Reference Example 1

3-Bromo-5-methyl-1-benzothiophene was obtained using the method described in International Publication No. WO2012/073888.

Reference Example 2

A mixture of Compound A and Compound C obtained in the same manner as in Comparative Example 1 was purified and separated by silica gel column chromatography to obtain 5-dibromomethyl-1-benzothiophene as a reddish brown solid.

¹ H-NMR (CDCl ₃ ) δ value: 7.45-7.52 (2H, m), 7.58 (1H, d, J = 8.3Hz), 7.87 (1H, d, J = 8.5Hz), 8.01 (1H, d, J = 5.6Hz), 8.32 (1H, s)

Preparation Example 1

Compound A was prepared from 10.0 g of 5-methyl-1-benzothiophene by the same method as in Example 6. The obtained reaction solution was distilled off under reduced pressure, and toluene and water were added thereto. The organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was separated and the solvent was distilled off under reduced pressure. 25 mL of water, 25 mL of toluene, 5.59 g of potassium carbonate, 5.27 g of potassium cyanide and 650 mg of tetrabutylammonium bromide were added to the obtained residue and stirred at 60° C. for 90 minutes. The reaction mixture was cooled to room temperature, the organic layer was separated and washed with water. The organic layer was separated and the solvent was distilled off under reduced pressure to obtain (1-benzothiophene-5-yl)acetonitrile.

Preparation Example 2

To the (1-benzothiophene-5-yl)acetonitrile obtained in Preparation Example 1, 15 mL of water, 10 mL of propylene glycol and 6.48 g of sodium hydroxide were added, and the mixture was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added thereto, and the aqueous layer was separated. The obtained aqueous layer was washed with toluene, 0.5 g of activated carbon was added thereto, and the mixture was stirred at 50° C. for 10 minutes. The insoluble matter was filtered out, and the residue was washed with water. The filtrate and washings were combined, and 40 mL of ethanol, 6 mL of ethyl acetate, 15 mL of water and 14 mL of hydrochloric acid were added thereto. The mixture was warmed to 50° C. and then cooled to 5° C. Water was added to the obtained mixture, and the solid component was collected by filtration to obtain 9.34 g of (1-benzothiophene-5-yl)acetic acid as a light yellowish white solid.

¹ H-NMR (CDCl ₃ ) δ value: 3.77 (2H, s), 7.24-7.32 (1H, m), 7.30 (1H, d, J = 5.5Hz), 7.44 (1H, d, J = 5.5Hz), 7.72-7.75 (1H, m), 7.84 (1H, d, J = 8.3Hz)

Preparation Example 3

According to the methods described in Japanese Patent Application Laid-Open No. 2012-046499 and International Publication No. WO2006/104088, 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol was obtained using 1-benzothiophene-5-acetic acid.

Industrial Applicability

The preparation method of the present invention is useful as an industrial production method for 5-bromomethyl-1-benzothiophene, and the 5-bromomethyl-1-benzothiophene can be used as an intermediate for the preparation of drugs.

Claims (7)

A method for preparing 1,5-bromomethyl-1-benzothiophene, comprising: (1) The step of introducing 5-methyl-1-benzothiophene, brominating agent and solvent into the reaction apparatus. (2) The process of irradiating the reaction apparatus with light in the wavelength range of 200–780 nm, and (3) The process of recovering 5-bromomethyl-1-benzothiophene from the reaction apparatus; in, The reaction apparatus is a flow-type photochemical reactor, and The solvent is selected from one or more esters. 2. The preparation method according to claim 1, wherein the brominating agent is selected from one or more of bromine, N-bromocaprolactam, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, bromo-pyridine complexes and copper(II) bromide. 3. The preparation method according to claim 1, wherein the brominating agent is one or two selected from N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin. 4. The preparation method according to claim 1, wherein the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin. 5. The preparation method according to any one of claims 1 to 4, wherein the solvent is selected from one or two of methyl acetate and ethyl acetate. 6. The preparation method according to any one of claims 1 to 4, wherein the reaction temperature is 5 to 70°C. 7. The preparation method according to claim 5, wherein the reaction temperature is 5–70°C.