TECHNICAL FIELD

The present invention relates to a method for producing 5-bromomethyl-1-benzothiophene which is useful as a production intermediate for pharmaceuticals.

BACKGROUND ART

1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol is a compound useful as a therapeutic agent for diseases of the central and peripheral nerves. This compound is produced, for example, from 1-benzothiophene-5-acetic acid (Patent Document 1). Then, 1-benzothiophene-5-acetic acid is produced, 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 an intermediate for pharmaceuticals.

On the other hand, as a method for producing Compound A, the method involving the bromination of 5-methyl-1-benzothiophene (hereinafter sometimes referred to as “Compound B”) has been known (Patent Documents 2 to 4).

PRIOR ART DOCUMENTS

Patent Documents

Patent Document 1

International Publication No. WO2006/104088 pamphlet
Patent Document 2International Publication No. WO2008/073142 pamphlet
Patent Document 3JP 2006-111553 A
Patent Document 4International Publication No. WO2005/092885 pamphlet

Non Patent Document

Non Patent Document 1

Journal of Medicinal Chemistry (J. Med. Chem.), 1997, Vol. 40, pp. 1049-1062

SUMMARY OF INVENTION

Technical Problem

The methods for producing Compound A described in Patent Documents 2 to 4 have the following drawbacks: (1) carbon tetrachloride is toxic; (2) thus, the use of carbon tetrachloride is prohibited; (3) 5-dibromomethyl-1-benzothiophene is produced as a by-product; (4) therefore, a complicated purification step is necessary.

An object of the present invention is to provide a method for industrially producing Compound A, which is simple and has no influence on human bodies.

Solution to Problem

Under such circumstances, the present inventors have conducted intensive researches, and consequently have found that Compound A is produced with simple operation by converting a conventional batch-type reaction to a flow-type reaction in the bromination step of Compound B, and completed the present invention.

The present invention provides the following.

[1] A method for producing 5-bromomethyl-1-benzothiophene comprising the steps of: (1) introducing 5-methyl-1-benzothiophene, a brominating agent and a solvent into a reactor; (2) irradiating the interior of the reactor with light having a wavelength range of 200 to 780 nm; and (3) recovering 5-bromomethyl-1-benzothiophene from the reactor, wherein the reactor is a flow-type photochemical reactor, and the solvent is one or two or more selected from esters and halogenated hydrocarbons.

[2] The method according to [1], wherein the brominating agent is one or two or more selected from 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 two 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 a reaction temperature is 5 to 70° C.

Advantageous Effects of Invention

The production method of the present invention is a method for producing Compound A from Compound B with simple operation. The production method of the present invention has the following advantages: (1) the method does not use carbon tetrachloride; (2) thus, the method is safe for human bodies; (3) the method produces less 5-dibromomethyl-1-benzothiophene which is a by-product; (3) therefore, the method does not require a complicated purification step; (5) the method produces Compound A in high yield; (6) the produced Compound A has high purity.

The production method of the present invention is useful as a method for industrially producing Compound A.

