JP2006348041A - Method for producing benzimidazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a benzimidazole derivative useful as a medicine and represented by general formula (XX) [G and J are each a benzimidazole derivative]. <P>SOLUTION: The method for producing the derivative of general formula (XX) uses a 3,4-disubstituted-benzo[b]thiophene derivative represented by general formula (X) or a high-purity 3-halomethyl-benzothiophene derivative in a short process. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing a benzimidazole derivative that is important as a compound useful in the field of pharmaceuticals.

［式中、Ｒ_１７ 〜Ｒ_２０は同時またはそれぞれ独立に、水素原子、ハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、もしくはシアノ基を表す。Ｘはヒドロキシル基またはハロゲン原子を表す。］
に示される、３−置換−ベンゾチオフェン誘導体は、薬理学的に活性な化合物の製造における中間体として極めて重要である。例えば式（ＸＩＩＩ）で示される３−置換−ベンゾ［ｂ］チオフェン誘導体のうち、Ｒ_１７からＲ_２０が水素原子、かつＸが臭素原子で示される化合物、Ｒ_１７がメチル基でＲ_１８からＲ_２０が水素原子、かつＸが臭素原子で示される化合物、Ｒ_１８がメチル基でＲ_１７、Ｒ_１９、Ｒ_２０が水素原子、かつＸが臭素原子で示される化合物、Ｒ_１７、Ｒ_１９がメチル基でＲ_１８、Ｒ_２０が水素原子、かつＸが臭素原子で示される化合物は、ＷＯ０１／５３２９１に示されているベンズイミダゾール誘導体の、合成中間体の原料等になりうるものであり、薬理学的に活性な化合物の製造における中間体として極めて重要といえる。ＷＯ０１／５３２９１に示されているベンズイミダゾール誘導体は、医薬上有用なベンズイミダゾール誘導体であり、気管支喘息等の呼吸器疾患、硬化性血管病変、血管内狭窄、末梢循環器障害を始めとする様々な疾患に対する予防剤及び/または治療剤に応用可能な化合物として有望と考えられる。 Many substituted-benzo [b] thiophene derivatives have been synthesized so far and have been used as raw materials for chemical products and pharmaceuticals. Among them, the following formula (XIII)

[In formula, R < ₁₇ > -R < ₂₀ > represents a hydrogen atom, a halogen atom, a trihalomethyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a cyano group simultaneously or each independently. X represents a hydroxyl group or a halogen atom. ]
The 3-substituted-benzothiophene derivatives shown in are very important as intermediates in the preparation of pharmacologically active compounds. For example, among the 3-substituted-benzo [b] thiophene derivatives represented by the formula (XIII), compounds in which R ₁₇ to R ₂₀ are hydrogen atoms and X is a bromine atom, R ₁₇ is a methyl group, and R ₁₈ to R A compound wherein ₂₀ is a hydrogen atom and X is a bromine atom, R ₁₈ is a methyl group, R ₁₇ , R ₁₉ and R ₂₀ are hydrogen atoms and a compound where X is a bromine atom, R ₁₇ and R ₁₉ are methyl A compound in which R ₁₈ and R ₂₀ are hydrogen atoms and X is a bromine atom can be a raw material for synthetic intermediates of benzimidazole derivatives shown in WO01 / 53291, It is extremely important as an intermediate in the production of chemically active compounds. The benzimidazole derivative shown in WO01 / 53291 is a pharmaceutically useful benzimidazole derivative, and includes various respiratory diseases such as bronchial asthma, sclerosing vascular lesions, intravascular stenosis, and peripheral circulatory disorders. It is considered promising as a compound applicable to preventive and / or therapeutic agents for diseases.

［式中、Ｒ₁はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、または炭素数１〜４のアルコキシ基を表す。Ｘはヒドロキシル基またはハロゲン原子を表す。］
で示される３，４−二置換−ベンゾ［ｂ］チオフェン誘導体はその構造的特徴により、ベンゾ［ｂ］チオフェン骨格合成の際に４位、６位の異性体が発生する。そして、その異性体の分離が非常に困難なため、３，４−二置換−ベンゾ［ｂ］チオフェン誘導体は合成された報告がない。しかしながら、３，４−二置換−ベンゾ［ｂ］チオフェン誘導体は、その特徴ある構造ゆえ、医薬品開発における高活性物質の原料として非常に期待される。 In particular, the following formula (I)

[Wherein, R ₁ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. X represents a hydroxyl group or a halogen atom. ]
Due to the structural characteristics of the 3,4-disubstituted-benzo [b] thiophene derivative represented by the formula, isomers at the 4th and 6th positions are generated during the synthesis of the benzo [b] thiophene skeleton. And since separation of the isomers is very difficult, 3,4-disubstituted-benzo [b] thiophene derivatives have not been synthesized. However, 3,4-disubstituted-benzo [b] thiophene derivatives are highly expected as raw materials for highly active substances in drug development because of their characteristic structures.

［式中、Ｒ_２１、Ｒ_２２は全て水素原子、またはＲ_２１，Ｒ_２２でベンゼン環を形成しても良い。］
で示される化合物を得、それを熱転移反応に供して下記式(ＸＶ)

［式中、Ｒ_２１、Ｒ_２２は全て水素原子、またはＲ_２１，Ｒ_２２でベンゼン環を形成しても良い。］
で示される化合物を得、さらにｐ‐トルエンスルホン酸存在下、水−ジオキサン中で熱転移反応に供して下記式(ＸＶＩ)

［式中、Ｒ_２１、Ｒ_２２は全て水素原子、またはＲ_２１，Ｒ_２２でベンゼン環を形成しても良い。］
が得られる反応が報告されている。 Examples of the technique relating to the synthesis of the compound of the present invention include the technique described in “J. Chem. Soc., Chem. Comm., 848 (1974)”. This is because a propargyl group is introduced into benzenethiol, followed by an oxidation reaction, and the following formula (XIV)

[Wherein R ₂₁ and R ₂₂ may be all hydrogen atoms, or R ₂₁ and R ₂₂ may form a benzene ring. ]
A compound represented by the following formula (XV) is obtained by subjecting it to a thermal transfer reaction:

[Wherein R ₂₁ and R ₂₂ may be all hydrogen atoms, or R ₂₁ and R ₂₂ may form a benzene ring. ]
And further subjected to a thermal transfer reaction in water-dioxane in the presence of p-toluenesulfonic acid to give the following formula (XVI)

[Wherein R ₂₁ and R ₂₂ may be all hydrogen atoms, or R ₂₁ and R ₂₂ may form a benzene ring. ]
Has been reported.

  However, this document does not describe any 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivatives, and describes only the conditions for the production in the presence of p-toluenesulfonic acid-dioxane. It is.

  Further, when synthesized under the conditions described in this document, the ratio of by-products in addition to the isomer 6-substituted-3-hydroxymethyl-benzo [b] thiophene derivative is higher than that of the production method of the present invention. Many of them are produced, and therefore purification by column chromatography is essential, so that they are not suitable for industrial production. Moreover, the fraction of the target substance is an approximately 3: 2 mixture of 4-substituted-3-hydroxymethyl-benzo [b] thiophene and 6-substituted-3-hydroxymethyl-benzo [b] thiophene. There is no description on the method for separating 4-substituted-3-hydroxymethyl-benzo [b] thiophene from the compound, and it cannot be completely separated even by column chromatography purification. In the synthetic methods reported to date, the synthesis of 4-substituted-3-hydroxymethyl-benzo [b] thiophene has been very difficult.

  In addition, the synthesis of 3-hydroxymethylbenzo [b] thiophene in this document also has a low yield of 64% due to the synthesis of by-products, and the subsequent halogenated (3-halomethyl-benzo [b] thiophene Considering synthesis etc., the number of processes increases, which is industrially disadvantageous.

  As another synthesis method of the 3-halomethyl-benzo [b] thiophene derivative, p-toluenethiol is reacted with bromoacetaldehyde diethyl acetal to form sulfide, and then cyclized with polyphosphoric acid to give 5-methyl-benzo [b ] After obtaining thiophene, hydrogen chloride gas-formaldehyde is allowed to act to introduce a chloromethyl group (J. Chem. Soc., C, 514 (1968)), or benzo [b] thiophene to Friedel A krafts reaction is performed to synthesize 3-chloroacetyl-benzo [b] thiophene derivatives as raw materials (J. Chem. Soc., Perkin Trans. 2, 1250, (1973)). And a halogenation method. However, in either method, halomethyl groups are introduced at both the 2- and 3-positions, and the selectivity thereof is not necessarily high, and above all, the 3-halomethyl-benzothiophene derivative is separated from the 2-halomethyl-benzothiophene derivative. But it is very difficult.

From the above situation, a 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivative represented by the formula (I) has been demanded, and an efficient and simple synthesis method has been desired.
There has also been a demand for an efficient and simple method for synthesizing 3-halomethyl-benzo [b] thiophene derivatives.

International Publication No. 01/53291 Pamphlet J. Chem. Soc., Chem. Comm., 848 (1974) J. Chem. Soc., C, 514 (1968) J. Chem. Soc., Perkin Trans. 2, 1250, (1973)

  An object of the present invention is to provide a 3,4-disubstituted-benzo [b] thiophene derivative, which has been difficult by conventional synthesis methods, and to provide a method for producing the derivative. Another object of the present invention is to provide a method for producing a 3-halomethyl-benzo [b] thiophene derivative having a short process and high purity.

  As a result of intensive studies to achieve the above object, the present inventors have found a 3,4-disubstituted-benzo [b] thiophene derivative useful as a raw material for pharmaceuticals and the like, and have found a selective synthesis method thereof. Further, an efficient synthesis method of 3-halomethyl-benzo [b] thiophene derivatives has been found.

［式中、Ｒ_１はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、または炭素数１〜４のアルコキシ基を表す。Ｘはヒドロキシル基またはハロゲン原子を表す。］
で示される３，４−二置換−ベンゾ［ｂ］チオフェン誘導体である。 The present invention relates to a compound of formula (I)

[Wherein, R ₁ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. X represents a hydroxyl group or a halogen atom. ]
Is a 3,4-disubstituted-benzo [b] thiophene derivative.

In the formula (I), X is preferably a hydroxyl group, and R ₁ is more preferably a methyl group.
In the formula (I), X is preferably a halogen, more preferably R ₁ is a methyl group and X is a bromine atom.

［式中、Ｒ_１はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、または炭素数１〜４のアルコキシ基を表す。］
と下記式（ＩＩＩ）

［式中、Ｒ_２はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、または炭素数１〜４のアルコキシ基を表す。］
で示されるベンゾ［ｂ］チオフェン誘導体を含む混合物を、溶媒中で結晶化させることによって、前記式（ＩＩ）で示されるベンゾ［ｂ］チオフェン誘導体を得る方法である。結晶化させる前記溶媒は、炭素数５〜８の直鎖、環状、もしくは分岐状の炭化水素と炭素数２から６のカルボン酸エステルの混合溶媒、または炭素数５〜８の直鎖、環状、もしくは分岐状の炭化水素と炭素数６から８の芳香族炭化水素の混合溶媒、またはアセトニトリルであることが好ましい。 The present invention also provides the following formula (II)

[Wherein, R ₁ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. ]
And the following formula (III)

[Wherein R ₂ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. ]
The benzo [b] thiophene derivative represented by the formula (II) is obtained by crystallizing a mixture containing the benzo [b] thiophene derivative represented by formula (II) in a solvent. The solvent to be crystallized is a mixed solvent of a straight chain, cyclic or branched hydrocarbon having 5 to 8 carbon atoms and a carboxylic acid ester having 2 to 6 carbon atoms, or a straight chain, cyclic having 5 to 8 carbon atoms, Alternatively, a mixed solvent of a branched hydrocarbon and an aromatic hydrocarbon having 6 to 8 carbon atoms, or acetonitrile is preferable.

［式中、Ｒ_３が水素でかつＲ_４はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、もしくは炭素数１〜４のアルコキシ基を表すか、またはＲ_３がハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、もしくは炭素数１〜４のアルコキシ基でかつＲ_４は水素を表す。］
で示される化合物に、炭素数1〜４のカルボン酸、もしくはそのカルボン酸無水物、またはトリフルオロ酢酸、もしくはそのトリフルオロ酢酸無水物のうちの１種類もしくは２種類以上と反応させることによって、下記式（Ｖ）

［式中、Ｒ_３およびＲ_４は上記式（ＩＶ）に同じ。Ｒ_５は水素原子、炭素数１〜３のアルキル基、またはトリフルオロメチル基を表す。］
で示されるベンゾ［ｂ］チオフェン誘導体の製造方法である。 Furthermore, the present invention provides the following formula (IV)

[Wherein R ₃ represents hydrogen and R ₄ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R ₃ represents a halogen atom, trihalo A methyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R ₄ represents hydrogen. ]
Is reacted with one or more of carboxylic acid having 1 to 4 carbon atoms, carboxylic acid anhydride, trifluoroacetic acid, or trifluoroacetic anhydride, Formula (V)

[Wherein, R ₃ and R ₄ are the same as those in the above formula (IV). R ₅ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a trifluoromethyl group. ]
A benzo [b] thiophene derivative represented by the formula:

  Furthermore, the present invention provides a benzo [b] compound represented by the above formula (II) by reducing the compound represented by the formula (V) with a metal hydride complex compound, or performing basic hydrolysis or acidic hydrolysis. A method for producing a thiophene derivative or a benzo [b] thiophene derivative represented by the formula (III). The reduction is preferably performed with sodium borohydride.

［式中、Ｒ_６はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、もしくは炭素数１〜４のアルコキシ基を表す。］
で示される化合物を得、
次にこれを酸化して下記式（ＶＩＩ）

［式中、Ｒ₆は上記式（ＶＩ）の定義に同じ。］
で示される化合物を得、
さらにこれを熱転移反応に供して、前記式（ＩＶ）で示される化合物を得、
これを、炭素数1〜４のカルボン酸もしくはそのカルボン酸無水物、またはトリフルオロ酢酸もしくはそのトリフルオロ酢酸無水物のうちの１種類もしくは２種類以上と反応させることによって、前記式（Ｖ）で示される化合物を得た後に、
エステル基をヒドロキシル基に変換して得られる前記式(ＩＩ) で示されるベンゾ［ｂ］チオフェン誘導体及び前記式(ＩＩＩ)で示されるベンゾ［ｂ］チオフェン誘導体の混合物を、溶媒中で晶析することによる、前記式(ＩＩ)で示される４−置換−３−ヒドロキシメチル−ベンゾ［ｂ］チオフェン誘導体の製造方法である。前記式（ＶＩ）において、Ｒ_６がメチル基であることが好ましい。 Furthermore, this invention introduce | transduces a propargyl group into m-substituted benzenethiol, and shows following formula (VI).

[Wherein, R ₆ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. ]
To obtain a compound represented by
Next, this is oxidized and the following formula (VII)

[Wherein, R ₆ is the same as defined in the above formula (VI). ]
To obtain a compound represented by
Further, this is subjected to a heat transfer reaction to obtain a compound represented by the formula (IV),
By reacting this with one or more of carboxylic acid having 1 to 4 carbon atoms or carboxylic acid anhydride thereof, or trifluoroacetic acid or trifluoroacetic acid anhydride thereof, in the above formula (V) After obtaining the compound shown,
A mixture of a benzo [b] thiophene derivative represented by the above formula (II) and a benzo [b] thiophene derivative represented by the above formula (III) obtained by converting an ester group into a hydroxyl group is crystallized in a solvent. This is a method for producing a 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivative represented by the above formula (II). In the formula (VI), R ₆ is preferably a methyl group.

［式中、Ｒ_１はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、もしくは炭素数１〜４のアルコキシ基を表す。Ｒ_７はハロゲン原子を表す。］
で示される４−置換−３−ハロメチル−ベンゾ［ｂ］チオフェン誘導体の製造方法である。前記式（ＶＩＩＩ）において、Ｒ_１がメチル基であることが好ましい。 Furthermore, the present invention is characterized in that the hydroxyl group of the 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivative represented by the formula (II) is further converted into a halogen atom, which is represented by the following formula (VIII)

[Wherein, R ₁ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. R ₇ represents a halogen atom. ]
Is a method for producing a 4-substituted-3-halomethyl-benzo [b] thiophene derivative represented by the formula: In the formula (VIII), R ₁ is preferably a methyl group.

［式中、Ｒ_８からＲ_１１は同時またはそれぞれ独立に水素原子、ハロゲン原子、トリハロメチル基、シアノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のアシルオキシ基、炭素数１〜４のアシルアミノ基、もしくはトリハロメトキシ基を表す。］
で示される化合物を等量以上の酸と反応させることによって、下記式（Ｘ）

［式中、Ｒ_８からＲ_１１は一般式（ＩＸ）と同じ。Ｒ_１２はハロゲン原子を表す。］
で示される３−ハロメチル−ベンゾ[ｂ]チオフェン誘導体化合物の製造方法である。 Furthermore, the present invention provides the following formula (IX)

[Wherein R ₈ to R ₁₁ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, 1 to 1 carbon atoms. 4 represents an alkylthio group, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group. ]
Is reacted with an equal amount or more of an acid to give a compound represented by the following formula (X):

[Wherein, R ₈ to R ₁₁ are the same as those in formula (IX). R ₁₂ represents a halogen atom. ]
Is a method for producing a 3-halomethyl-benzo [b] thiophene derivative compound represented by the formula:

［式中、Ｒ_１３及びＲ_１５が同時に、かつＲ_１４が独立にハロゲン原子、トリハロメチル基、シアノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のアシルオキシ基、炭素数１〜４のアシルアミノ基、もしくはトリハロメトキシ基で、かつＲ_１６が水素原子を表すか、あるいは、Ｒ_１６がハロゲン原子、トリハロメチル基、シアノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のアシルオキシ基、炭素数１〜４のアシルアミノ基、もしくはトリハロメトキシ基、かつＲ_１３〜Ｒ_１５が同時またはそれぞれ独立に水素原子、ハロゲン原子、トリハロメチル基、シアノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のアシルオキシ基、炭素数１〜４のアシルアミノ基、もしくはトリハロメトキシ基を表す。］
で示される化合物を得、化合物（ＸＩ）を酸化して、下記式（ＸＩＩ）

［式中、Ｒ_１３からＲ_１６は前記式（ＸＩ）に同じ。］
で示される化合物を得、
式（ＸＩＩ）で示される化合物を熱転移反応に供して、前記式（ＩＸ）で示される化合物を得、これを等量以上の酸と反応させて、式（Ｘ）で示される化合物を製造する方法である。 Furthermore, in the present invention, a propargyl group is introduced into a substituted benzenethiol, and the following formula (XI)

[Wherein, R ₁₃ and R ₁₅ are simultaneously and R ₁₄ is independently a halogen atom, a trihalomethyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or 1 to 1 carbon atoms. An alkylthio group having 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group, and R ₁₆ represents a hydrogen atom, or R ₁₆ is a halogen atom or a trihalomethyl group , A cyano group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or trihalomethoxy group and _R 13 _{to R 15} are simultaneously or each independently a hydrogen atom, a halogen atom, a trihalomethyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms 4 alkoxy group, an alkylthio group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, acylamino group or a trihalomethoxy group, having 1 to 4 carbon atoms. ]
And the compound (XI) is oxidized to give the following formula (XII)

[Wherein, R ₁₃ to R ₁₆ are the same as those in the formula (XI). ]
To obtain a compound represented by
The compound represented by the formula (XII) is subjected to a heat transfer reaction to obtain the compound represented by the above formula (IX), and this is reacted with an equal amount or more of an acid to produce the compound represented by the formula (X). It is a method to do.

In the present invention, R ₈ and R _{10 in the} formula (IX) and the formula (X) are simultaneously, R ₉ is independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and R ₁₁ is a hydrogen atom. Or R ₁₁ is an alkyl group having 1 to 4 carbon atoms, and R _{8 to} R ₁₀ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, or alkyl group having 1 to 4 carbon atoms. , An alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group, and the formula (XI) And R ₁₃ and R _{15 in} formula (XII) are simultaneously and R ₁₄ is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ₁₆ is a hydrogen atom, or R ₁₆ is carbon Numbers 1-4 An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and R _{1 to} R ₁₅ are simultaneously or independently selected from hydrogen atoms, halogen atoms, trihalomethyl groups, 4 alkylthio groups, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group is preferable.
In the formula (X) of the present invention, in the formula, R ₁₂ is preferably a chlorine atom or a bromine atom.

[式（ＸＸ）中、Ｒ_２３およびＲ_２４は、同時にもしくはそれぞれ独立に水素原子、ハロゲン原子、トリハロメチル基、シアノ基、水酸基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、またはＲ_２３およびＲ_２４は一緒になって−Ｏ−ＣＨ_２−Ｏ−、−Ｏ−ＣＨ_２ＣＨ_２−Ｏ−、もしくは−ＣＨ_２ＣＨ_２ＣＨ_２−（この場合、その炭素原子は１つもしくは複数の炭素数１〜４のアルキル基で置換されていてもよい。）を表す。
Ａは、置換もしくは無置換の炭素数１〜７の直鎖、環状、もしくは分岐状のアルキレン基またはアルケニレン基を表し、途中に−Ｏ−、−Ｓ−、−ＳＯ_２−、−ＮＲ_２５−（ここで、Ｒ_２５は水素原子または直鎖もしくは分岐状の炭素数１〜６のアルキル基を表す。）を一つもしくは複数個含んでいてもよい。これらの基がもちうる置換基は、ハロゲン原子、水酸基、ニトロ基、シアノ基、直鎖もしくは分岐状の炭素数１〜６のアルキル基、直鎖状もしくは分岐状の炭素数１〜６のアルコキシ基（隣接する２個がアセタール結合を形成している場合を含む。）、直鎖もしくは分岐状の炭素数１〜６のアルキルチオ基、直鎖もしくは分岐状の炭素数１〜６のアルキルスルホニル基、直鎖もしくは分岐状の炭素数１〜６のアシル基、直鎖もしくは分岐状の炭素数１〜６のアシルアミノ基、トリハロメチル基、トリハロメトキシ基、フェニル基、オキソ基、または一つ以上のハロゲン原子で置換されてもよいフェノキシ基である。これらの置換基は、アルキレン基またはアルケニレン基の任意の場所で一つもしくは複数個それぞれ独立に置換していてもよい。ただし、式（ＸＸ）中、Ｍが単結合でＭに結合するＡの炭素に水酸基とフェニル基が同時に置換する場合は除く。
Ｅは、−ＣＯＯＲ_２５、−ＳＯ_３Ｒ_２５、−ＣＯＮＨＲ_２５、−ＳＯ_２ＮＨＲ_２５、テトラゾール−５−イル基、５−オキソ−１，２，４−オキサジアゾール−３−イル基、または５−オキソ−１，２，４−チアジアゾール−３−イル基（ここで、Ｒ_２５は上記と同様のものを表す。）を表す。
Ｍは、単結合または−Ｓ（Ｏ）ｍ−を表し、ｍは０〜２の整数である。
ＧかつＪは、前記式（Ｉ）、または前記式（Ｘ）を表す。但し、Ｇは前記式（Ｉ）、並びに前記式（Ｘ）のベンゾチオフェンの３位のメチレンを表し、前記式（Ｉ）のＸ、並びに前記式（Ｘ）のＲ_１２は、ベンズイミダゾール環上の窒素原子に置き換わる。
Ｘは、−ＣＨ＝または窒素原子を表す。] Furthermore, the present invention is a method for producing a benzimidazole derivative (general formula (XX)) represented by the general formula (XX) from the formula (I) or the formula (X).

[In Formula (XX), R ₂₃ and R ₂₄ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, hydroxyl group, alkyl group having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms. A group, or R ₂₃ and R _{24 taken} together —O—CH ₂ —O—, —O—CH ₂ CH ₂ —O—, or —CH ₂ CH ₂ CH ₂ — (in which case the carbon atom is Which may be substituted with one or more alkyl groups having 1 to 4 carbon atoms.
A represents a substituted or unsubstituted linear, cyclic, or branched alkylene group or alkenylene group having 1 to 7 carbon atoms, and —O—, —S—, —SO ₂ —, —NR ₂₅ — is encapsulated in the middle. (Here, R ₂₅ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.) One or more of them may be contained. Substituents that these groups may have are halogen atom, hydroxyl group, nitro group, cyano group, linear or branched alkyl group having 1 to 6 carbon atoms, linear or branched alkoxy group having 1 to 6 carbon atoms. A group (including the case where two adjacent groups form an acetal bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. A linear or branched acyl group having 1 to 6 carbon atoms, a linear or branched acyl group having 1 to 6 carbon atoms, a trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo group, or one or more A phenoxy group which may be substituted with a halogen atom. One or more of these substituents may be independently substituted at any position of the alkylene group or alkenylene group. However, in the formula (XX), the case where a hydroxyl group and a phenyl group are simultaneously substituted on the carbon of A in which M is a single bond and is bonded to M is excluded.
E represents —COOR ₂₅ , —SO ₃ R ₂₅ , —CONHR ₂₅ , —SO ₂ NHR ₂₅ , a tetrazol-5-yl group, a 5-oxo-1,2,4-oxadiazol-3-yl group, or It represents a 5-oxo-1,2,4-thiadiazol-3-yl group (wherein R ₂₅ represents the same as above).
M represents a single bond or —S (O) m—, and m is an integer of 0 to 2.
G and J represent the formula (I) or the formula (X). Wherein G represents methylene at the 3-position of the benzothiophene of the formula (I) and the formula (X), and X of the formula (I) and R ₁₂ of the formula (X) are on the benzimidazole ring. Replaces the nitrogen atom.
X represents —CH═ or a nitrogen atom. ]

Examples of the benzothiophene derivative according to the present invention and a method for producing the benzothiophene derivative will be described below, but the present invention is not limited thereto.
First, examples of 3,4-disubstituted-benzo [b] thiophene derivatives and methods for producing the derivatives are given below.

［式中、Ｒ_１はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、もしくは炭素数１〜４のアルコキシ基を表す。Ｘはヒドロキシル基もしくはハロゲン原子を表す。］
で示される３，４−二置換−ベンゾ［ｂ］チオフェン誘導体である。Ｒ_１は、好ましくは、トリハロメチル基、メチル基を挙げることができ、さらに好ましくはメチル基を挙げることができる。また、Ｘは、好ましくはヒドロキシル基、臭素原子、塩素原子を挙げることができる。 The present invention relates to a compound of formula (I)

[Wherein, R ₁ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. X represents a hydroxyl group or a halogen atom. ]
Is a 3,4-disubstituted-benzo [b] thiophene derivative. R ₁ is preferably a trihalomethyl group or a methyl group, more preferably a methyl group. X is preferably a hydroxyl group, a bromine atom, or a chlorine atom.

As the compound of the formula (I), specifically those listed in Table 1 are preferable. In the table, particularly preferred compounds are the compounds of Compound Nos. 1, 2, and 3.

［式中、Ｒ_３が水素でかつＲ_４はハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基を表すか、またはＲ_３がハロゲン原子、トリハロメチル基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基でかつＲ_４は水素を表す。］
で示される化合物に、炭素数１〜４のカルボン酸、もしくはトリフルオロ酢酸、またはそのカルボン酸無水物もしくはトリフルオロ酢酸無水物のうちの１種類もしくは２種類以上と反応させることによって、式（Ｖ）

［式中、Ｒ_３及びＲ_４は、式（ＩＶ）の定義に同じ。Ｒ_５は水素原子か、または炭素数１〜３のアルキル基またはトリフルオロメチル基を表す。］
で示される化合物を製造する。 As a manufacturing method of Formula (I), Formula (IV)

[Wherein R ₃ represents hydrogen and R ₄ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R ₃ represents a halogen atom, trihalomethyl or A group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and R ₄ represents hydrogen. ]
Is reacted with one or more of carboxylic acid having 1 to 4 carbon atoms, or trifluoroacetic acid, or its carboxylic anhydride or trifluoroacetic anhydride. )

[Wherein R ₃ and R ₄ are the same as defined in formula (IV). R ₅ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a trifluoromethyl group. ]
Is produced.

  In the present invention, examples of the solvent used in the reaction from formula (IV) to formula (V) include toluene, tetrahydrofuran, dioxane, i-propyl acetate, n-propyl acetate and the like. Preferably, toluene, tetrahydrofuran, and dioxane are used.

  Examples of the carboxylic acid or acid anhydride include acetic acid, trifluoroacetic acid, acetic anhydride, trifluoroacetic anhydride, and the like. Preferred are trifluoroacetic acid and trifluoroacetic anhydride, and particularly preferred is trifluoroacetic anhydride.

  Thereafter, the ester group of the compound represented by the formula (V) is converted into a hydroxyl group to obtain a mixture containing the compounds represented by the formula (II) and the formula (III). In order to convert the ester group of the compound represented by the formula (V) into the hydroxyl group of the compound represented by the formula (II), acid hydrolysis, basic hydrolysis, reduction with a metal hydride complex compound, etc. Do. Preferred are basic hydrolysis and reduction with a metal hydride complex. As the base for basic hydrolysis, lithium hydroxide, sodium hydroxide and the like are preferable. Examples of the metal hydride complex compound include lithium aluminum hydride and sodium borohydride, and sodium borohydride is preferable.

  Next, the 4-substituted-3-hydroxymethyl-benzothiophene derivative represented by the formula (II) is obtained by crystallizing the mixture containing the compounds represented by the formula (II) and the formula (III) in a solvent. Can be obtained. The solvent to be crystallized is not particularly limited, but in a mixed solvent of a linear, cyclic, or branched hydrocarbon having 5 to 8 carbon atoms and a carboxylic acid ester having 2 to 6 carbon atoms, or 5 to 8 carbon atoms. And a method of crystallization in a mixed solvent of a straight chain, cyclic or branched hydrocarbon and an aromatic hydrocarbon having 6 to 8 carbon atoms, or acetonitrile.

  Preferable examples of the hydrocarbon include pentane, hexane, cyclohexane, heptane, and octane. Of these, particularly preferred are hexane and cyclohexane. These hydrocarbons may be used alone or in a mixed solvent. Preferred examples of the aromatic hydrocarbon include benzene, toluene and xylene. Of these, toluene is particularly preferable. As the carboxylic acid of the carboxylic acid ester, formic acid, acetic acid, propionic acid and the like are preferable. Further, as the ester, methyl ester, ethyl ester, propyl ester, isopropyl ester and the like are preferable. The carboxylic acid ester is preferably methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate, or ethyl propionate, and particularly preferably ethyl acetate.

  Solvent combinations of preferred crystallization conditions include hexane-ethyl acetate, cyclohexane-ethyl acetate, hexane-cyclohexane-ethyl acetate, hexane-toluene, cyclohexane-toluene, hexane-cyclohexane-toluene, hexane-xylene, cyclohexane-xylene, Examples include crystallization in hexane-cyclohexane-xylene, or acetonitrile.

  Crystallization conditions include straight-chain, cyclic, or branched hydrocarbons having 5 to 8 carbon atoms and a mixed solvent of carboxylic acid ester having 2 to 6 carbon atoms, or straight-chain and cyclic groups having 5 to 8 carbon atoms. Or a method of refluxing in a mixed solvent of a branched hydrocarbon and an aromatic hydrocarbon having 6 to 8 carbon atoms or in acetonitrile, followed by cooling and crystallization, or an aromatic hydrocarbon having 6 to 8 carbon atoms Alternatively, after dissolving in a carboxylic acid ester having 2 to 6 carbon atoms, a method of crystallization in a mixed solvent by adding a linear, cyclic or branched hydrocarbon having 5 to 8 carbon atoms can be mentioned.

  The ratio of the mixed solvent is hydrocarbon having 5 to 8 carbon atoms: carboxylic acid ester = 1: 2 to 9: 1, preferably hydrocarbon having 5 to 8 carbon atoms: carboxylic acid ester = 1: 2. -5: 1. Moreover, as a ratio in the case of using C6-C8 aromatic hydrocarbon, C5-C8 hydrocarbon: aromatic hydrocarbon = 1: 2-5: 1 are mentioned, Preferably, carbon number 5-8 hydrocarbons: aromatic hydrocarbons = 1: 2-3: 1. Examples of preferable crystallization conditions include hexane: ethyl acetate = 1: 2 to 5: 1, or a mixed solvent of cyclohexane and hexane: ethyl acetate = 1: 2 to 5: 1, or hexane: toluene = 1: Or a mixed solvent of cyclohexane and hexane: toluene = 1: 2 to 3: 1. In addition, as a preferable ratio of cyclohexane and hexane, cyclohexane: hexane = 1: 3-3: 1 can be mentioned.

The amount of the solvent with respect to the substrate is not particularly limited, but preferably 1 to 10 times the amount of the substrate weight, and particularly preferably 2 to 5 times the substrate weight.
If necessary, a 4-substituted-3-halomethyl-benzothiophene derivative represented by the formula (VIII) is obtained by converting the hydroxyl group of the compound represented by the formula (II) into a halogen atom. Can do.

  Examples of the reagent for halomethylation from the formula (II) to the formula (VIII) of the present invention include hydrogen halide, phosphorus halide, sulfonic acid chloride, thionyl halide, etc., preferably phosphorus halide, halogen Mention may be made of thionyl bromide, particularly preferably phosphorus tribromide.

A method for synthesizing the compound represented by the formula (II) of the present invention from commercially available raw material compounds will be described below. Although this method can be selected as appropriate, the following method is preferable because it can be synthesized efficiently and with high purity. A specific example will be described below.

(First step)
This step is a step of producing a compound represented by (VI) by introducing a propargyl group into the mercapto group of m-toluenethiol represented by (XVII).
The introduction of the propargyl group is carried out using a halogenated propargyl, for example, propargyl bromide, propargyl chloride, etc. in the presence of a basic substance. As the basic substance, for example, potassium carbonate and sodium carbonate are used for inorganic bases, and for example, triethylamine, pyridine, 4-dimethylaminopyridine and the like are used for organic bases. Examples of the solvent include toluene, acetone, acetic acid ethyl ester, tetrahydrofuran, acetonitrile, 2-butanone, and among them, toluene and 2-butanone can be mentioned as preferable solvents. The reaction can be obtained at room temperature to reflux temperature for several tens of minutes to several hours.

(Second step)
This step is a step of producing a compound represented by the formula (VI) from the formula (VI) by oxidation of the compound. The oxidation reaction of the sulfur atom is carried out by, for example, oxidizing agents such as potassium persulfate, hydrogen peroxide, metaperiodates, perchlorates, m-chlorobenzoic acid, and an appropriate solvent such as aromatics such as toluene and xylene. A group hydrocarbon, alcohol, acetone, and water are used alone or in combination to carry out the reaction. In this step, a method of stirring 1 to 1.2 equivalents of sodium metaperiodate in an alcohol-water solvent such as methanol, ethanol, isopropanol at room temperature for several tens of minutes to several hours is a preferred example. Can do.

(Third step)
This step is a step for producing a compound represented by the formula (IV) from the formula (VII) by a transfer cyclization reaction of sulfoxide.
In the case of the sulfoxide used in the present invention, preferred solvents include dioxane, propyl acetate, toluene, xylene and the like, more preferably dioxane, toluene, and particularly preferably toluene. The amount of the solvent is preferably 10 times the substrate weight or more, more preferably 15 to 30 times the substrate weight.
The reaction temperature is preferably 60 ° C. or more, particularly preferably 80 ° to 100 °.
In this step, the compound represented by formula (VII) proceeds even if heated after being dissolved in the solvent, but the solvent is heated to the reaction temperature in advance, and the formula (VII) is added to the heated solvent. The method of dripping the solution of the compound represented by VII) is preferable.
The heating time is not particularly limited, but it is preferable that the heating time is preferably several tens of minutes to two hours after dropping at the reaction temperature, particularly preferably within 1 hour from the end of dropping the substrate.
By making it react on these conditions, the production | generation of a by-product can be suppressed extremely and a yield can be improved.

(4th process)
In this step, the cyclized product (formula (IV)) obtained in the third step is further reacted with carboxylic acid or carboxylic anhydride to produce a compound represented by formula (V).
In this step, the esterification transfer reaction proceeds by adding carboxylic acid or carboxylic anhydride to the reaction system without concentrating the reaction solvent used in the third step. Further, the same reaction proceeds even if the solvent in the third step is concentrated and reacted in another solvent. The carboxylic acid in this step is preferably trifluoroacetic acid, and the carboxylic acid anhydride is preferably trifluoroacetic anhydride. The carboxylic acid or carboxylic acid anhydride is preferably 0.5 to 1.2 equivalents of the substrate, particularly preferably 0.5 to 0.8 equivalents are preferably added dropwise to the substrate solution.
As reaction temperature at the time of dripping carboxylic acid or carboxylic anhydride in reaction of this process, 0 to 50 degreeC is preferable, and it is more preferable to carry out at 20 to 30 degreeC.
The reaction in this step is completed in several minutes to several hours when performed at room temperature.

(5th process)
This step is a step of producing a compound represented by formula (II) or formula (III) by hydroxylation of the ester represented by formula (V) obtained in the fourth step.
The conditions are preferably basic hydrolysis or reduction with a metal hydride complex. Although it does not specifically limit as a base of basic hydrolysis, Preferably, lithium hydroxide and sodium hydroxide can be mentioned. The solvent for hydrolysis is not particularly limited, but a tetrahydrofuran-water system is preferable. In the case of reduction with a metal hydride complex compound, examples of the metal hydride complex compound include lithium aluminum hydride, sodium borohydride, sodium cyanotrihydroborate, etc., preferably sodium borohydride. Can do. The amount of the basic hydrolysis base or metal hydride complex compound is preferably 0.5 to 1 equivalent of the substrate.
Although the solvent of the reaction system is not particularly limited, preferably, tetrahydrofuran and toluene can be mentioned.

(Sixth step)
This step comprises the steps of a 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivative represented by the formula (II) and a 6-substituted-3-hydroxymethyl-benzo [b] thiophene derivative represented by the formula (III). In this step, the compounds represented by formula (II) and formula (III) are separated from the mixture.
As a solvent for crystallization in this step, hexane, cyclohexane-ethyl acetate, or hexane-toluene can be mentioned as a preferred solvent. Examples of preferable crystallization conditions include hexane: ethyl acetate = 1: 2 to 5: 1, or a mixed solvent of cyclohexane and hexane: ethyl acetate = 1: 2 to 5: 1, hexane: toluene = 1: 2 to 3 : 1, mixed solvent of cyclohexane and hexane :: toluene = 1: 2 to 3: 1. In addition, as a preferable ratio of cyclohexane and hexane, cyclohexane: hexane = 1: 3-3: 1 can be mentioned.
The amount of the solvent with respect to the substrate is not particularly limited, but preferably 1 to 10 times the amount of the substrate weight, particularly preferably 2 to 5 times the substrate weight.
By this step, the compound represented by formula (II) can be separated from the mixture of compounds represented by formula (II) and formula (III) by crystallization.

本工程は４−置換−３−ヒドロキシメチル−ベンゾ［ｂ］チオフェン誘導体のヒドロキシル基をハロゲン原子に交換する工程である。
ハロゲン交換のハロメチル化の試薬としては、ハロゲン化水素、ハロゲン化リン、スルホン酸クロリド、ハロゲン化チオニル等が挙げられるが、好ましくは、ハロゲン化リン、ハロゲン化チオニル、特に好ましくは三臭化リンを挙げることができる。
溶媒としては、シクロヘキサン、ヘキサン等の炭化水素、ベンゼン、トルエン、キシレン等の芳香族炭化水素が挙げられるが、好ましくは、シクロヘキサン、トルエンを挙げることができる。反応は室温から還流温度で、数十分から数時間で得ることができる。反応後に必要に応じて、式（ＶＩＩＩ）で表される化合物を結晶化してもよい。結晶化溶媒としては、ヘプタン、ヘキサン、シクロヘキサン等の炭化水素を挙げることができるが、好ましくはシクロヘキサン、ヘプタンを挙げることができる。 (Seventh step)
Further, the method for synthesizing the compound represented by the formula (VIII) from the compound represented by the formula (II) is not particularly limited, but the following method is more preferable.

This step is a step of exchanging the hydroxyl group of the 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivative with a halogen atom.
Examples of the halogen exchange halomethylation reagent include hydrogen halide, phosphorus halide, sulfonic acid chloride, thionyl halide, etc., preferably phosphorus halide, thionyl halide, particularly preferably phosphorus tribromide. Can be mentioned.
Examples of the solvent include hydrocarbons such as cyclohexane and hexane, and aromatic hydrocarbons such as benzene, toluene and xylene, preferably cyclohexane and toluene. The reaction can be obtained from room temperature to reflux temperature in several tens of minutes to several hours. If necessary, the compound represented by the formula (VIII) may be crystallized after the reaction. Examples of the crystallization solvent include hydrocarbons such as heptane, hexane, and cyclohexane, preferably cyclohexane and heptane.

［式中、Ｒ_８からＲ_１１は同時またはそれぞれ独立に水素原子、ハロゲン原子、トリハロメチル基、シアノ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のアルキルチオ基、炭素数１〜４のアシルオキシ基、炭素数１〜４のアシルアミノ基、もしくはトリハロメトキシ基を表す。］
で示される化合物を等量以上の酸と反応させることで、式（Ｘ）

［式中、Ｒ_８からＲ_１１は式（ＩＸ）に同じ。Ｒ_１２はハロゲン原子を表す。］
で示される３−ハロメチル−ベンゾチオフェン誘導体の製造する方法である。 Next, a method for synthesizing the 3-halomethyl-benzo [b] thiophene derivative will be described in detail below.
The present invention is directed to formula (IX)

[Wherein R ₈ to R ₁₁ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, 1 to 1 carbon atoms. 4 represents an alkylthio group, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group. ]
Is reacted with an equal amount or more of an acid to give a compound of formula (X)

[Wherein R ₈ to R ₁₁ are the same as those in formula (IX). R ₁₂ represents a halogen atom. ]
Is a method for producing a 3-halomethyl-benzothiophene derivative represented by the formula:

R ₈ to R ₁₁ in the present invention are preferably a hydrogen atom and an alkyl group having 1 to 4 carbon atoms.
The positions of the hydrogen atom and the alkyl group are arbitrary simultaneously or independently. In particular, all of them are hydrogen atoms, or R ₈ , R ₁₀ , and R ₁₁ are hydrogen atoms and R ₉ is 1 to 4 carbon atoms. Or R ₉ and R ₁₁ are each a hydrogen atom, and R ₈ and R ₁₀ are each preferably an alkyl group having 1 to 4 carbon atoms.

As the compound of the formula (X), those specifically described in Table 2 are preferable. In the table, particularly preferred compounds are the compounds of Compound Nos. 7, 8, and 9.

  In the present invention, the acid used for the reaction from formula (IX) to formula (X) includes hydrogen chloride gas, hydrogen bromide gas, hydrogen chloride-dioxane solution, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like. Among them, a hydrogen chloride-dioxane solution and hydrobromic acid are particularly preferable. The amount of acid needs to be equal to or greater than the substrate, but is preferably 1.2 to 3 equivalents, more preferably 1.2 to 1.5 equivalents.

The solvent of the present invention is not particularly limited, but preferably dioxane, propyl acetate, and toluene are used. As the amount thereof, it is better to add 5 times or more, preferably 10 to 20 times the substrate weight.
The reaction temperature in the present invention is preferably 0 ° C. to 50 ° C., particularly preferably 0 ° C. to 30 ° C.

The method for synthesizing the compound represented by the formula (IX) is not particularly limited, but the method shown below is preferable.

(First step)
This step is a step of producing a compound represented by the formula (XI) by introducing a propargyl group into the mercapto group of the substituted benzenethiol represented by the formula (XVIII).
The introduction of the propargyl group is carried out using a halogenated propargyl, for example, propargyl bromide, propargyl chloride, etc. in the presence of a basic substance. Examples of basic substances include potassium carbonate and sodium carbonate for inorganic bases, and triethylamine, pyridine, 4-dimethylaminopyridine for organic bases, acetone, acetic acid ethyl ester, tetrahydrofuran, acetonitrile, 2-butanone, A propargyl group can be introduced in a solvent such as toluene at room temperature to reflux temperature in a few hours.

(Second step)
This step is a step of producing the compound represented by the formula (XII) by oxidizing the compound represented by the formula (XI). In this step, a method of stirring 1.2 equivalents of sodium metaperiodate in an alcohol-water solvent system such as methanol, ethanol or isopropanol at room temperature is preferred. This reaction is completed in several hours under the above conditions.

(Third step)
This step is a step of producing a compound represented by the formula (IX) by a transfer cyclization reaction of a sulfoxide of the compound represented by the formula (XII). In the thermal transfer reaction in this step, the method described in JCSChem. Comm., 848-849, 1974 is helpful.
In the case of the reaction of sulfoxide used in the present invention, preferred solvents include dioxane, propyl acetate, toluene, xylene and the like. The amount of the solvent is not particularly limited, but is preferably 10 times the substrate weight or more, more preferably 15 to 30 times the substrate weight. By making it react with this solvent amount, the production | generation of a by-product can be suppressed extremely and a yield can be improved. The reaction temperature is not particularly limited, but is preferably 80 ° C. or higher, and more preferably 100 ° C. to the reflux temperature of the solvent.
The reaction is accomplished in tens of minutes to hours when performed at reflux temperature.

(4th process)
This step is a step for producing a compound represented by the formula (X) by further reacting the cyclized product of the compound represented by the formula (IX) obtained in the third step with an acid.
As for the solvent in this step, the halomethylation transfer reaction proceeds by adding an acid to the reaction system without concentrating the reaction solvent used in the third step. Further, the same reaction proceeds even if the solvent in the third step is concentrated and reacted in another solvent. As the acid in this reaction, hydrogen chloride gas, hydrogen bromide gas, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrogen chloride-dioxane solution and the like are preferable. The reaction temperature in this reaction is 0 to 50 ° C., preferably 0 to 30 ° C. The reaction is achieved in a few tens of minutes to several hours.

  By using the benzothiophene derivative of the formula (IX) produced by the method described above, a pharmaceutically useful benzimidazole derivative can be synthesized, for example, according to the method described in WO01 / 53291.

  Pharmacologically active and useful benzimidazole derivatives (general formula (XX)) are produced using 3-substituted-benzo [b] thiophene derivatives represented by formula (XIII) or formula (I) as intermediates. It is possible.

[式（ＸＸ）中、Ｒ_２３およびＲ_２４は、同時にもしくはそれぞれ独立に水素原子、ハロゲン原子、トリハロメチル基、シアノ基、水酸基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、またはＲ_２３およびＲ_２４は一緒になって−Ｏ−ＣＨ_２−Ｏ−、−Ｏ−ＣＨ_２ＣＨ_２−Ｏ−、もしくは−ＣＨ_２ＣＨ_２ＣＨ_２−（この場合、その炭素原子は１つもしくは複数の炭素数１〜４のアルキル基で置換されていてもよい。）を表す。
Ａは、置換もしくは無置換の炭素数１〜７の直鎖、環状、もしくは分岐状のアルキレン基またはアルケニレン基を表し、途中に−Ｏ−、−Ｓ−、−ＳＯ_２−、−ＮＲ_２５−（ここで、Ｒ_２５は水素原子または直鎖もしくは分岐状の炭素数１〜６のアルキル基を表す。）を一つもしくは複数個含んでいてもよい。これらの基がもちうる置換基は、ハロゲン原子、水酸基、ニトロ基、シアノ基、直鎖もしくは分岐状の炭素数１〜６のアルキル基、直鎖状もしくは分岐状の炭素数１〜６のアルコキシ基（隣接する２個がアセタール結合を形成している場合を含む。）、直鎖もしくは分岐状の炭素数１〜６のアルキルチオ基、直鎖もしくは分岐状の炭素数１〜６のアルキルスルホニル基、直鎖もしくは分岐状の炭素数１〜６のアシル基、直鎖もしくは分岐状の炭素数１〜６のアシルアミノ基、トリハロメチル基、トリハロメトキシ基、フェニル基、オキソ基、または一つ以上のハロゲン原子で置換されてもよいフェノキシ基である。これらの置換基は、アルキレン基またはアルケニレン基の任意の場所で一つもしくは複数個それぞれ独立に置換していてもよい。ただし、式（ＸＸ）中、Ｍが単結合でＭに結合するＡの炭素に水酸基とフェニル基が同時に置換する場合は除く。
Ｅは、−ＣＯＯＲ_２５、−ＳＯ_３Ｒ_２５、−ＣＯＮＨＲ_２５、−ＳＯ_２ＮＨＲ_２５、テトラゾール−５−イル基、５−オキソ−１，２，４−オキサジアゾール−３−イル基、または５−オキソ−１，２，４−チアジアゾール−３−イル基（ここで、Ｒ_２５は上記と同様のものを表す。）を表す。
Ｍは、単結合または−Ｓ（Ｏ）ｍ−を表し、ｍは０〜２の整数である。
Ｇ、かつＪは前記式（Ｉ）、または（Ｘ）を表す。但し、Ｇは前記式（Ｉ）、並びに（Ｘ）のベンゾチオフェンの３位のメチレンを表し、前記式（Ｉ）のＸ、並びに前記式（Ｘ）のＲ_１２はベンズイミダゾール環上の窒素原子を表す。
Ｘは、−ＣＨ＝または窒素原子を表す。］

[In Formula (XX), R ₂₃ and R ₂₄ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, hydroxyl group, alkyl group having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms. A group, or R ₂₃ and R _{24 taken} together —O—CH ₂ —O—, —O—CH ₂ CH ₂ —O—, or —CH ₂ CH ₂ CH ₂ — (in which case the carbon atom is Which may be substituted with one or more alkyl groups having 1 to 4 carbon atoms.
A represents a substituted or unsubstituted linear, cyclic, or branched alkylene group or alkenylene group having 1 to 7 carbon atoms, and —O—, —S—, —SO ₂ —, —NR ₂₅ — is encapsulated in the middle. (Here, R ₂₅ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.) One or more of them may be contained. Substituents that these groups may have are halogen atom, hydroxyl group, nitro group, cyano group, linear or branched alkyl group having 1 to 6 carbon atoms, linear or branched alkoxy group having 1 to 6 carbon atoms. A group (including the case where two adjacent groups form an acetal bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. A linear or branched acyl group having 1 to 6 carbon atoms, a linear or branched acyl group having 1 to 6 carbon atoms, a trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo group, or one or more A phenoxy group which may be substituted with a halogen atom. One or more of these substituents may be independently substituted at any position of the alkylene group or alkenylene group. However, in the formula (XX), the case where a hydroxyl group and a phenyl group are simultaneously substituted on the carbon of A in which M is a single bond and is bonded to M is excluded.
E represents —COOR ₂₅ , —SO ₃ R ₂₅ , —CONHR ₂₅ , —SO ₂ NHR ₂₅ , a tetrazol-5-yl group, a 5-oxo-1,2,4-oxadiazol-3-yl group, or It represents a 5-oxo-1,2,4-thiadiazol-3-yl group (wherein R ₂₅ represents the same as above).
M represents a single bond or —S (O) m—, and m is an integer of 0 to 2.
G and J represent the above formula (I) or (X). However, G represents a 3-position methylene benzothiophene of the formula (I), and (X), R ₁₂ is a nitrogen atom on the benzimidazole ring of the formula X in (I), and the formula (X) Represents.
X represents —CH═ or a nitrogen atom. ]

In the benzimidazole derivative (XX), when E is COOR ₂₅ and M is S, it can be produced by the synthesis method (A) or the synthesis method (B) shown below.

[式中、Ｚはハロゲンまたはアンモニウム塩を示し、Ｒ_２３、Ｒ_２４、Ｒ_２５、Ａ、Ｇ、Ｊ、およびＸは前記定義に同じである。] Synthesis method (A)

[Wherein Z represents a halogen or an ammonium salt, and R ₂₃ , R ₂₄ , R ₂₅ , A, G, J, and X are the same as defined above. ]

That is, the nitro group of the 2-nitroaniline derivative (a1) is reduced to obtain orthophenylenediamine (a2). This was reacted with CS ₂ to obtain a compound (a3), and then reacted with a halide ester derivative (a4) to obtain (a5), and further to the above formula (VIII) or the above formula (X) The compound (a7) can be obtained by reacting the represented halide derivative (a6). Further, by hydrolyzing this as necessary, it is possible to R ₂₅ to obtain a benzimidazole derivative (a8) is a hydrogen atom.
The reduction of the nitro group is performed by reacting with hydrogen gas at a temperature of room temperature to 100 ° C. under acidic, neutral, alkaline conditions in the presence of a catalyst such as Pd—C according to the conditions of a normal catalytic reduction reaction. Can do. Moreover, it can also carry out by the method of processing using zinc and tin under acidic conditions, and the method of using zinc dust under neutral or alkaline conditions.
The reaction of the orthophenylenediamine derivative (a2) and CS ₂ can be carried out, for example, by the Journal of Organic Chemistry (J. Org. Chem.) 1954, 1963-637 (pyridine solution) or The Journal of -It can carry out by the method as described in Medicinal Chemistry (J. Med. Chem.) 1993 36th volume 1175-1187 (ethanol solution).
The reaction of the thiobenzimidazoles (a3) with the halide ester (a4) is carried out in the presence of a base such as NaH, Et ₃ N, NaOH, K ₂ CO ₃ according to the conditions of a normal S-alkylation reaction. It can carry out by stirring at the temperature of deg.
The reaction of the thiobenzimidazoles (a5) with a halide derivative or ammonium salt (a6) is carried out according to the conditions of a normal N-alkylation or N-acylation reaction, for example, NaH, Et ₃ N, NaOH, K ₂ CO _3. In the presence of a base such as Cs ₂ CO ₃ , stirring can be performed at a temperature of 0 ° C. to 200 ° C.
As the elimination reaction of the carboxy protecting group R ₂₅ , it is preferable to use a method of hydrolysis using an alkali such as lithium hydroxide or an acid such as hydrochloric acid or trifluoroacetic acid.

Synthesis method (B)

That is, the amino group of the 2-nitroaniline derivative (a1) is protected with an appropriate protecting group L to obtain (b1). This is reacted with the halide derivative (a6) represented by the formula (VIII) or the formula (X) to obtain (b2), and L is deprotected to obtain (b3). The nitro group in (b3) is reduced to obtain the orthophenylenediamine derivative (b4). This is reacted with CS ₂ or KSC (= S) OEt, after the compound (b5), this is reacted with a halide ester derivative (a4), it is possible to obtain the benzimidazole derivative (a7). Moreover, by hydrolyzing the reaction it as necessary, it is possible to obtain a benzimidazole derivative R ₂₅ is a hydrogen atom.
It is also possible to obtain the compound (b3) directly by reacting the 2-nitroaniline derivative (a1) with the halide derivative (a6) without protection. Examples of the protecting group L include a trifluoroacetyl group, an acetyl group, a t-butoxycarbonyl group, and a benzyl group. The reaction of the orthophenylenediamine derivative (b4) and CS ₂ can be carried out in the same manner as in the synthesis method (A). The reaction with KSC (= S) OEt is, for example, organic synthesis (OS) 1963 4 The method described in pages 569-570 can be used. Other reactions can be carried out in the same manner as in the synthesis method (A).
In the benzimidazole derivative (XX), when E is tetrazol-5-yl and M is S, it can be produced by the synthesis method (E) shown below.

[式中Ｒ_２３、Ｒ_２４、Ａ、Ｇ、Ｊ、およびＸは前記定義に同じである。］ Synthesis method (E)

[Wherein R ₂₃ , R ₂₄ , A, G, J and X are the same as defined above. ]

The nitrile body (e1) is reacted with various azide compounds to convert to the tetrazole body (e2). Examples of the azide compound include trialkyltin azide compounds such as trimethyltin azide, hydrazoic acid or its ammonium salt. When an organotin azide compound is used, it is preferably used in an amount of about 1 to 4 moles relative to the compound (e1). When using hydrazoic acid or its ammonium salt, sodium azide and tertiary amine such as ammonium chloride or triethylamine are preferably used in an amount of about 1 to 5 moles relative to compound (e1). Each reaction is performed at a temperature of 0 ° C. to 200 ° C. by using a solvent such as toluene, benzene, or DMF.
In the benzimidazole derivative (XX), when M is SO or SO ₂ , it can be produced by the synthesis method (F) shown below.

[式中、Ｒ_２３、Ｒ_２４、Ｒ_２５、Ａ、Ｇ、Ｊ、およびＸは前記定義に同じ。］ Synthesis method (F)

[Wherein, R ₂₃ , R ₂₄ , R ₂₅ , A, G, J, and X are the same as defined above. ]

That is, the sulfoxide derivative (f1) and / or the sulfone derivative (f2) can be obtained by reacting the benzimidazole compound (a7) with a peroxide compound in an appropriate solvent. Examples of the peroxide compound used include perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, and hydrogen peroxide. Examples of the solvent used include chloroform and dichloromethane. The ratio of the compound (a7) and the peroxide compound used is not particularly limited and may be appropriately selected within a wide range. However, it is generally preferable to use about 1.2 times to 5 times the molar amount. Each reaction is usually performed at about 0 to 50 ° C., preferably 0 ° C. to room temperature, and is generally completed in about 4 to 20 hours.
In the benzimidazole derivative (XX), when M is a single bond, it can be produced by the synthesis method (G) shown below.

[式中、Ｘ、Ａ、Ｇ、Ｊ、およびＲ_２５は前記定義に同じ。] Synthesis method (G)

[Wherein, X, A, G, J, and R ₂₅ are the same as defined above. ]

That is, the diamine compound (b4) can be reacted with a known acid chloride derivative (g1) to obtain a benzimidazole derivative (g2). Also optionally the -COOR ₂₅ of (g2) by _{hydrolysis, can} be _{R 25} to obtain a benzimidazole derivative (g3) a hydrogen atom.
The cyclization reaction is described in The Journal of Medicinal Chemistry (J. Med. Chem.) 1993, 36, 1175-1187.

  The invention is further illustrated by the following examples. However, the following examples do not limit the scope of the present invention.

Example 1 Synthesis of 3-methyl-1-prop-2-ynylthiobenzene (general formula (VI))
A 5 L three-necked flask was equipped with a condenser, an internal thermometer, a mechanical stirrer, and a dropping funnel. 673 g of potassium carbonate and 1500 mL of methyl ethyl ketone were placed in the flask. In a dropping funnel, 500 g of m-toluenethiol and 200 mL of methyl ethyl ketone were added and dropped in 10 minutes. The mixture was stirred at room temperature for 1 hour. The internal temperature rose to 28 degrees. It was put on a water bath, and 333 mL of propargyl bromide and 300 mL of methyl ethyl ketone were put into the dropping funnel to start dropping. By controlling the dropping, the dropping was carried out in 20 minutes while maintaining the internal temperature around 55 to 65 degrees. The mixture was stirred for 50 minutes in a water bath. While washing with 900 mL of ethyl acetate as it is, filtration through a Nutsche and concentration under reduced pressure, 1500 mL of ethyl acetate and 2 L of water and 100 mL of 1N HCl were added to separate the organic layer and the aqueous layer, and extraction was performed twice with 500 mL of ethyl acetate. did. The extract was washed twice with 1000 mL of saturated brine and dried over anhydrous magnesium sulfate. After filtration, it was concentrated to obtain 601.14 g of a crude product (yield 92%, purity 88%). Only 300 g of crude product was distilled. 239.68 g (80% recovery, purity> 98%) of 3-methyl-1-prop-2-ynylthiobenzene was obtained at 100 to 102 ° C./7 mmHg.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.36-7.03 (4H, m, Ar), 3.56 (2H, d, CH ₂ ), 2.34, (3H, s, Me), 2.24 (1H, t, CH)

Example 2 Synthesis of 3-methyl-1-prop-2- ynylsulfylfinylbenzene (general formula (VII)) An internal thermometer, a mechanical stirrer, and a 1 L dropping funnel were attached to a 10 L three-necked flask. 427.78 g of sodium periodate, 2000 mL of water, and 2000 mL of methanol were placed in a flask. The mixture was stirred at room temperature for 1 hour as it was but was not completely dissolved, so 2000 mL of water was further added. After confirming the complete dissolution of sodium periodate, 3-methyl-1-prop-2-ynylthiobenzene (300.01 g) and methanol (1000 mL) were placed in the dropping funnel and added dropwise in 30 minutes at room temperature. Stir. After 2 hours, the ice bath was cooled over 1 hour, followed by filtration with Nutsche. The filtrate was washed thoroughly with 2 L of ethyl acetate and concentrated under reduced pressure. Extraction was performed 3 times with 1000 mL of ethyl acetate from the 4 L aqueous layer. The organic layer was washed twice with 1000 mL of saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 314.45 g of 3-methyl-1-prop-2-ynylsulfylfinylbenzene oil. It was. The crude product was converted to 3000 mL of methanol solution and extracted twice with 3000 mL of hexane to obtain the desired product 3-methyl-1-prop-2-ynylsulfylfinylbenzene having a purity of 98% or more (yield) 79%, yield 248.42 g).
¹ H-NMR (400 MHz, CDCl _3, ppm) 2.27 (s, 1 H, CH), 2.37 (s, 3 H, Me), 3.56 (abq, 2 H, -C H _2- ), 7.27 (dt, 1 H, Ar ), 7.34 (t, 1H, Ar), 7.41 (dt, 1H, Ar), 7.47 (dt, 1H, Ar)

Example 3 (4-Methylbenzo [b] thiophen-3-yl) methyl 2,2,2-trifluoroacetate and (6-methylbenzo [b] thiophen-3-yl) methyl 2,2,2-trifluoroacetate Synthesis of mixture (general formula (V)) An internal thermometer, a magnetic stirrer, and a 1000 mL dropping funnel were attached to a 10 L three-necked flask. 3000 mL of toluene was placed in a flask and placed in an oil bath having a bath temperature of 95 degrees. After confirming the internal temperature of 85 degrees, 3-methyl-1-prop-2-ynylsulfinylbenzene (251.25 g) dissolved in 700 mL of toluene was added dropwise over 15 minutes. At the end of dropping, 500 mL of toluene was added dropwise to maintain the internal temperature between 85 and 95 degrees. It cooled to 20 degree | times over 1 hour from 40 minutes after completion | finish of raw material dripping. The reaction vessel was placed in an ice bath, and trifluoroacetic anhydride (120 mL) was placed in the dropping funnel. The solution was added dropwise over 20 minutes in an ice bath. The mixture was stirred for 30 minutes at room temperature. The reaction solution was slowly poured into 4 L saturated aqueous sodium bicarbonate. The organic layer and the aqueous layer were separated and extracted with 500 mL of toluene. The organic layer was washed twice with 1500 mL of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, orange oil, (4-methylbenzo [b] thiophen-3-yl) methyl 2,2,2-trifluoroacetate and (6-methylbenzo [b] Thiophen-3-yl) methyl 2,2,2-trifluoroacetate mixture (356.72 g) was obtained.
¹ H-NMR (400MHz, CDCl _3, ppm) 2.47 (s, 4.5H), 2.72 (s, 3H), 5.56 (s, 2H,), 5.67 (s, 3H), 7.16-7.28 (m, 8H) , 7.45 (s, 1.5H), 7.49 (s, 1H), 7.58-7.78 (m, 4H)

Example 4 (4-Methylbenzo [b] thiophen-3-yl) methane-1-ol and (6-methylbenzo [b] thiophen-3-yl) methane-1-ol mixture by hydrolysis reaction (general formula (II ) And (III)) A stirrer bar, a 100 mL dropping funnel, and an internal thermometer were attached to a 300 mL three-necked flask. (4-Methylbenzo [b] thiophen-3-yl) methyl 2,2,2-trifluoroacetate and (6-methylbenzo [b] thiophen-3-yl) methyl 2,2 obtained by the reaction of Example 3 , 2-trifluoroacetate mixture 30.05 g was dissolved in 100 mL of tetrahydrofuran and placed in a flask. The internal temperature was then cooled to 20 ° C. A 1N aqueous sodium hydroxide solution (100 mL) was placed in the dropping funnel. The solution was added dropwise in 10 minutes and stirred as it was for 60 minutes at room temperature. This reaction solution was put into a 500 mL separating funnel, and 300 mL of hexane was further added. The organic layer and the aqueous layer were separated as they were, and the organic layer was washed 3 times with 500 mL of water and twice with 500 mL of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to a brown oil, (4-methylbenzo [b] thiophen-3-yl) methane-1-ol and (6-methylbenzo [b] thiophen-3-yl. ) A methane-1-ol mixture (28.24 g) was obtained.

Example 5 Purification of (4-Methylbenzo [b] thiophen-3-yl) methane-1-ol (General Formula (II))-1
To the brown oil obtained in Example 4, 20 mL of ethyl acetate was added and stirred for 10 minutes. Thereafter, 100 mL of hexane was added in three portions. After stirring for 2 hours, the solution was filtered and dried to obtain 8.33 g (yield 27.8%) of (4-methylbenzo [b] thiophen-3-yl) methane-1-ol as pale orange crystals. . The purity was 98%.
¹ H-NMR (400 MHz, CDCl _3, ppm) 2.82 (s, 3 H, 4-Me), 5.00 (s, 2 H, -C H ₂ -OH), 7.10 (d, 1 H, J ₅ , ₆ = 8 Hz, H-5), 7.24 (t, 1H, J _5,6 = J _6,7 = 8Hz, H-6), 7.40 (s, 1H, H-2), 7.70 (d, 1H, J _6,7 = (8Hz ,, H-7)
¹³ C-NMR (100 MHz, CDCl _3, ppm) 20.8 (4-Me), 61.4 ( -C H ₂ -OH), 120.8 (C-7), 122.6 (C-6), 124.5 (C-2), 126.2 (C-5), 133.7 (C-4), 136.2 (C-3a), 137.4 (C-3), 141.9 (C-7a)

Example 6 (4-Methylbenzo [b] thiophen-3-yl) methane-1-ol (general formula (II)) and (6-methylbenzo [b] thiophen-3-yl) methane-1-ol by reduction reaction Synthesis of (General Formula (III)) Mixture A 3000 mL three-necked flask was equipped with a mechanical stirrer, a 200 mL dropping funnel, and an internal thermometer. (4-Methylbenzo [b] thiophen-3-yl) methyl 2,2,2-trifluoroacetate and (6-methylbenzo [b] thiophen-3-yl) methyl 2,2 obtained by the reaction of Example 3 , 2-trifluoroacetate mixture (300.00 g) dissolved in 1500 mL of toluene was placed in a flask and the flask was placed in a water bath. 30.00 g of sodium borohydride was charged into the flask. Methanol (150 mL) was added to the dropping funnel. The solution was added dropwise in 60 minutes and stirred at room temperature for 60 minutes. Water (1000 mL) was added to the flask, and celite filtration was performed. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with 500 mL of toluene. The organic layer was washed twice with 1000 mL of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, yellow oil, (4-methylbenzo [b] thiophen-3-yl) methane-1-ol and (6-methylbenzo [b] thiophen-3-yl ) A mixture of methane-1-ol (295.12 g) was obtained.
¹ H-NMR (400MHz, CDCl _3, ppm) 2.387 (s, 3H), 2.67 (s, 5H), 4.77 (s, 2H,), 4.87 (s, 3H), 7.02-7.16 (m, 6H), 7.55-7.63 (m, 5H)

Example 7 Purification of (4-methylbenzo [b] thiophen-3-yl) methane-1-ol (general formula (II))-2
To the yellow oil obtained in Example 6, 100 mL of ethyl acetate was added and stirred for 10 minutes. Thereafter, 400 mL of hexane is added in four portions. The mixture was stirred as it was for 2 hours and then filtered and dried to obtain 80.05 g of white to pale yellow crystalline (4-methylbenzo [b] thiophen-3-yl) methane-1-ol (yield 27%). The purity was 98% or more.
¹ H-NMR (400MHz, CDCl _3, ppm) 2.77 (s, 3H, 4-Me), 4.99 (d, 2H, -C H ₂ -OH), 7.12 (dt, 1H, J _5,6 = 8Hz, J _{5, Me} = 0.8Hz, H-5), 7.21 (t, 1H, J _5,6 = J _6,7 = 8Hz, H-6), 7.38 (s, 1H, H-2), 7.68 (dd , 1H, J _6,7 = 8Hz, H-7)

Example 8 Purification of (4-methylbenzo [b] thiophen-3-yl) methane-1-ol (general formula (II))-3
(4-Methylbenzo [b] thiophen-3-yl) methane-1-ol and (6-methylbenzo [b] thiophen-3-yl) methane-1-ol (ratio of 4-methyl / 6-methyl) = about 6 / 1) To 4.95 g of the mixture, 25 ml of acetonitrile was added and refluxed, followed by cooling at room temperature and further cooling in the refrigerator overnight. Thereafter, filtration, washing with acetonitrile, and drying were performed to obtain 3.15 g of white to pale yellow crystal (4-methylbenzo [b] thiophen-3-yl) methane-1-ol (recovery rate = 64%). Purity = 99%
¹ H-NMR (400 MHz, CDCl _3, ppm):
2.82 (s, 3H, 4-Me), 5.00 (s, 2H, -C H ₂ -OH), 7.10 (d, 1H, J _5,6 = 8Hz, H-5), 7.24 (t, 1H, J _5,6 = J _6,7 = 8Hz, H-6), 7.40 (s, 1H, H-2), 7.70 (d, 1H, J _6,7 = 8Hz ,, H-7)
¹³ C-NMR (100 MHz, CDCl _3, ppm):
20.8 (4-Me), 61.4 ( -C H ₂ -OH), 120.8 (C-7), 122.6 (C-6), 124.5 (C-2), 126.2 (C-5), 133.7 (C-4 ), 136.2 (C-3a), 137.4 (C-3), 141.9 (C-7a)

Example 9 Purification of 4-methylbenzo [b] thiophen-3-yl) methane-1-ol (general formula (II))-4
(4-Methylbenzo [b] thiophen-3-yl) methane-1-ol and (6-methylbenzo [b] thiophen-3-yl) methane-1-ol (ratio of 4-methyl / 6-methyl) = about 4 26 ml of toluene was added to 26 g of the mixture of (3), and the mixture was refluxed. Then, the mixture was cooled at room temperature, and 26 ml of hexane was added, and the mixture was further stirred overnight at room temperature. After filtration, the crystals were washed with 20 ml of toluene-hexane (1/1) and 10 ml of hexane and then dried, and 7.3 g of white to pale yellow crystals, 4-methylbenzo [b] thiophen-3-yl) methane-1- All were obtained (recovery rate = 28%). Purity = 99%.
¹ H-NMR (200 MHz, CDCl _3, ppm):
2.79 (s, 3H, 4-Me), 5.01 (d, 2H, -C H ₂ -OH), 7.10-7.24 (m, 2H, H-5, H-6), 7.41 (s, 1H, H- 2), 7.69 (d, 1H, J _6,7 = 8Hz ,, H-7)

Example 10 Synthesis of 3- (bromomethyl) -4-methylbenzo [b] thiophene (general formula (VIII)) A 1 L three-necked flask was equipped with a magnetic stirrer, a 100 mL dropping funnel, and an internal thermometer. (4-Methylbenzo [b] thiophen-3-yl) methane-1-ol (69.95 g) was dissolved in 200 mL of cyclohexane and placed in a flask. Phosphorus tribromide (18 mL) was placed in the dropping funnel. The mixture was added dropwise at room temperature over 20 minutes (internal temperature increased to 30 degrees), and stirred at room temperature for 60 minutes at room temperature for 1 hour. The solution was added to ice water (1 L), the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with 1 L of toluene. The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate (1 L) and twice with saturated brine (1 L). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a pale yellow solid (99.69 g). The obtained crude product was recrystallized with 200 mL of hot cyclohexane to obtain 3- (bromomethyl) -4-methylbenzo [b] thiophene as a white solid (52.19 g, yield 55%).
¹ H-NMR (400 MHz, CDCl _3, ppm) 2.90 (s, 3 H, 4-Me), 4.89 (s, 2 H, -C H ₂ -Br), 7.15 (d, 1 H, J ₅ , ₆ = 8 Hz, H-5), 7.24 (t, 1H, J _5,6 = J _6,7 = 8Hz, H-6), 7.48 (s, 1H, H-2), 7.68 (d, 1H, J _6,7 = (8Hz ,, H-7)

Example 11 Synthesis of 4-methyl-1- ( prop-2-ynylsulfinyl) benzene (general formula XII) To 40 g (322 mmol) of p-toluenethiol, 200 ml of 2-butanone and 53.4 g (386 mmol) of potassium carbonate were added. The mixture was ice-cooled, 26.7 ml (354 mmol) of 1-bromo-propyne was added, and the reaction vessel was stirred for 2 hours while cooling with water. After 2 hours, the reaction system was filtered, the precipitate was washed with 50 ml of 2-butanone, and the filtrate was concentrated under reduced pressure to give 4-methyl-1-prop-2-ynylthiobenzene (general formula ( XI)) 49.9 g were obtained. (Rough yield: 96%)
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.38 (2H, d, Ar), 7.06 (2H, d, Ar), 3.56 (2H, s, CH ₂ ), 2.33, (3H, s, Me), 2.21 (1H, t, CH)

Subsequently, 68.7 g (321 mmol) of sodium periodate was added to 250 ml of water and dissolved, and 49,6 g (306 mmol) of 4-methyl-1-prop-2-ynylthiobenzene (general formula (XI)) was dissolved. Methanol solution (250 ml) was added dropwise and stirred at room temperature for 2.5 hours. After 2.5 hours, filtration, the solid was washed with 100 ml of ethyl acetate, the filtrate was concentrated under reduced pressure, 200 ml of water was added, extraction was performed 3 times with ethyl acetate (150 ml), and the resulting organic layer was washed with 150 ml of water, The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain 50.6 g of 4-methyl-1- (prop-2-ynylsulfinyl) benzene. (Rough yield 93%)
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.61 (2H, d, Ar), 7.34 (2H, d, Ar), 3.62 (2H, dd, CH ₂ ), 2.33, (3H, s, Me), 2.32 (1H, t, CH)

Example 12 Synthesis of (prop-2-ynylsulfinyl) benzene (general formula XII) Thiophenol (55.34 g, 502.3 mmol) was dissolved in 150 ml of acetonitrile, and potassium carbonate (2.07 g, 15.0 mmol) was dissolved. In addition, the mixture was bathed in water, 49.2 ml (652.9 mmol) of propargyl bromide was added dropwise over 30 minutes, and 100 ml of acetonitrile was further added. Thereafter, the mixture was stirred at room temperature for 1 hour and 20 minutes, and after 1 hour and 35 minutes, propargyl bromide (3 ml) was added and further stirred for 15 minutes. Then, filtration, concentration under reduced pressure, and drying under reduced pressure, 71.50 g of oil was obtained. 70.50 g (0.476 mol) of the oil was dissolved in 500 ml of methanol, added to 500 ml of an aqueous solution of sodium periodate (108.3 g, 0.506 mol), and stirred at room temperature. After 1 hour, filtration, concentration under reduced pressure, separation of the lower layer, extraction of the aqueous layer with ethyl acetate (250 ml × 3), drying of the organic layer and the lower layer with bow glass, concentration under reduced pressure, and drying ( 77.8 g of prop-2-ynylsulfinyl) benzene was synthesized. Crude yield = 96%.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.53-7.74 (5H, m, Ar), 3.65 (2H, ddd, CH ₂ ), 2.35 (1H, t, CH)

Example 13 Synthesis of 3,5-dimethyl -1- (propy-2-inylsulfinyl) benzene (general formula (XII)) 5.56 g (40.2 mmol) of 3,5-dimethylbenzenethiol was dissolved in 20 ml of acetonitrile. Propargyl bromide 3.63 ml (48.3 mmol) and potassium carbonate 6.91 g (50 mmol) were sequentially added. Thereafter, the mixture was refluxed, filtered after 1 hour, concentrated under reduced pressure, and dried under reduced pressure to obtain 7.79 g of oil. This was dissolved in 70 ml of methanol, 40 ml of an aqueous solution of sodium periodate (9.19 g, 43 mmol) was added dropwise, and further 30 ml of methanol and 20 ml of water were added and stirred at room temperature. After 1.5 hours of filtration, the precipitate was washed with methanol, and concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate (100 ml × 2), and the organic layer was dried with bow glass, concentrated under reduced pressure, and dried. 7.66 g of 5-dimethyl-1- (prop-2-ynylsulfinyl) benzene was synthesized. The crude yield was 99%.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.31 (2H, s, Ar), 7.15 (1H, s, Ar), 3.63 (2H, t, CH ₂ ), 2.39 (6H, 2, Me ), 2.35 (1H, t, CH)

Example 14 Synthesis of 5-methyl-3-methylene-2-hydrobenzo [b] thiophen-2-ol (general formula (IX)) 107.0 mg (0.6 mmol) of the compound obtained in Example 11 was mixed with propyl acetate. Dissolved in 1.6 ml and refluxed for 20 minutes. Subsequently, the mixture was concentrated under reduced pressure and dried to obtain 108.5 mg of 5-methyl-3-methylene-2-hydrobenzo [b] thiophen-2-ol. The crude yield was 105%.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.24 (1H, s, Ar), 7.05 (2H, s, Ar), 6.17 (1H, d, CH) 5.78 (1H, s, = CH) , 5.49 (1H, s, = CH), 2.30 (3H, s, Me)

Example 15 Synthesis of 3-methylene-2-hydrobenzo [b] thiophen-2-ol (general formula (IX)) 301 mg of the compound obtained in Example 12 was dissolved in 4.5 ml of dioxane, and 100 ° C. for 2 hours. Heated. After cooling, the mixture was concentrated under reduced pressure to synthesize 292 mg of 3-methylene-2-hydrobenzo [b] thiophen-2-ol as a yellow transparent oil.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.06-7.48 (4H, m, Ar), 6.15 (1H, d, CH), 5.84 (1H, s, = CH), 5.55 (1H, s , = CH), 2.45 (3H, s, Me)

Example 16 Synthesis of 4,6-dimethyl-3-methylene-2-hydrobenzo [b] thiophen-2-ol (general formula (IX)) 117.6 mg (0.61 mmol) of the compound obtained in Example 13 was added to acetic acid. It was dissolved in 2 ml of propyl, refluxed for 20 minutes, cooled, concentrated under reduced pressure, and dried to synthesize 2,3-dihydro-4,6-dimethyl-3-methylene-benzo [b] thiophen-2-ol. The crude yield was 95%.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.89 (1H, s, Ar), 6.72 (1H, s, Ar), 5.94 (1H, d, CH) 5.69 (1H, s, = CH) , 5.61 (1H, s, = CH), 2.43 (3H, s, Me), 2.26 (3H, s, Me)

Example 17 Synthesis of 3- (bromomethyl) -5-methylbenzo [b] thiophene (general formula (X)) 71.9 mg (0.40 mmol) of the compound obtained in Example 14 was dissolved in 1 ml of propyl acetate. 0.0569 ml (0.5 mmol) of% hydrobromic acid was added and left at room temperature for 20 minutes. Thereafter, 3 ml of ethyl acetate was added, washed with water, and the organic layer was dried over magnesium sulfate, filtered and dried under reduced pressure to obtain 88.2 mg of 3- (bromomethyl) -5-methylbenzo [b] thiophene. The yield was 91%.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.68 (1H, d, H-7), 7.65 (1H, s, H-4), 7.41 (1H, s, H-2), 7.15 ( 1H, dd, H-6), 4.67 (2H, s, CH ₂ ), 2.45 (3H, s, Me)

Example 18 Synthesis of 3- (chloromethyl) -benzo [b] thiophene (general formula (X)) 270 mg (1.64 mmol) of the compound obtained in Example 15 was dissolved in 4 ml of propyl acetate, and 4M hydrogen chloride dioxane solution was obtained. 0.0615 ml (2.46 mmol) was added and left at room temperature for 30 minutes. Thereafter, the mixture was concentrated, 10 ml of water was added, extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered under reduced pressure, and dried to obtain 271 mg of 3- (chloromethyl) -benzo [b] thiophene. The yield was 90%.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.88-7.90 (2H, m, Ar), 7.30-7.50 (3H, m, Ar), 4.86 (2H, s, CH ₂ )

Example 19 Synthesis of 3- (bromomethyl) -4,6-dimethylbenzo [b] thiophene (general formula (X)) 55.3 mg of the compound obtained in Example 16 was dissolved in 1 ml of propyl acetate and 48% odor was obtained. Hydrochloric acid 39.9 μl was added and left at room temperature. After 20 minutes, 3 ml of ethyl acetate was added, washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and dried to synthesize 3- (bromomethyl) -4,6-dimethylbenzo [b] thiophene. The yield was 90%.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.40 (1H, d, H-5), 7.33 (1H, s, H-5), 6.92 (1H, s, H-2), 4.81 ( 2H, s, CH ₂ ), 2.81 (3H, s, 4-Me), 2.34 (3H, s, 6-Me)

Example 20 Synthesis of 3- (chloromethyl) -5 -methylbenzo [b] thiophene (general formula (X)) 873.4 mg (4.9 mmol) of the compound obtained in Example 11 was dissolved in 15 ml of dioxane. The mixture was stirred at 70 ° C. for 70 minutes. The reaction system was cooled to room temperature, 1.5 ml (6 mmol) of 4M hydrogen chloride-dioxane was added, and the mixture was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, 0.80 ml of cyclohexane was added, heated at 70 ° C. for 10 minutes, cooled to room temperature, the precipitate was filtered, 590.6 mg of 3- (chloromethyl) -5-methylbenzo [b] thiophene was added. Obtained. The yield was 61%.
Calculated value M = 196.70, analysis value m / z = 196 [M +]

Example 21 Synthesis of 3- (bromomethyl) -5-methylbenzo [b] thiophene (general formula (X)) 7.18 g (40.3 mmol) of the compound obtained in Example 11 was dissolved in 110 ml of dioxane and 100 ° C. At reflux for 100 minutes. Thereafter, the mixture was cooled, 7.42 g (44 mmol) of 48% hydrobromic acid was added, and the mixture was allowed to stand at room temperature for 1 hour. Then, water was added, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 9.04 g of 3- (bromomethyl) -5-methylbenzo [b] thiophene. The yield was 93%.
Calculated value M = 241.10, analysis value m / z = 241 [M +]

Example 22 Synthesis of 3- (bromomethyl) -5-methylbenzo [b] thiophene (general formula (X)) The compound obtained in Example 11 (29.7 g, 167 mmol) was dissolved in 445 ml of propyl acetate at 100 ° C. Heated for 1 hour. Then, after cooling with ice to an internal temperature of 10 ° C., 22.8 ml of 48% hydrobromic acid was added, and the mixture was allowed to stand for 1 hour and 30 minutes under ice cooling. The aqueous layer was separated, washed with 50 ml of water, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and dried to synthesize 35.3 g of brown transparent oily 3- (bromomethyl) -5-methylbenzo [b] thiophene. did. (Yield = 88%)
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.74 (1H, d, H-7), 7.68 (1H, s, H-4), 7.47 (1H, s, H-2), 7.23 ( 1H, dd, H-6), 4.73 (2H, s, CH ₂ ), 2.51 (3H, s, Me)

Example 23 Synthesis of 3- (chloromethyl) -benzo [b] thiophene (general formula (X)) 5.02 g (30.6 mmol) of the compound obtained in Example 12 was dissolved in 50 ml of 1,4-dioxane. Heated to 100 degrees, cooled after 5 hours and 30 minutes, and the internal temperature of the reaction system was adjusted to 10 degrees. Subsequently, 8.42 ml (33.7 mmol) of 4M hydrogen chloride-dioxane solution was added and left at room temperature. After 15 minutes, the reaction solution was concentrated, dissolved in 50 ml of ethyl acetate, washed with 40 ml of water, and the organic layer was dried over magnesium sulfate. After concentration, in order to remove dioxane, it was dissolved again in 50 ml of ethyl acetate, washed with 40 ml of water three times, the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and 3- (chloromethyl) -benzo [b] thiophene 5 .18 g was obtained. The yield was 93%.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.91-7.85 (2H, m, Ar), 7.36-7.48 (3H, m, Ar), 4.85 (2H, t, CH ₂ )

Example 24 Synthesis of 3- (bromomethyl) -4,6-dimethylbenzo [b] thiophene (general formula (X)) 2.26 g (11.7 mmol) of the compound obtained in Example 13 was added to 40 ml of propyl acetate. Dissolved and refluxed for 30 minutes. After cooling, 1.59 ml (14 mmol) of 48% hydrobromic acid was added and left at room temperature for 30 minutes. Thereafter, ethyl acetate was added, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 2.49 g of 3- (bromomethyl) -4,6-dimethylbenzo [b] thiophene. The yield was 84%.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.46 (1H, s, H-5), 7.38 (1H, s, H-7), 6.98 (1H, s, H-2), 4.85 ( 2H, s, CH ₂ ), 2.85 (3H, s, 4-Me), 2.40 (3H, s, 6-Me)

Comparative Example J.I. Chem. Soc. , Chem. Comm. , 848 (1974), and the following conditions were reported.
218.4 mg of 3-methyl-phenyl-propargyl-sulfoxide was dissolved in 3 ml (15 times the amount) of dioxane and refluxed for 2 hours and 30 minutes. Thereafter, 1 ml of water and 21.7 mg of p-toluenesulfonic acid monohydrate were added and heated at 70 ° C. for 2 hours. At this stage, TLC (hexane-ethyl acetate = 5: 1) confirmed a main product spot at Rf = 0.23 and a by-product spot at 0.41, 0.55, 0.70, 0.83. It was. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 280.1 mg of residue. This was purified by thin-phase chromatography (Merck 1.13794 PLC plates 20 × 20 cm kissei gel 60 0.5 mm, developed system: hexane-ethyl acetate = 5: 1), and fraction of main product Was recovered to obtain 131.5 mg of brown oil. From the ¹ H-NMR and two-dimensional NMR of this fraction, the ratio of 3-hydroxy-4-methyl-benzo [b] thiophene to 3-hydroxy-6-methyl-benzo [b] thiophene was about 3: 2. It turned out to be. Even when this fraction was allowed to stand, it was only partially solidified, and 3-hydroxy-4-methyl-benzo [b] thiophene could not be isolated.
¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 7.12-7.75 (11H, m, Ar, 4-Me-deriv., 6-Me-deriv.), 5.00 (3H, s, CH ₂ , 4 -deriv.), 4.90 (2H, s, CH ₂ , 6-deriv.), 2.79 (4.5H, s, Me, 4-deriv.), 2.47 (3H, s, Me, 6-deriv.), 1.77 (2H, brs, OH, 4-Me-deriv., 6-Me-deriv.)

  According to the present invention, a 4-substituted-3-hydroxymethyl-benzothiophene derivative useful as a pharmaceutical raw material can be provided. Further, since the synthesis method in the present invention can be selectively produced with high yield, its industrial value is very large. Furthermore, 3-halomethyl-benzothiophene derivatives can be synthesized from substituted benzenethiols in a short process and in a simple manner, which is industrially superior.

Claims (11)

The method to manufacture the benzimidazole derivative represented by general formula (XX) containing (1) and (2).

[In Formula (XX), R ₂₃ and R ₂₄ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, hydroxyl group, alkyl group having 1 to 4 carbon atoms, or alkyl group having 1 to 4 carbon atoms. An alkoxy group, or R ₂₃ and R _{24 taken} together —O—CH ₂ —O—, —O—CH ₂ CH ₂ —O—, or —CH ₂ CH ₂ CH ₂ — (in this case, the carbon atom May be substituted with one or more alkyl groups having 1 to 4 carbon atoms.
A represents a substituted or unsubstituted linear, cyclic, or branched alkylene group or alkenylene group having 1 to 7 carbon atoms, and —O—, —S—, —SO ₂ —, —NR ₂₅ — is encapsulated in the middle. (Here, R ₂₅ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.) One or more of them may be contained. Substituents that these groups may have are halogen atom, hydroxyl group, nitro group, cyano group, linear or branched alkyl group having 1 to 6 carbon atoms, linear or branched alkoxy group having 1 to 6 carbon atoms. A group (including the case where two adjacent groups form an acetal bond), a linear or branched alkylthio group having 1 to 6 carbon atoms, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. A linear or branched acyl group having 1 to 6 carbon atoms, a linear or branched acyl group having 1 to 6 carbon atoms, a trihalomethyl group, a trihalomethoxy group, a phenyl group, an oxo group, or one or more A phenoxy group which may be substituted with a halogen atom. One or more of these substituents may be independently substituted at any position of the alkylene group or alkenylene group. However, in the formula (XX), the case where a hydroxyl group and a phenyl group are simultaneously substituted on the carbon of A in which M is a single bond and is bonded to M is excluded.
E represents —COOR ₂₅ , —SO ₃ R ₂₅ , —CONHR ₂₅ , —SO ₂ NHR ₂₅ , a tetrazol-5-yl group, a 5-oxo-1,2,4-oxadiazol-3-yl group, or It represents a 5-oxo-1,2,4-thiadiazol-3-yl group (wherein R ₂₅ represents the same as above).
M represents a single bond or —S (O) m—, and m is an integer of 0 to 2.
G and J represent formula (II), (VIII), or formula (X). Wherein G represents methylene at the 3-position of the benzothiophene of formula (II), (VIII), or formula (X), the hydroxyl group of formula (II) or R _{7 of} (VIII), or of formula (X) R ₁₂ replaces a nitrogen atom on the benzimidazole ring.
X represents —CH═ or a nitrogen atom. ]
(1) The manufacturing method of (a) or (b).
(A) The following formula (II)

[Wherein, R ₁ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. ]
And the following formula (III)

[Wherein R ₂ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. ]
A benzo [b] thiophene derivative represented by the above formula (II) is obtained by crystallizing a mixture containing the benzo [b] thiophene derivative represented by formula (II) in a solvent,
By converting the hydroxyl group of the 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivative represented by the formula (II) to a halogen atom, the following formula (VIII)

[Wherein, R ₁ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. R ₇ represents a halogen atom. ]
A method for producing a 4-substituted-3-halomethyl-benzo [b] thiophene derivative represented by the formula:
(B) Formula (IX) below

[Wherein R ₈ to R ₁₁ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, 1 to 1 carbon atoms. 4 represents an alkylthio group, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group. ]
A compound represented by the following formula (X) is reacted with an equal amount or more of an acid.

[Wherein, R ₈ to R ₁₁ are the same as defined in formula (IX). R ₁₂ represents a halogen atom. ]
A method for producing a 3-halomethyl-benzo [b] thiophene derivative represented by the formula:
(2) A method for producing a compound represented by the formula (XX) from a compound represented by the formula (VIII) or the formula (X).   (1) In (a), the solvent to be crystallized is a mixed solvent of a linear, cyclic, or branched hydrocarbon having 5 to 8 carbon atoms and a carboxylic acid ester having 2 to 6 carbon atoms, or 5 carbon atoms. The method for producing a benzimidazole derivative according to claim 1, which is a mixed solvent of -8 linear, cyclic or branched hydrocarbons and aromatic hydrocarbons having 6 to 8 carbon atoms, or acetonitrile. (1) In (a), the benzo [b] thiophene derivative represented by the formula (II) or the benzo [b] thiophene derivative represented by the formula (III)
Formula (IV) below

[Wherein R ₃ represents a hydrogen atom and R ₄ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, or R ₃ represents a halogen atom, A trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, and R ₄ represents hydrogen. ]
By reacting the compound represented by the following formula with one or more of carboxylic acid having 1 to 4 carbon atoms, carboxylic acid anhydride thereof, or trifluoroacetic acid or trifluoroacetic acid anhydride, Formula (V)

[Wherein, R ₃ and R ₄ are the same as those in the above formula (IV). R ₅ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a trifluoromethyl group. ]
After producing a benzo [b] thiophene derivative represented by
3. A production method produced by reduction, basic hydrolysis, or acidic hydrolysis of a compound represented by the formula (V) with a metal hydride complex compound. A process for producing a benzimidazole derivative according to claim 1. The method for producing a benzimidazole derivative according to claim 3, wherein, in the formula (V), R ₅ is a trifluoromethyl group.   A production method for producing the benzo [b] thiophene derivative represented by the formula (II) or the formula (III) by reducing the compound represented by the formula (V) with sodium borohydride. The method for producing a benzimidazole derivative according to claim 3 or 4, wherein: (1) In (a), the 4-substituted-3-hydroxymethyl-benzo [b] thiophene derivative represented by the formula (II) is
When a propargyl group is introduced into m-substituted benzenethiol, the following formula (VI)

[Wherein, R ₆ represents a halogen atom, a trihalomethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. ]
To obtain a compound represented by
Next, this is oxidized and the following formula (VII)

[Wherein R ₆ is the same as defined in the above formula (VI). ]
To obtain a compound represented by
Further, this is subjected to a heat transfer reaction to obtain a compound represented by the formula (IV),
By reacting this with one or more of carboxylic acid having 1 to 4 carbon atoms or carboxylic acid anhydride thereof, or trifluoroacetic acid or trifluoroacetic acid anhydride, in the above formula (V) After obtaining the compound shown,
A mixture of a benzo [b] thiophene derivative represented by the formula (II) and a benzo [b] thiophene derivative represented by the formula (III) obtained by converting an ester group into a hydroxyl group is crystallized in a solvent. The manufacturing method of the benzimidazole derivative | guide_body of Claim 1 characterized by including the manufacturing method by making. The method for producing a benzimidazole derivative according to claim ₆ , wherein R ₆ in the formula (VI) is a methyl group. (1) The method for producing a benzimidazole derivative according to claim 1, wherein, in (a), R _{1 in the} formula (VIII) is a methyl group. (1) In (b), a propargyl group is introduced into the substituted benzenethiol, and the following formula (XI)

[Wherein R ₁₃ and R ₁₅ are simultaneously and R ₁₄ is independently a hydrogen atom, a halogen atom, a trihalomethyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, carbon An alkylthio group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group, and R ₁₆ represents a hydrogen atom, or R ₁₆ is a halogen atom, Trihalomethyl group, cyano group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, acyloxy group having 1 to 4 carbon atoms, acylamino having 1 to 4 carbon atoms group or a trihalomethoxy group and _R 13 _{to R 15} are simultaneously or each independently a hydrogen atom, a halogen atom, a trihalomethyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms, Alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, acylamino group or a trihalomethoxy group, having 1 to 4 carbon atoms. ]
And the compound (XI) is oxidized to give the following formula (XII)

[Wherein, R ₁₃ to R ₁₆ are the same as those in the formula (XI). ]
To obtain a compound represented by
The compound represented by the formula (XII) is subjected to a heat transfer reaction to obtain a compound represented by the formula (IX), which is reacted with an equal amount or more of an acid to obtain a compound represented by the formula (X). The manufacturing method of the benzimidazole derivative of Claim 1 characterized by including the method of manufacturing. R ₈ and R _{10 in the} formula (IX) and the formula (X) are simultaneously and R ₉ is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ₁₁ represents a hydrogen atom, or , R ₁₁ is an alkyl group having 1 to 4 carbon atoms, and R _{8 to} R ₁₀ are simultaneously or independently hydrogen atom, halogen atom, trihalomethyl group, cyano group, alkyl group having 1 to 4 carbon atoms, carbon number 1 An alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group, and the above formula (XI) and the above formula ( XII) R ₁₃ and R ₁₅ are simultaneously and R ₁₄ is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ₁₆ represents a hydrogen atom, or R ₁₆ is an alkyl group having 1 to 4 carbon atoms. The Archi Group and _R 13 _{to R 15} are simultaneously or each independently a hydrogen atom, a halogen atom, a trihalomethyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, 1 to 4 carbon atoms, The method for producing a benzimidazole derivative according to claim 1, wherein the alkylthio group is an acyloxy group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, or a trihalomethoxy group. The method for producing a benzimidazole derivative according to claim 1, 9 or 10, wherein in the formula (X), R ₁₂ is a chlorine atom or a bromine atom.