CN1821229A

CN1821229A - Processes for preparing benzo[b]thiophene derivatives

Info

Publication number: CN1821229A
Application number: CN 200610009572
Authority: CN
Inventors: 齐藤博; 土屋直树; 水野刚志; 井田智英; 泽井善行
Original assignee: Teijin Ltd
Current assignee: Teijin Ltd
Priority date: 2001-02-22
Filing date: 2002-02-22
Publication date: 2006-08-23
Anticipated expiration: 2022-02-22
Also published as: CN1944415A; CN1944415B; CN100548990C

Abstract

The present invention relates to the preparation process of benzimidazole derivative in the general expression as shown.

Description

The preparation method of benzimidizole derivatives

The application is application number the dividing an application for the PCT application in the country's stage that enters of " benzo [b] thiophene derivant and preparation method thereof " that be CN02801290.9 (international filing date is on February 22nd, 2002), denomination of invention.

Technical field

The present invention relates to the preparation method of benzimidizole derivatives.

Background technology

Up to now, replacement-benzo [b] thiophene derivant majority is synthetic, is used as the raw material of makeup, medicine etc. more.Wherein, the 3-replacement-benzothiophene derivative of following formula (XIII) expression is extremely important as the preparation intermediate that has active compound on the pharmacology.

[in the formula, R ₁₇～R ₂₀Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, carbonatoms 1～4, the alkoxyl group or the cyano group of carbonatoms 1～4 independently of one another.X represents hydroxyl or halogen atom.]

For example, in 3-replacement-benzo [b] thiophene derivant of formula (XIII) expression, R ₁₇To R ₂₀For hydrogen atom and X are the compound that bromine atoms is represented; R ₁₇Be methyl, R ₁₈To R ₂₀For hydrogen atom and X are the compound that bromine atoms is represented; R ₁₈Be methyl, R ₁₇, R ₁₉, R ₂₀For hydrogen atom and X are the compound that bromine atoms is represented; R ₁₇, R ₁₉Be methyl, R ₁₈, R ₂₀For hydrogen atom and X are that the compound that bromine atoms is represented can become raw material of the synthetic intermediate of disclosed benzimidizole derivatives among the WO01/53291 etc., we can say extremely important as the preparation intermediate that has active compound on the pharmacology.Disclosed benzimidizole derivatives is pharmaceutically useful benzimidizole derivatives among the WO01/53291, thinks to be hopeful compound as can be narrow in based on respiratory system diseases such as bronchial asthma, hardening vascular lesion, blood vessel, using in the preventive of the various diseases of tip recycle system obstacle and/or the therapeutical agent.

3 of particularly following formula (I) expression, 4-two replacement-benzos [b] thiophene derivant produce 4,6 isomer according to its constitutional features when synthesizing benzo [b] thiophene skeleton.

[in the formula, R ₁Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4.X represents hydroxyl or halogen atom.]

In addition, because the separation of its isomer is very difficult, therefore do not synthesize 3, the report of 4-two replacement-benzos [b] thiophene derivant.But, 3,4-two replacement-benzos [b] thiophene derivant has the structure of feature owing to it, thereby expects very much the raw material as the high reactivity material in the drug development.

As the technology relevant with synthetic The compounds of this invention, technology of record in " J.Chem.Soc., Chem.Comm., 848 (1974) " for example.Wherein reported following reaction, promptly in benzenethiol, imported propargyl, then obtained the compound of following formula (XIV) expression by oxidizing reaction,

[in the formula, R ₂₁, R ₂₂Can all be hydrogen atom, perhaps also can pass through R ₂₁, R ₂₂Form phenyl ring.]

This compound in hot shift reaction, is obtained the compound of following formula (XV) expression,

In the presence of tosic acid, in water-dioxane,, obtain following formula (XVI) again in hot shift reaction

But, in the document,, also only put down in writing condition in the presence of tosic acid-dioxane for the preparation method not about any record of 4-replacement-3-methylol-benzo [b] thiophene derivant.

In addition, if under the condition of document record, synthesize, compare with preparation method of the present invention, except that 6-replacement-3-methylol-benzo [b] thiophene derivant as isomer, also generate a large amount of by products, thereby must adopt column chromatography to make with extra care, therefore inapplicable fully on industrial production process.And, the level of desired substance is divided into about 3: 2 mixture of 4-replacement-3-methylol-benzo [b] thiophene and 6-replacement-3-methylol-benzo [b] thiophene, for by the method for this mixture separation 4-replacement-3-methylol-benzo [b] thiophene without any record, in addition, promptly using column chromatography to make with extra care can not separate fully.Adopt very difficulty of synthetic 4-replacement-3-methylol-benzo [b] thiophene of the synthetic method of reporting up to now.

In addition, synthetic for 3-methylol benzo [b] thiophene in the document is also because by product synthetic, thereby yield is low to moderate 64%, consider later halogenation (synthetic 3-halogenated methyl-benzo [b] thiophene) etc., because the step increase, therefore industrial unfavorable.

In addition; other synthetic methods as 3-halogenated methyl-benzo [b] thiophene derivant; following method is arranged; that is, make toluenethiol and the reaction of bromoacetaldehyde condensed ethandiol are made sulfide, use the Tripyrophosphoric acid cyclisation then; after obtaining 5-methyl-benzo [b] thiophene; make hydrogen chloride gas-formaldehyde effect, introduce method (J.Chem.Soc., the C of chloromethyl; 514 (1968)); perhaps benzo [b] thiophene is carried out Knut Fridell Kerafyrm thatch (Friedel-Crafts) reaction, synthetic 3-chloracetyl-benzo [b] thiophene derivant (J.Chem.Soc., Perkin Trans.2 as raw material; 1250; (1973)), after its hydrolysis, reduce; halogenated method etc.But, adopt any method, all introduce halogenated methyl at 2,3, its selectivity may not be high, in addition, adopts any method, and it is all very difficult to separate 3-halogenated methyl-benzothiophene derivative by 2-halogenated methyl-benzothiophene derivative.

By above situation as can be known, press for 4-replacement-3-methylol-benzo [b] thiophene derivant of formula (I) expression, in addition, need its effective and easy synthetic method.

In addition, the effective and easy synthetic method that also needs 3-halogenated methyl-benzo [b] thiophene derivant.

Disclosure of the Invention

The object of the present invention is to provide 3 of employing synthetic method difficulty in the past, 4-two replacement-benzos [b] thiophene derivant, and its preparation method is provided.In addition, the present invention also aims to provide the preparation method of 3-halogenated methyl-benzo [b] thiophene derivant that step is short and purity is high.

The inventor has carried out concentrated research to achieve these goals, found that as the raw material of medicine etc. useful 3,4-two replacement-benzos [b] thiophene derivant has also been found its optionally synthetic method.In addition, also found the efficient synthesis of 3-halogenated methyl-benzo [b] thiophene derivant.

The present invention relates to 3 of formula (I) expression, 4-two replacement-benzos [b] thiophene derivant.

In above-mentioned formula (I), preferred X is a hydroxyl, and, more preferably R ₁Be methyl.

In addition, in above-mentioned formula (I), preferred X is a halogen, and, more preferably R ₁Be methyl, X is a bromine atoms.

In addition, the present invention relates to obtain the method for benzo [b] thiophene derivant of following formula (II) expression, obtain by making the mixture crystallization in solvent that contains benzo [b] thiophene derivant that following formula (II) and following formula (III) represent.

[in the formula, R ₁Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4.]

[in the formula, R ₂Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4.]

Make it the mixed solvent or the acetonitrile of aromatic hydrocarbons of straight chain, ring-type or a chain hydrocarbon and the carbonatoms 6 to 8 of the mixed solvent of carboxylicesters of the straight chain, ring-type of the preferred carbonatoms 5～8 of the above-mentioned solvent of crystalline or a chain hydrocarbon and carbonatoms 2 to 6 or carbonatoms 5～8.

And, the invention still further relates to the preparation method of benzo [b] thiophene derivant that following formula V represents, reacting more than a kind or 2 kinds in the compound by making following formula (IV) expression and the carboxylic acid of carbonatoms 1～4 or carboxylic acid anhydride or trifluoroacetic acid or the trifluoroacetic anhydride obtains.

[in the formula, R ₃Be hydrogen and R ₄Alkyl or the alkoxyl group of carbonatoms 1～4, the perhaps R of expression halogen atom, trihalogenmethyl, carbonatoms 1～4 ₃Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group and the R of carbonatoms 1～4 ₄Expression hydrogen.]

[in the formula, R ₃And R ₄(IV) is identical with above-mentioned formula.R ₅The alkyl or the trifluoromethyl of expression hydrogen atom, carbonatoms 1～3.]

And, the invention still further relates to the preparation method of benzo [b] thiophene derivant or benzo [b] thiophene derivant that above-mentioned formula (III) is represented of above-mentioned formula (II) expression, obtain with the reduction of metal hydride complex compound, alkaline hydrolysis or acidic hydrolysis by the compound that above-mentioned formula V is represented.Reduction is preferably carried out with sodium borohydride.

And, the invention still further relates to the preparation method of 4-replacements-3-methylol-benzo [b] thiophene derivant of above-mentioned formula (II) expression, by to-introduce propargyl in the substituted benzene mercaptan, obtain the compound that following formula (VI) is represented,

[in the formula, R ₆Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4.]

Then,, obtain the compound of following formula (VII) expression with its oxidation,

[in the formula, R ₆Identical with the definition of above-mentioned formula (VI).]

Again it is supplied in hot shift reaction, obtain the compound of above-mentioned formula (IV) expression, make the carboxylic acid of itself and carbonatoms 1～4 or the reaction more than a kind or 2 kinds in carboxylic acid anhydride or trifluoroacetic acid or the trifluoroacetic anhydride, obtain the compound that above-mentioned formula V is represented, change ester group into hydroxyl then, obtain benzo [b] thiophene derivant of above-mentioned formula (II) expression and the mixture of benzo [b] thiophene derivant that above-mentioned formula (III) is represented, this mixture is carried out partial crystallization obtain in solvent.In above-mentioned formula (VI), preferred R ₆Be methyl.

And, the invention still further relates to the preparation method of 4-replacement-3-monochloromethyl-benzo [b] thiophene derivant of following formula (VIII) expression,

[in the formula, R ₁Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4.R ₇The expression halogen atom.]

It is characterized in that, further change the hydroxyl of 4-replacement-3-methylol-benzo [b] thiophene derivant of above-mentioned formula (II) expression into halogen atom.In above-mentioned formula (VIII), preferred R ₁Be methyl.

And, the invention still further relates to the preparation method of 3-monochloromethyl-benzo [b] thiophene derivant compound of following formula (X) expression,

Compound by making following formula (IX) expression obtains with the acid-respons more than the equivalent.

[in the formula, R ₈To R ₁₁Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another.]

[in the formula, R ₈To R ₁₁(IX) is identical with general formula.R ₁₂The expression halogen atom.]

And, the invention still further relates to the method for the compound of preparation formula (X) expression, by in substituted benzene mercaptan, introducing propargyl, obtain the compound of following formula (XI) expression,

[in the formula, R ₁₃And R ₁₅While and R ₁₄Represent the alkyl of halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently, and R ₁₆Expression hydrogen atom, perhaps R ₁₆Expression halogen atom, trihalogenmethyl, cyano group, the alkyl of carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4, and R ₁₃～R ₁₅Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another.]

Oxygenated compound (XI) obtains the compound that following formula (XII) is represented,

[in the formula, R ₁₃To R ₁₆(XI) is identical with above-mentioned formula.]

The compound of formula (XII) expression in hot shift reaction, is obtained the compound of above-mentioned formula (IX) expression, make itself and the above acid-respons of equivalent, obtain the compound that formula (X) is represented.

The R of preferred above-mentioned formula of the present invention (IX) and above-mentioned formula (X) ₈And R ₁₀While and R ₉The alkyl of representing hydrogen atom, carbonatoms 1～4 independently, and R ₁₁Expression hydrogen atom, perhaps R ₁₁The alkyl of expression carbonatoms 1～4, and R ₈～R ₁₀Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another, and the R of above-mentioned formula (XI) and above-mentioned formula (XII) ₁₃And R ₁₅While and R ₁₄The alkyl of representing hydrogen atom or carbonatoms 1～4 independently, and R ₁₆Expression hydrogen atom, perhaps R ₁₆The alkyl of expression carbonatoms 1～4, and R ₁₃～R ₁₅Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another.

In above-mentioned formula of the present invention (X), R in the preferred formula ₁₂Be chlorine atom or bromine atoms.

And, the invention still further relates to method by the benzimidizole derivatives (general formula (XX)) of above-mentioned formula (I) or above-mentioned formula (X) preparation general formula (XX) expression.

[in the formula (XX), R ₂₄And R ₂₄Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, hydroxyl, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, perhaps R independently of one another ₂₃And R ₂₄Expression-O-CH becomes one ₂-O-,-O-CH ₂CH ₂-O-or-CH ₂CH ₂CH ₂-(at this moment, this carbon atom also can be replaced by the alkyl of one or more carbonatomss 1～4.)。

A represents to replace or straight chain, ring-type or the chain alkylidene group or the alkylene group of unsubstituted carbonatoms 1～7, and the centre also can contain one or more-O-,-S-,-SO ₂-,-NR ₂₅-(wherein, R ₂₅The alkyl of expression hydrogen atom or straight or branched carbonatoms 1～6.)。The substituting group that these groups can have is that the alkyl of halogen atom, hydroxyl, nitro, cyano group, straight or branched carbonatoms 1～6, the alkoxyl group of straight or branched carbonatoms 1～6 (comprise that 2 adjacent groups form the situation of acetal bonds.), the acyl amino of the acyl group of the alkyl sulphonyl of the alkylthio of straight or branched carbonatoms 1～6, straight or branched carbonatoms 1～6, straight or branched carbonatoms 1～6, straight or branched carbonatoms 1～6, trihalogenmethyl, three halogen methoxyl groups, phenyl, oxo base or the phenoxy group that can be replaced by 1 above halogen atom.These substituting groups can replace one or more independently of one another in the optional position of alkylidene group or alkylene group.But in the formula (XX), M is a singly-bound, hydroxyl and phenyl simultaneously with the carbon of M bonded A on except the situation about replacing.

E represents-COOR ₂₅,-SO ₃R ₂₅,-CONHR ₂₅ ³,-SO ₂NHR ₂₅, tetrazolium-5-base, 5-oxo-1,2,4-oxadiazole-3-base or 5-oxo-1,2,4-thiadiazoles-3-base (wherein, R ₂₅Represent group same as described above.)。

M represent singly-bound or-S (O) _m-, m is 0～2 integer.

G and J represent above-mentioned formula (I) or above-mentioned formula (X).But G represents the methylene radical of 3 of the thionaphthenes of above-mentioned formula (I) and above-mentioned formula (X), the R of the X of above-mentioned formula (I) and above-mentioned formula (X) ₁₂Replace the nitrogen-atoms to the benzoglyoxaline ring.

X represents-CH=or nitrogen-atoms.]

The working of an invention mode

Exemplify the example of benzothiophene derivative of the present invention and preparation method thereof below, but the present invention is not limited by they.

At first, exemplify 3, the example of 4-two replacement-benzos [b] thiophene derivant and preparation method thereof.

R ₁Preferred trihalogenmethyl, methyl, more preferably methyl.In addition, the preferred hydroxyl of X, bromine atoms, chlorine atom.

As the compound of formula (I), the compound of concrete preferred table 1 record.Particularly preferred compound is the compound of compound number 1,2,3 in the table.

Table 1

Compound N o.	R ₁	X
Compound N o.	R ₁	X	1	Me	OH
2	Me	Cl	1	Me	OH
2	Me	Cl	3	Me	Br
4	CF ₃	OH	3	Me	Br
4	CF ₃	OH	5	CF ₃	Cl
6	CF ₃	Br	5	CF ₃	Cl

(Me represents methyl.)

As the preparation method of formula (I), reacting more than a kind or 2 kinds in the compound by making formula (IV) expression and the carboxylic acid of carbonatoms 1～4 or trifluoroacetic acid or its carboxylic acid anhydride or the trifluoroacetic anhydride prepares the compound that formula V is represented.

[in the formula, R ₃And R ₄Identical with formula (IV) definition.R ₅The alkyl or the trifluoromethyl of expression hydrogen atom, carbonatoms 1～3.]

Among the present invention, as the solvent that uses in the reaction of formula V by formula (IV), for example toluene, tetrahydrofuran (THF), dioxane, isopropyl acetate, n-propyl acetate etc.Preferred toluene, tetrahydrofuran (THF), dioxane.

In addition, as carboxylic acid or acid anhydrides, for example acetate, trifluoroacetic acid, diacetyl oxide, trifluoroacetic anhydride etc.Preferred trifluoroacetic acid, trifluoroacetic anhydride, preferred especially trifluoroacetic anhydride.

Then, the ester group by compound that formula V is represented changes hydroxyl into, obtains containing the mixture of the compound of formula (II) and formula (III) expression.When the ester group of the compound that formula V is represented changes the hydroxyl of compound of formula (II) expression into, by acid hydrolysis, basic hydrolysis or utilize the reduction etc. of metal hydride complex compound to carry out.The preferred bases hydrolysis, utilize the reduction of metal hydride complex compound.As the alkali of basic hydrolysis, preferred lithium hydroxide, sodium hydroxide etc.In addition, as the metal hydride complex compound, preferred lithium aluminum hydride, sodium borohydride etc., preferred sodium borohydride.

Secondly, by making this mixture crystallization in solvent that contains the compound of formula (II) and formula (III) expression, can access the 4-replacement-3-methylol-benzothiophene derivative of formula (II) expression.Making it the crystalline solvent is not particularly limited, can exemplify in the mixed solvent of carboxylicesters of straight chain at carbonatoms 5～8, ring-type or a chain hydrocarbon and carbonatoms 2～6, perhaps the method for partial crystallization in the mixed solvent of the aromatic hydrocarbons of straight chain, ring-type or a chain hydrocarbon and the carbonatoms 6 to 8 of carbonatoms 5～8 or acetonitrile.

As the preferred embodiment of hydrocarbon, can exemplify pentane, hexane, hexanaphthene, heptane, octane.Wherein, preferred especially hexane, hexanaphthene.In addition, these hydrocarbon can use with single solvent, also can use with mixed solvent.As the preferred embodiment of aromatic hydrocarbons, can exemplify benzene,toluene,xylene.Wherein, preferred especially toluene.As the carboxylic acid of carboxylicesters, preferable formic acid, acetate, propionic acid etc.In addition, as the preferred methyl esters of ester, ethyl ester, propyl ester, isopropyl ester etc.The preferred methyl acetate of carboxylicesters, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate, ethyl propionate, special ethyl acetate.

As the solvent combination of preferred partial crystallization condition, can exemplify the method for partial crystallization in hexane-ethyl acetate, hexanaphthene-ethyl acetate, hexane-hexanaphthene-ethyl acetate, hexane-toluene, hexanaphthene-toluene, hexane-hexanaphthene-toluene, hexane-dimethylbenzene, hexanaphthene-dimethylbenzene, hexane-hexanaphthene-dimethylbenzene or acetonitrile.

Condition as partial crystallization, can exemplify in the mixed solvent of carboxylicesters of straight chain at carbonatoms 5～8, ring-type or chain hydrocarbon-carbonatoms 2～6, perhaps in the mixed solvent of the aromatic hydrocarbons of the straight chain of carbonatoms 5～8, ring-type or a chain hydrocarbon and carbonatoms 6 to 8, perhaps reflux in the acetonitrile, the method of partial crystallization is carried out in cooling then, after perhaps being dissolved in the carboxylicesters of the aromatic hydrocarbons of carbonatoms 6～8 or carbonatoms 2～6, the straight chain, ring-type or the chain hydrocarbon that add carbonatoms 5～8, thus in mixed solvent the method for partial crystallization.

As the ratio of mixed solvent, the hydrocarbon of carbonatoms 5～8 for example: carboxylicesters=1: 2～9: 1, the hydrocarbon of preferred carbonatoms 5～8: carboxylicesters=1: 2～5: 1.In addition, the ratio during as the aromatic hydrocarbons that uses carbonatoms 6～8, for example hydrocarbon of carbonatoms 5～8: aromatic hydrocarbons=1: 2～5: 1, the hydrocarbon of preferred carbonatoms 5～8: aromatic hydrocarbons=1: 2～3: 1.As the example of preferred partial crystallization condition, for example hexane: the mixed solvent of ethyl acetate=1: 2～5: 1, hexanaphthene and hexane: ethyl acetate=1: 2～5: 1, hexane: the mixed solvent of toluene=1: 2～3: 1 or hexanaphthene and hexane: toluene=1: 2～3: 1.In addition, as the preferred proportion of hexanaphthene and hexane, for example hexanaphthene: hexane=1: 3～3: 1.

Solvent phase is not particularly limited for the amount of substrate, is 1 times to 10 times amount with respect to substrate weight preferably, 2 times to 5 times amounts of special preferred substrate weight.

As required, the hydroxyl of the compound of formula (II) expression by will obtaining changes halogen atom into, can access the 4-replacement-3-monochloromethyl-benzothiophene derivative of formula (VIII) expression.

As the halomethylation reagent by formula (II) acquisition formula (VIII) of the present invention, can exemplify hydrogen halide, Phosphorates phosphorus Halides, SULPHURYL CHLORIDE, thionyl halide etc., preferred Phosphorates phosphorus Halides, thionyl halide, preferred especially phosphorus tribromide.

Method by compound shown in the synthetic formula of the present invention (II) of commercially available starting compound is as described below.This method can suitably be selected, but following method can be effectively and high purity ground synthesize, thereby preferred.Exemplifying object lesson below describes.

(step 1)

Introduce propargyl in the sulfydryl of this step toluenethiol between formula (XVII) expression, the step of the compound of preparation (VI) expression.

The acetylenic halide propyl group is used in the introducing of propargyl, and for example Bromopropargyl, chloro propargyl etc. carry out in the presence of alkaline matter.As alkaline matter, mineral alkali uses for example salt of wormwood, yellow soda ash etc., and organic bases uses for example triethylamine, pyridine, 4-Dimethylamino pyridine etc.As solvent, for example toluene, acetone, ethyl acetate, tetrahydrofuran (THF), acetonitrile, 2-butanone etc., wherein, as preferred solvent for example toluene, 2-butanone.Be reflected at room temperature to reflux temperature, carry out tens of minutes～a few hours can obtain.

(step 2)

This step is the oxidation by compound, by the step of the compound of formula (VI) preparation formula (VII) expression.The oxidizing reaction of sulphur atom, be used alone or in combination for example oxygenant and appropriate solvent such as Potassium Persulphate, aqueous hydrogen peroxide solution, metaperiodic acid salt, perchloric acid salt, m-chloro M-nitro benzoic acid, for example aromatic hydrocarbons such as toluene, dimethylbenzene, alcohols, acetone, water react.In this step, as preferred examples for example with 1～1.2 normal sodium metaperiodate in the solvent of alcohol-water such as methyl alcohol, ethanol, Virahol, the method for ten minutes～a few hours of stirred for several under room temperature.

(step 3)

This step is the transfer cyclization by sulfoxide, by the step of the compound of formula (VII) preparation formula (IV) expression.

When using sulfoxide among the present invention, as preferred solvent, for example dioxane, propyl acetate, toluene, dimethylbenzene etc., more preferably dioxane, toluene, preferred especially toluene.10 times of the amount preferred substrate weight of solvent more than the amount, more preferably 15 of substrate weight times of amount to 30 times amounts.

More than preferred 60 degree of temperature of reaction, preferred especially 80 degree are to 100 degree.

In this step, the compound of formula (VII) expression also can react, but preferably in advance solvent is heated to this temperature of reaction being dissolved in the solvent post-heating, the drips of solution of the compound of formula (VII) expression is added to the method in the solvent of heating.

To being not particularly limited heat-up time, preferably under this temperature of reaction, dripped post-heating tens of minutes～2 hours, be controlled in 1 hour the heat-up time that especially preferably will drip after substrate finishes.

By making it reaction under these conditions, can extremely control the generation of by product, improve yield.

(step 4)

This step is that the cyclisation body (formula (IV)) that step 3 is obtained reacts the step of the compound that the preparation formula V is represented again with carboxylic acid or carboxylic acid anhydride.

In this step,, the reaction solvent that uses in the step 3 is not concentrated, in this reaction system, add carboxylic acid or carboxylic acid anhydride, thereby carry out the esterification shift reaction for solvent.In addition, even the solvent of enrichment step 3 makes it reaction under other solvents, also can carry out same reaction.As the carboxylic acid of this step, preferred trifluoroacetic acid, as carboxylic acid anhydride, preferred trifluoroacetic anhydride.Carboxylic acid or carboxylic acid anhydride preferably drip 0.5～1.2 equivalent of substrate, preferred especially 0.5～0.8 equivalent in substrate solution.

Temperature of reaction during as carboxylic acid in this step reaction of dropping or carboxylic acid anhydride, is more preferably carried out under 20 ℃ to 30 ℃ by preferred 0 ℃ to 50 ℃.

When the reaction of this step is at room temperature carried out, in several minutes～a few hours, finish.

(step 5)

This step is the hydroxylation of the ester cpds represented by the formula V that step 4 obtains, the step of the compound of preparation formula (II) or formula (III) expression.

As condition, preferred alkaline hydrolysis or utilize the reduction of metal hydride complex compound.Alkali as alkaline hydrolysis is not particularly limited, preferred lithium hydroxide, sodium hydroxide.Solvent for hydrolysis also is not particularly limited, preferred tetrahydrofuran (THF)-aqueous systems.In addition, utilize metal hydride complex compound reductive occasion, as the metal hydride complex compound, for example lithium aluminum hydride, sodium borohydride, cyano group three sodium borohydrides etc., preferred sodium borohydride.0.5～1 equivalent of the amount preferred substrate of the alkali of alkaline hydrolysis or metal hydride complex compound.

Dissolvant of reaction system is not particularly limited, preferred tetrahydrofuran (THF), toluene.

(step 6)

This step is the step by the compound of the mixture separation formula (II) of 6-replacement-3-methylol-benzo [b] thiophene derivant of 4-replacement-3-methylol-benzo [b] thiophene derivant of formula (II) expression and formula (III) expression and formula (III) expression.

Carry out the solvent of partial crystallization as this step, as preferred solvent for example hexane, hexanaphthene-ethyl acetate or hexane-toluene system.As the example of preferred partial crystallization condition, for example hexane: the mixed solvent of ethyl acetate=1: 2～5: 1, hexanaphthene and hexane: ethyl acetate=1: 2～5: 1, hexane: the mixed solvent of toluene=1: 2～3: 1, hexanaphthene and hexane: toluene=1: 2～3: 1 etc.In addition, as the preferred proportion of hexanaphthene and hexane, for example hexanaphthene: hexane=1: 3～3: 1.

Solvent phase is not particularly limited for the amount of substrate, is 1 times of amount to 10 times amount with respect to substrate weight preferably, 2 times of amount to 5 times amounts of special preferred substrate weight.

By this step, can isolate the compound of formula (II) expression by partial crystallization by the mixture of the compound of formula (II) and formula (III) expression.

(step 7)

In addition, the method as by the compound of a compounds accepted way of doing sth (VIII) expression of formula (II) expression is not particularly limited, the method shown in more preferably following.

This step is the step that the hydroxyl of 4-replacement-3-methylol-benzo [b] thiophene derivant is changed into halogen atom.

As the halogenated methylation reagent of halogen exchange, for example halocarbon, Phosphorates phosphorus Halides, SULPHURYL CHLORIDE, thionyl halide etc., preferred Phosphorates phosphorus Halides, thionyl halide, preferred especially phosphorus tribromide.

As solvent, aromatic hydrocarbonss such as hydrocarbon such as hexanaphthene, hexane, benzene,toluene,xylene for example, preferred hexanaphthene, toluene.Reaction can be carried out tens of minutes to a few hours in room temperature to reflux temperature.As required, also can be after reaction with the compound crystal of formula (VIII) expression.As the crystallization solvent, hydrocarbon such as heptane, hexane, hexanaphthene for example, preferred hexanaphthene, heptane.

Below, the synthetic method of 3-halogenated methyl-benzo [b] thiophene derivant is elaborated.

The invention still further relates to the preparation method of the 3-monochloromethyl-benzothiophene derivative of formula (X) expression,

Compound by making formula (IX) expression obtains with the acid-respons more than the equivalent.

[in the formula, R ₈To R ₁₁(IX) is identical with formula.R ₁₂The expression halogen atom.]

R among the present invention ₈To R ₁₁The alkyl of preferred hydrogen atom, carbonatoms 1～4.

In addition, the position of hydrogen atom, alkyl simultaneously or be arbitrarily independently of one another, preferred especially all is hydrogen atom, perhaps R ₈, R ₁₀And R ₁₁Be hydrogen atom and R ₉Be the alkyl of carbonatoms 1～4, perhaps R ₉And R ₁₁Be hydrogen atom and R ₈, R ₁₀Situation for the alkyl of carbonatoms 1～4.

As the compound of formula (X), the compound of record in the concrete preferred table 2.In the table, particularly preferred compound is the compound of compound number 7,8,9.

Table 2

Compound N o.	R ₈	R ₉	R ₁₀	R ₁₁	R ₁₂
Compound N o.	R ₈	R ₉	R ₁₀	R ₁₁	R ₁₂	7	H	H	H	H	Br
8	H	Me	H	H	Br	7	H	H	H	H	Br
8	H	Me	H	H	Br	9	Me	H	Me	H	Br
10	H	H	H	H	Cl	9	Me	H	Me	H	Br
10	H	H	H	H	Cl	11	H	Me	H	H	Cl
12	Me	H	Me	H	Cl	11	H	Me	H	H	Cl

(Me represents methyl.)

Among the present invention, as the acid of using in the reaction by formula (IX) acquisition formula (X), for example hydrogen chloride gas, bromize hydrogen gas, hydrogenchloride-dioxane solution, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI etc., preferred especially hydrogenchloride-dioxane solution, Hydrogen bromide.In addition, Suan amount must be added more than the equivalent of substrate preferred 1.2～3 equivalents, more preferably 1.2～1.5 equivalents.

In addition, as solvent of the present invention, not special qualification the, preferred dioxane, propyl acetate, toluene.As its amount, 5 times that can add substrate weight more than the amount, preferably add 10 times of amount to 20 times amounts.

As temperature of reaction of the present invention, preferred 0 ℃ to 50 ℃, under 0 ℃ to 30 ℃, carry out.

Synthetic method for the compound of formula (IX) expression is not particularly limited the method shown in being preferably as follows.

(step 1)

This step is to introduce propargyl in the sulfydryl of the substituted benzene mercaptan of formula (XVII) expression, the step of the compound of preparation (XI) expression.

The acetylenic halide propyl group is used in the introducing of propargyl, and for example Bromopropargyl, chloro propargyl etc. carry out in the presence of alkaline matter.As alkaline matter, mineral alkali uses for example salt of wormwood, yellow soda ash etc., organic bases uses for example triethylamine, pyridine, 4-Dimethylamino pyridine etc., can be in acetone, ethyl acetate, tetrahydrofuran (THF), acetonitrile, 2-butanone, toluene equal solvent, to reflux temperature, introduce propargyl with a few hours in room temperature.

(step 2)

This step is by the compound oxidation with formula (XI) expression, the step of the compound of preparation formula (XII) expression.In this step, preferably in the solvent system of alcohol-water such as methyl alcohol, ethanol, Virahol, with 1.2 normal sodium metaperiodates stirring method under room temperature.This reaction finishes reaction under these conditions in a few hours.

(step 3)

This step is the transfer cyclization of sulfoxide of the compound of through type (XII) expression, the step of the compound of preparation formula (IX) expression.In the hot shift reaction of this step, with reference to J.C.S.Chem.Comm., 848-849, the method for record in 1974.

When using sulfoxide to react among the present invention, as preferred solvent, for example dioxane, propyl acetate, toluene, dimethylbenzene etc.The amount of solvent is not particularly limited, and 10 times of preferred substrate weight more than the amount, more preferably 15 of substrate weight times of amount to 30 times amounts.By reacting with this quantity of solvent, can extremely suppress the generation of by product, improve yield.Temperature of reaction is not particularly limited, and more than preferred 80 degree, more preferably carries out to the reflux temperature of above-mentioned solvent at 100 degree.

Be reflected at when carrying out under the reflux temperature, can in tens of minutes to a few hours, finish.

(step 4)

This step be formula (IX) expression that step 3 is obtained compound the cyclisation body again with acid-respons, the step of the compound of preparation formula (X) expression.

About the solvent in this step, the reaction solvent that uses in the step 3 is not concentrated, in this reaction system, add acid, thereby carry out the halomethylation shift reaction.In addition, even the solvent of enrichment step 3 makes it reaction under other solvents, also can carry out same reaction.As the acid of this reaction, preferred hydrogen chloride gas, bromize hydrogen gas, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, hydrogenchloride-dioxane solution etc.The temperature of reaction of this reaction is 0 ℃ to 50 ℃, preferably carries out under 0 ℃ to 30 ℃.Be reflected in tens of minutes to a few hours and finish.

Use according to for example method of WO01/53291 record, can be synthesized pharmaceutically useful benzimidizole derivatives by the benzothiophene derivative of the formula (IX) of method for preparing.

3-replacements-benzo [b] thiophene derivant of formula (XIII) or formula (I) expression as intermediate, can be prepared have activity and useful benzimidizole derivatives (general formula (XX)) on pharmacology.

[in the formula (XX), R ₂₃And R ₂₄Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, hydroxyl, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, perhaps R independently of one another ₂₃And R ₂₄Expression-O-CH becomes one ₂-O-,-O-CH ₂CH ₂-O-or-CH ₂CH ₂CH ₂-(at this moment, this carbon atom also can be replaced by the alkyl of one or more carbonatomss 1～4.)。

E represents-COOR ₂₅,-SO ₃R ₂₅,-CONHR ₂₅,-SO ₂NHR ₂₅, tetrazolium-5-base, 5-oxo-1,2,4-oxadiazole-3-base or 5-oxo-1,2,4-thiadiazoles-3-base (wherein, R ₂₅Represent group same as described above.)。

M represent singly-bound or-S (O) _m-, m is 0～2 integer.

G and J represent above-mentioned formula (I) or (X).But G represents the methylene radical of 3 of above-mentioned formula (I) and thionaphthenes (X), the R of the X of above-mentioned formula (I) and above-mentioned formula (X) ₁₂Nitrogen-atoms on the expression benzoglyoxaline ring.

X represents-CH=or nitrogen-atoms.]

In benzimidizole derivatives (XX), E is COOR ₂₅, when M is S, can be prepared by following synthetic method (A) or synthetic method (B).

Synthetic method (A)

[in the formula, Z represents halogen or ammonium salt, R ₂₃, R ₂₄, R ₂₅, A, G, J be identical with above-mentioned definition with X.]

That is to say that the nitro of reductase 12-N-methyl-p-nitroaniline derivative (a1) obtains O-Phenylene Diamine (a2).Make CS ₂With its reaction, make compound (a3) after, make haloester derivative (a4) and its reaction, obtain (a5), make the halo derivatives (a6) and its reaction of above-mentioned formula (VIII) or above-mentioned formula (X) expression again, can access compound (a7).In addition, as required,, can access R by with its hydrolysis ₂₅Benzimidizole derivatives (a8) for hydrogen atom.

The condition of common catalytic reduction reaction is adopted in the reduction of nitro, for example by in the presence of catalyzer such as Pd-C, under acid, neutrality, alkaline condition, makes it to carry out with hydrogen reaction under the temperature of room temperature～100 ℃.In addition, also can adopt under acidic conditions the method for using zinc or tin to handle, under neutrality or alkaline condition, use the method for zinc powder to carry out.

O-phenylene diamine derivatives (a2) and CS ₂Reaction can be undertaken by the method for 19 volume 631-637 pages or leaves (pyridine solution) of J.Org.Chem.1954 for example or J.Med.Chem.1993 36 volume 1175-1187 pages or leaves (ethanolic soln) records.

The reaction of Thiobenzimidazole class (a3) and halogen ester (a4) can be by the condition according to common S-alkylated reaction, for example at NaH, Et ₃N, NaOH, K ₂CO ₃Under the existence in alkali, under 0 ℃～200 ℃ temperature, stir and carry out.

The reaction of Thiobenzimidazole class (a5) and halo derivatives or ammonium salt (a6) can be passed through according to the common N-alkylation or the condition of N-acylation reaction, for example at NaH, Et ₃N, NaOH, K ₂CO ₃, Cs ₂CO ₃Under the existence in alkali, under 0 ℃～200 ℃ temperature, stir and carry out.

As carboxyl-protecting group R ₂₅The reaction of leaving away, the preferred method that adopts acid such as alkali such as using lithium hydroxide or hydrochloric acid, trifluoroacetic acid to be hydrolyzed.

Synthetic method (B)

That is to say that the amino with suitable protecting group L protection 2-N-methyl-p-nitroaniline derivative (a1) obtains (b1).Halo derivatives (a6) reaction that itself and above-mentioned formula (VIII) or above-mentioned formula (X) are represented obtains (b2), by the L deprotection is obtained (b3).The nitro of reduction (b3) obtains O-phenylene diamine derivatives (b4).Make itself and CS ₂Or KSC (=S) OEt reacts, and makes compound (b5), and itself and haloester derivative (a4) are reacted, and can obtain benzimidizole derivatives (a7).In addition, as required, can obtain R by making its reaction that is hydrolyzed ₂₅Benzimidizole derivatives for hydrogen atom.

Also can directly obtain compound (b3) by making not the halo derivatives of guard mode (a6) to 2-N-methyl-p-nitroaniline derivative (a1) reaction.As protecting group L, can exemplify trifluoroacetyl group, ethanoyl, tert-butoxycarbonyl, phenmethyl etc.In addition, O-phenylene diamine derivatives (b4) and CS ₂Reaction, can carry out equally with synthetic method (A), (=S) the reaction of OEt, (organoic synthesis, OS) method of 1963 4 volume 569-570 pages or leaves record is carried out can to pass through for example organic synthesis with KSC.Other reaction can be carried out equally with synthetic method (A).

In benzimidizole derivatives (XX), E is tetrazolium-5-base, when M is S, can be prepared by synthetic method shown below (E).

Synthetic method (E)

[in the formula, R ₂₃, R ₂₄, A, G, J be identical with above-mentioned definition with X.]

Make nitrile compound (e1) and various triazo-compound reactions, change tetrazole compound (e2) into.As triazo-compound, trialkyltin triazo-compound, hydronitric acid or its ammonium salt etc. such as tin trimethyl trinitride for example.When using the organotin triazo-compound, can use the amount of 1～4 times of mole with respect to compound (e1).In addition, when using hydronitric acid or its ammonium salt, can use the amount of sodiumazide and 1～5 times of mole of tertiary amines such as ammonium chloride or triethylamine with respect to compound (e1).Each reaction uses toluene, benzene, DMF equal solvent to carry out by under 0 ℃～200 ℃ temperature.

In benzimidizole derivatives (XX), M is SO or SO ₂The time, can be prepared by following synthetic method (F).

Synthetic method (F)

[in the formula, R ₂₃, R ₂₄, R ₂₅, A, G, J be identical with above-mentioned definition with X.]

That is to say,, can access sulfoxide derivant (f1) and/or sulfone derivatives (f2) by in appropriate solvent, making benzimidazole compound (a7) and peroxide compound reaction.As operable peroxide compound, for example peroxybenzoic acid, metachloroperbenzoic acid, peracetic acid, hydrogen peroxide etc. are as the solvent that uses, for example chloroform, methylene dichloride etc.As the usage ratio of compound (a7) with peroxide compound, be not particularly limited, can in the scope of broad, suitably select the amount of 1.2 times of mole～5 times moles of general preferred use.Each reaction is carried out under the preferred 0 ℃～room temperature usually at 0～50 ℃, generally finishes in 4～20 hours.

In benzimidizole derivatives (XX), when M is singly-bound, can be prepared by following synthetic method (G).

Synthetic method (G)

[in the formula, X, A, G, J and R ₂₅Identical with above-mentioned definition.]

That is to say, make diamine compound (b4) and known chloride derivative (g1) reaction, can access benzimidizole derivatives (g2).In addition, as required, by with (g2)-COOR ₂₅Hydrolysis can access R ₂₅Benzimidizole derivatives (g3) for hydrogen atom.

In addition, cyclization is documented in the J.Med.Chem.1993 36 volume 1175-1187 pages or leaves.

Embodiment

Further specify the present invention by following embodiment.But following embodiment not delimit the scope of the invention.

Synthesizing of embodiment 1 3-methyl isophthalic acid-Propargyl sulphur benzene (general formula (VI))

On 5L 3 neck flasks, prolong, internal thermometer, mechanical stirrer, dropping funnel are installed.Salt of wormwood 673g and methylethylketone 1500mL pack in flask.Pack in dropping funnel a toluenethiol 500g and methylethylketone 200mL dripped with 10 minutes.Directly at room temperature stirred 1 hour.Internal temperature is risen to 28 degree.Apply water-bath, pack in dropping funnel propargyl bromide 333mL and methylethylketone 300mL begin to drip.Drip by control, internal temperature is remained near 55～65 degree, dripped with 20 minutes simultaneously.Keep this state under water-bath, to stir 50 minutes.Directly wash, filter with B simultaneously, carry out concentrating under reduced pressure, add ethyl acetate 1500mL and water 2L, add 1N HCl 100mL again, separate organic layer and water layer, the ethyl acetate extraction of usefulness 500mL 2 times with ethyl acetate 900mL.With saturated aqueous common salt 1000mL washing 2 times, use anhydrous magnesium sulfate drying.After the filtration, concentrate, obtain crude product 601.14g (yield 92%, purity 88%).Only crude product 300g is distilled.Under 100～102 ℃/7mmHg, obtain 3-methyl isophthalic acid-Propargyl sulphur benzene 239.68g (rate of recovery 80%, purity＞98%).

¹H-NMR(270MHz，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)

Synthesizing of embodiment 2 3-methyl isophthalic acid-Propargyl sulfinyl benzene (general formula (VII))

On 10L 3 neck flasks, internal thermometer, mechanical stirrer, 1L dropping funnel are installed.Sodium periodate 427.78g and water 2000mL and methyl alcohol 2000mL pack in flask.Directly at room temperature stirred 1 hour, but, therefore add the water of 2000mL again owing to do not dissolve fully.After confirming that sodium periodate dissolves fully, the 3-methyl isophthalic acid of packing in dropping funnel-Propargyl sulphur benzene (300.01g) and methyl alcohol (1000mL) with dropping in 30 minutes, at room temperature stir.After 2 hours, after 1 hour, filter with B with the ice bath cooling.With ethyl acetate 2L thorough washing filtrate, concentrating under reduced pressure.By the water layer of 4L, with ethyl acetate 1000mL extraction 3 times.Behind saturated aqueous common salt 1000mL washing organic layer 2 times, use anhydrous magnesium sulfate drying, after the filtration, concentrate, thereby obtain the oily matter 314.45g of 3-methyl isophthalic acid-Propargyl sulfinyl benzene.This crude product is made the methanol solution of 3000mL, with the hexane extraction of 3000mL 2 times, is 98% the above object product 3-methyl isophthalic acid-Propargyl sulfinyl benzene (yield 79%, receipts amount 248.42g) thereby obtain purity.

¹H-NMR(400MHz，CDCl ₃，ppm)2.27(s，1H，CH)，2.37(s，3H，Me)，3.56(abq，2H，-CH ₂-)，7.27(dt，1H，Ar)，7.34(t，1H，Ar)，7.41(dt，1H，Ar)，7.47(dt，1H，Ar)

Embodiment 3 (4-methyl benzo [b] thiene-3-yl-) methyl 2,2,2-trifluoro-acetate and (6-methyl benzo [b] thiene-3-yl-) methyl 2,2, the mixture of 2-trifluoro-acetate (logical formula V) synthetic

On 10L 3 neck flasks, internal thermometer, mechanical stirrer, 1000mL dropping funnel are installed.The toluene 3000mL that packs in flask applies the oil baths of bathing temperature 95 degree.After confirming that internal temperature is 85 degree, be dissolved in 3-methyl isophthalic acid-Propargyl sulfinyl benzene (251.25g) in the 700mL toluene with dropping in 15 minutes.Drip when finishing,, drip toluene 500mL for internal temperature being remained between 85～95 degree.After the dropping raw material has finished 40 minutes, be cooled to 20 with 1 hour and spend.Reaction vessel is placed ice bath, the trifluoroacetic anhydride of in dropping funnel, packing into (120mL).Under the condition of ice bath, dripped with 20 minutes.Directly at room temperature stirred 30 minutes.This reaction soln is injected the 4L saturated sodium bicarbonate aqueous solution lentamente.Separate organic layer and water layer, 500mL extracts with toluene.Wash organic layer 2 times with saturated aqueous common salt 1500mL.Behind the anhydrous magnesium sulfate drying organic layer, filter, concentrate, obtain orange buttery (4-methyl benzo [b] thiene-3-yl-) methyl 2,2,2-trifluoro-acetate and (6-methyl benzo [b] thiene-3-yl-) methyl 2,2, the mixture of 2-trifluoro-acetate (356.72g).

¹H-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)

The mixture of embodiment 4 by synthetic (4-methyl benzo [b] thiene-3-yl-) methane-1-pure and mild (6-methyl benzo [b] thiene-3-yl-) methane-1-alcohol of hydrolysis reaction (general formula (II) and (III))

Stirring rod and 100mL dropping funnel and internal thermometer are installed on 300mL 3 neck flasks.(4-methyl benzo [b] thiene-3-yl-) methyl 2 that will obtain by the reaction of embodiment 3,2,2-trifluoro-acetate and (6-methyl benzo [b] thiene-3-yl-) methyl 2,2, the mixture 30.05g of 2-trifluoro-acetate is dissolved among the tetrahydrofuran (THF) 100mL, the flask of packing into.Directly be cooled to 20 ℃ of internal temperatures.The 1N aqueous sodium hydroxide solution (100mL) of in dropping funnel, packing into.Drip with 10 minutes, keep this state directly at room temperature to stir 60 minutes.This reaction soln is packed in the 500mL separating funnel, add hexane 300mL again.Directly separate organic layer and water layer, water 500mL washing organic layer 3 times is again with saturated aqueous common salt 500mL washing 2 times.Behind the anhydrous magnesium sulfate drying organic layer, filter, concentrate, obtain the mixture (28.24g) of brown buttery (4-methyl benzo [b] thiene-3-yl-) methane-1-pure and mild (6-methyl benzo [b] thiene-3-yl-) methane-1-alcohol.

Refining-1 of embodiment 5 (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (general formula (II))

Add ethyl acetate 20mL in the brown oil that in embodiment 4, obtains, stirred 10 minutes.Divide 3 times then and add hexane 100mL.After stirring 2 hours under this state, to filter, drying obtains greenish orange look crystalline (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol 8.33g (yield 27.8%).Purity is 98%.

¹H-NMR(400MHz，CDCl ₃，ppm)2.82(s，3H，4-Me)，5.00(s，2H，-CH 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)

¹³C-NMR(100MHz，CDCl ₃，ppm)20.8(4-Me)，61.4(-CH 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)

Embodiment 6 is by the mixture of synthetic (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (general formula (II)) of reduction reaction and (6-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (general formula (III))

On the 3 neck flasks of 3000mL, settle mechanical stirrer and 200mL dropping funnel and internal thermometer.(4-methyl benzo [b] thiene-3-yl-) methyl 2 that will obtain by the reaction of embodiment 3,2,2-trifluoro-acetate and (6-methyl benzo [b] thiene-3-yl-) methyl 2,2, the mixture of 2-trifluoro-acetate (300.00g) is dissolved among the toluene 1500mL, the solution that obtains is packed in the flask, flask is applied water-bath.In flask, drop into sodium borohydride 30.00g.The methyl alcohol (150mL) of in dropping funnel, packing into.Drip with 60 minutes, under this state in stirring at room 60 minutes.In flask, add entry (1000mL), carry out diatomite filtration.Separate organic layer and water layer, with toluene 500mL aqueous layer extracted.Wash organic layer 2 times with saturated aqueous common salt 1000mL.Behind the anhydrous magnesium sulfate drying organic layer, filter, concentrate, obtain the mixture (295.12g) of (4-methyl benzo [b] thiene-3-yl-) methane-1-pure and mild (6-methyl benzo [b] thiene-3-yl-) methane-1-alcohol of yellow oily.

¹H-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)

Refining-2 of embodiment 7 (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (general formula (II))

In the yellow oil that embodiment 6 obtains, add ethyl acetate 100mL, stirred 10 minutes.Divide 4 times then and add hexane 400mL.After stirring 2 hours under this state, to filter, drying obtains white to light yellow crystal (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol 80.05g (yield 27%).Purity is more than 98%.

¹H-NMR(400MHz，CDCl ₃，ppm)2.77(s，3H，4-Me)，4.99(d，2H，-CH 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)

Embodiment 8 (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (general formula I I)) refining-3

In the mixture 4.95g of (4-methyl benzo [b] thiene-3-yl-) pure and mild (6-methyl benzo [b] thiene-3-yl-) methane-1-alcohol of methane-1-(ratio of 4 methyl bodies/6 methyl bodies=about 6/1), add acetonitrile 25mL, reflux, be cooled to room temperature then, but spend the night in refrigerator and cooled again.Filter then, with acetonitrile washing, drying, the white that obtains 3.15g is to light yellow crystal (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (rate of recovery=64%).Purity=99%

¹H-NMR(400MHz，CDCl ₃，ppm)：

2.82(s，3H，4-Me)，5.00(s，2H，-CH 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)

¹³C-NMR(100MHz，CDCl ₃，ppm)：

20.8(4-Me)，61.4(-CH 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)

Embodiment 9 4-methyl benzo [b] thiene-3-yl-s) refining-4 of methane-1-alcohol (general formula (II))

In the mixture 26g of (4-methyl benzo [b] thiene-3-yl-) pure and mild (6-methyl benzo [b] thiene-3-yl-) methane-1-alcohol of methane-1-(ratio of 4 methyl bodies/6 methyl bodies=about 4/3), add toluene 26mL, reflux, be cooled to room temperature then, add hexane 26mL, at room temperature stir again and spend the night.Filter then, dry then with toluene-hexane (1/1) 20mL, hexane 10mL washing crystal, obtain 7.3g white to light yellow crystal (4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (rate of recovery=28%).Purity=99%.

¹H-NMR(200MHz，CDCl ₃，ppm)：

2.79(s，3H，4-Me)，5.01(d，2H，-CH 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)

Synthesizing of embodiment 10 3-(brooethyl)-4-methyl benzo [b] thiophene (general formula (VIII))

Magnetic stirrer and 100mL dropping funnel and internal thermometer are installed on 1L3 neck flask.(4-methyl benzo [b] thiene-3-yl-) methane-1-alcohol (69.95g) is dissolved among the hexanaphthene 200mL flask of packing into.The phosphorus tribromide (18mL) of in dropping funnel, packing into.Dripped (internal temperature rises to 30 degree) with 20 minutes under the room temperature, at room temperature stirred 60 minutes, under 60 degree, stirred 1 hour.Solution is added in the frozen water (1L), separates organic layer and water layer, with toluene 1L aqueous layer extracted.Wash organic layer 2 times with saturated sodium bicarbonate aqueous solution (1L), use saturated aqueous common salt (1L) washing organic layer 2 times again.Behind the anhydrous magnesium sulfate drying organic layer, filter, concentrate, obtain faint yellow solid (99.69g).The crude product that obtains is carried out recrystallization with hot hexanaphthene 200mL, obtain 3-(brooethyl)-4-methyl benzo [b] thiophene (52.19g, yield 55%) of white solid.

¹H-NMR(400MHz，CDCl ₃，ppm)2.90(s，3H，4-Me)，4.89(s，2H，-CH ₂-Br)，7.15(d，1H，J _5，6＝8Hz，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)

Synthesizing of embodiment 11 4-methyl isophthalic acids-(Propargyl sulfinyl) benzene (general formula X II)

Add 2-butanone 200ml, salt of wormwood 53.4g (386mmol) in to toluenethiol 40g (332mmol), with ice-cooled, add 1-bromo-propine 26.7ml (354mmol), the water reactor vessel cooled stirred 2 hours simultaneously.After 2 hours, the filtering reaction system, with 2-butanone 50ml washing precipitate, concentrating under reduced pressure filtrate obtains yellow transparent buttery 4-methyl isophthalic acid-Propargyl sulphur benzene (general formula (XI)) 49.9g.(thick yield: 96%)

¹H-NMR(270MHz，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)

Then, in water 250ml, add sodium periodate 68.7g (321mmol), make it dissolving, drip the methanol solution (250ml) of 4-methyl isophthalic acid-Propargyl sulphur benzene (general formula (XI)) 49.6g (306mmol), stirred 2.5 hours under the room temperature.2.5 after hour; filter; with ethyl acetate 100ml washing solid; concentrating under reduced pressure filtrate adds entry 200ml, with ethyl acetate (150ml) extraction 3 times; the organic layer that water 150ml washing obtains; use dried over mgso, concentrating under reduced pressure obtains 4-methyl isophthalic acid-(Propargyl sulfinyl) benzene 50.6g.(thick yield 93%)

¹H-NMR(270MHz，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)

Synthesizing of embodiment 12 (Propargyl sulfinyl) benzene (general formula X II)

(55.34g 502.3mmol) is dissolved among the acetonitrile 150ml, and (2.07g 15.0mmol), applies water-bath, with 30 minutes dropping propargyl bromide 49.2ml (652.9mmol), adds acetonitrile 100ml again to add salt of wormwood with thiophenol.Then, at room temperature stirred 1 hour 20 minutes, append propargyl bromide (3ml) after 1 hour 35 minutes, restir 15 minutes.Then, filter, concentrating under reduced pressure, drying under reduced pressure obtains the oily matter of 71.50g.70.50g (0.476mol) oily matter wherein is dissolved among the methyl alcohol 500ml, and (108.3g among aqueous solution 500ml 0.506mol), stirs under the room temperature to be added to sodium periodate.After 1 hour, filter, concentrating under reduced pressure separates lower floor, with ethyl acetate extraction water layer (250ml * 3), and with dry organic layer of saltcake and above-mentioned lower floor, concentrating under reduced pressure, drying has been synthesized (Propargyl sulfinyl) benzene 77.8g.Thick yield=96%.

¹H-NMR(270MHz，CDCl ₃)δ(ppm)：7.53-7.74(5H，m，Ar)，3.65(2H，ddd，CH ₂)，2.35(1H，t，CH)

Embodiment 13 3,5-dimethyl-1-(Propargyl sulfinyl) benzene (general formula (XII)) synthetic

With 3,5-dimethyl benzene mercaptan 5.56g (40.2mmol) is dissolved among the acetonitrile 20ml, adds propargyl bromide 3.63ml (48.3mmol), salt of wormwood 6.91g (50mmol) successively.Reflux then, filter after 1 hour, concentrating under reduced pressure, drying under reduced pressure obtains the oily matter of 7.79g.It is dissolved among the methyl alcohol 70ml, and (9.19g, aqueous solution 40ml 43mmol) append methyl alcohol 30ml, water 20ml again, stir under the room temperature to drip sodium periodate.1.5 filter after hour, use the methanol wash post precipitation, concentrating under reduced pressure, with ethyl acetate extraction water layer (100ml * 2), with the dry organic layer of saltcake, concentrating under reduced pressure, drying has synthesized 3,5-dimethyl-1-(Propargyl sulfinyl) benzene 7.66g.Thick yield is 99%.

¹H-NMR(270MHz，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)

Synthesizing of embodiment 14 5-methyl-3-methylene radical-2-hydrogen benzo [b] thiophene-2-alcohol (general formula (IX))

The compound 107.0mg (0.6mmol) that obtains among the embodiment 11 is dissolved among the propyl acetate 1.6ml, refluxed 20 minutes.Then, concentrating under reduced pressure makes it dry, obtains 5-methyl-3-methylene radical-2-hydrogen benzo [b] thiophene-2-alcohol 108.5mg.Thick yield is 105%.

¹H-NMR(400MHz，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)

Synthesizing of embodiment 15 3-methylene radical-2-hydrogen benzo [b] thiophene-2-alcohol (general formula (IX))

The compound 301mg that obtains among the embodiment 12 is dissolved among the dioxane 4.5ml, and heating is 2 hours under 100 degree.After the cooling, concentrating under reduced pressure has synthesized yellow transparent buttery 3-methylene radical-2-hydrogen benzo [b] thiophene-2-alcohol 292mg.

¹H-NMR(270MHz，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)

Embodiment 16 4,6-dimethyl-3-methylene radical-2-hydrogen benzo [b] thiophene-2-alcohol (general formula (IX)) synthetic

The compound 117.6mg (0.61mmol) that obtains among the embodiment 13 is dissolved among the propyl acetate 2ml, refluxed 20 minutes, after the cooling, concentrating under reduced pressure, drying has synthesized 2,3-dihalo--4,6-dimethyl-3-methylene radical-benzo [b] thiophene-2-alcohol.Thick yield is 95%.

¹H-NMR(400MHz，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)

Synthesizing of embodiment 17 3-(brooethyl)-5-methyl benzo [b] thiophene (general formula (X))

The compound 71.9mg (0.40mmol) that obtains among the embodiment 14 is dissolved among the propyl acetate 1ml, adds 48% Hydrogen bromide 0.0569ml (0.5mmol), placed 20 minutes under the room temperature.Then, add ethyl acetate 3ml, wash with water, use the dried over mgso organic layer, filtration under diminished pressure, drying obtains 3-(brooethyl)-5-methyl benzo [b] thiophene 88.2mg.Yield is 91%.

¹H-NMR(270MHz，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)

Synthesizing of embodiment 18 3-(chloromethyl)-benzo [b] thiophene (general formula (X))

The compound 270mg (1.64mmol) that obtains among the embodiment 15 is dissolved among the propyl acetate 4ml, adds 4M hydrogenchloride dioxane solution 0.0615ml (2.46mmol), placed 30 minutes under the room temperature.Concentrate then, add entry 10ml, use ethyl acetate extraction, use the dried over mgso organic layer, filtration under diminished pressure, drying obtains 3-(chloromethyl)-benzo [b] thiophene 271mg.Yield is 90%.

¹H-NMR(270MHz，CDCl ₃)δ(ppm)：7.88-7.90(2H，m，Ar)，7.30-7.50(3H，m，Ar)，4.86(2H，s，CH ₂)

Embodiment 19 3-(brooethyl)-4,6-dimethylbiphenyl [b] thiophene (general formula (X)) synthetic

The compound 55.3mg that obtains among the embodiment 16 is dissolved among the propyl acetate 1ml, adds 48% Hydrogen bromide, 39.9 μ l, place under the room temperature.Add ethyl acetate 3ml after 20 minutes, wash with water, use dried over mgso, concentrating under reduced pressure, drying has been synthesized 3-(brooethyl)-4,6-dimethylbiphenyl [b] thiophene.Yield is 90%.

¹H-NMR(270MHz，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)

Synthesizing of embodiment 20 3-(chloromethyl)-5-methyl benzo [b] thiophene (general formula (X))

The compound 873.4mg (4.9mmol) that obtains among the embodiment 11 is dissolved among the dioxane 15ml 100 ℃ of following heated and stirred 70 minutes.Reaction system is cooled to room temperature, adds 4M hydrogenchloride-dioxane 1.5ml (6mmol), stirred 1 hour under the room temperature.The concentrating under reduced pressure reaction system adds hexanaphthene 0.80ml, and 70 ℃ of heating 10 minutes down are cooled to room temperature, and filtering precipitate obtains 3-(chloromethyl)-5-methyl benzo [b] thiophene of 590.6mg.Yield is 61%.

Calculated value M=196.70, analytical value m/z=196[M+]

Synthesizing of embodiment 21 3-(brooethyl)-5-methyl benzo [b] thiophene (general formula (X))

The compound 7.18g (40.3mmol) that obtains among the embodiment 11 is dissolved among the dioxane 110ml, refluxed 100 minutes down at 100 ℃.Cooling adds 48% Hydrogen bromide 7.42g (44mmol) then, places 1 hour under the room temperature.Then, add entry, use ethyl acetate extraction, use dried over mgso, concentrating under reduced pressure obtains 3-(brooethyl)-5-methyl benzo [b] thiophene of 9.04g.Yield is 93%.

Calculated value M=241.10, analytical value m/z=241[M+]

Synthesizing of embodiment 22 3-(brooethyl)-5-methyl benzo [b] thiophene (general formula (X))

(29.7g 167mmol) is dissolved among the propyl acetate 445ml, and heating is 1 hour under 100 degree with the compound that obtains among the embodiment 11.Then, with ice-cooled, internal temperature is adjusted to 10 degree after, add 48% Hydrogen bromide 22.8ml, under ice-cold condition, placed 1 hour 30 minutes.Isolate water layer, the dried over mgso organic layer is used in water 50ml washing, concentrating under reduced pressure, and drying has been synthesized dark brown transparent buttery 3-(brooethyl)-5-methyl benzo [b] thiophene 35.3g.(yield=88%)

¹H-NMR(270MHz，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)

Synthesizing of embodiment 23 3-(chloromethyl)-benzo [b] thiophene (general formula (X))

The compound 5.02g (30.6mmol) that obtains among the embodiment 12 is dissolved in 1, among the 4-dioxane 50ml, is heated to 100 degree, 5 hours 30 minutes postcooling are adjusted to 10 degree with the reaction system internal temperature.Then, add 4M hydrogenchloride-dioxane solution 8.42ml (33.7mmol), be placed to room temperature.After 15 minutes, concentration of reaction solution makes it to be dissolved among the ethyl acetate 50ml, and the dried over mgso organic layer is used in water 40ml washing.After concentrating, in order to remove dioxane, make it once more to be dissolved among the ethyl acetate 50ml, the dried over mgso organic layer is used in water 40ml washing 3 times, and concentrating under reduced pressure obtains 3-(chloromethyl)-benzo [b] thiophene 5.18g.Yield is 93%.

¹H-NMR(270MHz，CDCl ₃)δ(ppm)：7.91-7.85(2H，m，Ar)，7.36-7.48(3H，m，Ar)，4.85(2H，t，CH ₂)

Embodiment 24 3-(brooethyl)-4,6-dimethylbiphenyl [b] thiophene (general formula (X)) synthetic

The compound 2.26g (11.7mmol) that obtains among the embodiment 13 is dissolved among the propyl acetate 40ml, refluxed 30 minutes.Cooling adds 48% Hydrogen bromide 1.59ml (14mmol) then, places 30 minutes under the room temperature.Then, add ethyl acetate, wash with water, use dried over mgso, concentrating under reduced pressure obtains the 3-(brooethyl)-4 of 2.49g, 6-dimethylbiphenyl [b] thiophene.Yield is 84%.

¹H-NMR(270MHz，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

According to J.Chem.Soc., Chem.Comm., 848 (1974), following carrying out under the condition of report.

3-methyl-phenyl-propargyl-sulfoxide 218.4mg is dissolved among the dioxane 3ml (15 times of amounts), refluxed 2 hours 30 minutes.Then, add entry 1ml, tosic acid monohydrate 21.7mg, heating is 2 hours under 70 degree.Confirmed to have the spot of principal product in this stage with TLC (hexane-ethyl acetate=5: 1), the spot of by product has been arranged at Rf=0.41,0.55,0.70,0.83 at Rf=0.23.Behind the concentrating under reduced pressure, add entry, use ethyl acetate extraction, use the dried over mgso organic layer, concentrating under reduced pressure obtains the residue of 280.1mg.It (is used 2 Merck system 1.13794 PLC plates 20 * 20cm kisei gel 60 0.5mm, the expansion system: hexane-ethyl acetate=5: 1) make with extra care, reclaim the fraction of principal product, obtain the brown oil of 131.5mg with thin-layer chromatography.By this fraction ¹H-NMR and 2 dimension the NMR ratio of 3-hydroxy-4-methyl-benzo [b] thiophene and 3-hydroxyl-6-methyl-benzo [b] thiophene as can be known are about 3: 2.In addition,, also have only partly solidifiedly, can not separate 3-hydroxy-4-methyl-benzo [b] thiophene even this fraction is placed.

¹H-NMR(270MHz，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.)

Industrial applicibility

According to the present invention, can be provided as the useful 4-replacement-3-methylol-benzothiophene derivative of pharmaceutical raw material. In addition, synthetic method of the present invention can optionally and with high yield be prepared, so its industrial value is very large. And can and synthesize easily 3-halomethyl-benzothiophene derivative by substituted benzene mercaptan step weak point, industrial also good.

Claims

1. the preparation method of the benzimidizole derivatives of a general formula (XX) expression, it comprises preparation method (1) and (2),

In the formula (XX), R ₂₃And R ₂₄Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, hydroxyl, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, perhaps R independently of one another ₂₃And R ₂₄Expression-O-CH becomes one ₂-O-,-O-CH ₂CH ₂-O-or-CH ₂CH ₂CH ₂-, at this moment, this carbon atom also can be replaced by the alkyl of one or more carbonatomss 1～4,

A represents to replace or straight chain, ring-type or the chain alkylidene group or the alkylene group of unsubstituted carbonatoms 1～7, and the centre also can contain one or more-O-,-S-,-SO ₂-,-NR ₂₅-, wherein, R ₂₅The alkyl of expression hydrogen atom or straight or branched carbonatoms 1～6; the substituting group that these groups can have is a halogen atom; hydroxyl; nitro; cyano group; the alkyl of straight or branched carbonatoms 1～6; the alkoxyl group of straight or branched carbonatoms 1～6 (comprising that 2 adjacent groups form the situation of acetal bonds); the alkylthio of straight or branched carbonatoms 1～6; the alkyl sulphonyl of straight or branched carbonatoms 1～6; the acyl group of straight or branched carbonatoms 1～6; the acyl amino of straight or branched carbonatoms 1～6; trihalogenmethyl; three halogen methoxyl groups; phenyl; oxo base or the phenoxy group that can be replaced by the halogen atom more than 1; these substituting groups can replace one or more independently of one another in the optional position of alkylidene group or alkylene group; but; in the formula (XX); M is a singly-bound; hydroxyl and phenyl simultaneously with the carbon of M bonded A on except the situation about replacing

E represents-COOR ₂₅,-SO ₃R ₂₅,-CONHR ₂₅,-SO ₂NHR ₂₅, tetrazolium-5-base, 5-oxo-1,2,4-oxadiazole-3-base or 5-oxo-1,2,4-thiadiazoles-3-base, wherein, R ₂₅Represent group same as described above,

M represent singly-bound or-S (O) _m-, m is 0～2 integer,

G and J represent following formula (I) or following formula (X), and still, G represents the methylene radical of 3 of the thionaphthenes of following formula (I) or following formula (X), the R of the X of following formula (I) or following formula (X) ₁₂Replace the nitrogen-atoms to the benzoglyoxaline ring,

X represents-CH=or nitrogen-atoms,

Preparation method (1):

Obtain benzo [b] thiophene derivant that following formula (II) is represented by the mixture crystallization in solvent that makes benzo [b] thiophene derivant that contains following formula (II) and following formula (III) expression,

In the formula, R ₁Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4,

In the formula, R ₂Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4,

Above-mentioned solvent is the mixed solvent or the acetonitrile of aromatic hydrocarbons of straight chain, ring-type or a chain hydrocarbon and the carbonatoms 6 to 8 of the mixed solvent of carboxylicesters of the straight chain, ring-type of carbonatoms 5～8 or a chain hydrocarbon and carbonatoms 2 to 6 or carbonatoms 5～8, then

Change halogen atom into by hydroxyl and obtain 4-replacement-3-monochloromethyl-benzo [b] thiophene derivant that following formula (VIII) is represented 4-replacements-3-methylol-benzo [b] thiophene derivant of above-mentioned formula (II) expression,

In the formula, R ₁Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4, R ₇The expression halogen atom,

Perhaps

Obtain 3-monochloromethyl-benzo [b] thiophene derivant that following formula (X) is represented by compound and the acid-respons more than the equivalent that makes following formula (IX) expression,

In the formula, R ₈To R ₁₁Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another

In the formula, R ₈To R ₁₁Identical with the definition in the general formula (IX), R ₁₂The expression halogen atom, preparation method (2):

By (VIII) or (X) preparation (XX).

2. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 1 (XX) expression, wherein, benzo [b] thiophene derivant of benzo [b] thiophene derivant of formula (II) expression or formula (III) expression is to prepare with the reduction of metal hydride complex compound, alkaline hydrolysis or acidic hydrolysis by the compound that benzo [b] thiophene derivant that following formula V is represented is represented

In the formula, R ₃Be hydrogen atom and R ₄Alkyl or the alkoxyl group of carbonatoms 1～4, the perhaps R of expression halogen atom, trihalogenmethyl, carbonatoms 1～4 ₃Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group and the R of carbonatoms 1～4 ₄Expression hydrogen, R ₅The alkyl or the trifluoromethyl of expression hydrogen atom, carbonatoms 1～3.

3. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 2 (XX) expression, wherein, benzo [b] thiophene derivant of formula (II) or formula (III) expression is to prepare with sodium borohydride reduction by the compound that above-mentioned formula V is represented.

4. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 1 (XX) expression, its Chinese style (II) prepares by following method: the compound by making following formula (IV) expression and the carboxylic acid or the carboxylic acid anhydride of carbonatoms 1～4, perhaps reacting more than a kind or 2 kinds in trifluoroacetic acid or the trifluoroacetic anhydride, after obtaining compound that benzo [b] thiophene derivant that following formula V represents represents, change the ester group of formula V into hydroxyl, obtain benzo [b] thiophene derivant of above-mentioned formula (II) expression and the mixture of benzo [b] thiophene derivant that above-mentioned formula (III) is represented, the crystallization in solvent of this mixture is obtained

In the formula, R ₃Be hydrogen atom and R ₄Alkyl or the alkoxyl group of carbonatoms 1～4, the perhaps R of expression halogen atom, trihalogenmethyl, carbonatoms 1～4 ₃Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group and the R of carbonatoms 1～4 ₄Expression hydrogen,

In the formula, R ₃And R ₄(IV) is identical with above-mentioned formula, R ₅The alkyl or the trifluoromethyl of expression hydrogen atom, carbonatoms 1～3.

5. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 4 (XX) expression, in above-mentioned formula V, R ₅Be trifluoromethyl.

6. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 1 (XX) expression, its Chinese style (II) prepare by following method: by to-introduce propargyl in the substituted benzene mercaptan, obtain the compound that following formula (VI) is represented,

In the formula, R ₆Expression halogen atom, trihalogenmethyl, the alkyl of carbonatoms 1～4 or the alkoxyl group of carbonatoms 1～4,

In the formula, R ₆It is identical with the definition of above-mentioned formula (VI),

Again it is supplied in hot transfer reaction; Obtain the compound of above-mentioned formula (IV) expression; Make itself and the carboxylic acid of carbon number 1～4 or the one kind or two or more reaction in carboxylic acid anhydrides or trifluoroacetic acid or the TFAA; Obtain the compound of above-mentioned formula (V) expression; Then the ester group with formula (V) changes hydroxyl into; Obtain benzo [b] thiophene derivant of above-mentioned formula (II) expression and the mixture of benzo [b] thiophene derivant that above-mentioned formula (III) represents; This mixture is carried out crystallization and obtain in solvent

Above-mentioned solvent is the mixed solvent or the acetonitrile of aromatic hydrocarbons of straight chain, ring-type or a chain hydrocarbon and the carbonatoms 6 to 8 of the mixed solvent of carboxylicesters of the straight chain, ring-type of carbonatoms 5～8 or a chain hydrocarbon and carbonatoms 2 to 6 or carbonatoms 5～8.

7. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 6 (XX) expression, in above-mentioned formula (VI), R ₆Be methyl.

8. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 1 (XX) expression, in above-mentioned formula (VIII), R ₁Be methyl.

9. the preparation method of the benzimidizole derivatives of general formula as claimed in claim 1 (XX) expression, wherein, the compound of above-mentioned formula (X) expression obtains by following method:

By in substituted benzene mercaptan, introducing propargyl, obtain the compound of following formula (XI) expression,

In the formula, R ₁₃And R ₁₅While and R ₁₄Represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently, and R ₁₆Expression hydrogen atom, perhaps R ₁₆Expression halogen atom, trihalogenmethyl, cyano group, the alkyl of carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4, and R ₁₃～R ₁₅Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another

In the formula, R ₁₃To R ₁₆(XI) is identical with above-mentioned formula, and the compound of above-mentioned formula (XII) expression in hot shift reaction, is obtained the compound of above-mentioned formula (IX) expression, makes itself and acid-respons more than the equivalent.

10. as claim 1 or 9 described preparation methods, the R of above-mentioned formula (IX) and above-mentioned formula (X) ₈And R ₁₀While and R ₉The alkyl of representing hydrogen atom or carbonatoms 1～4 independently, and R ₁₁Expression hydrogen atom, perhaps R ₁₁The alkyl of expression carbonatoms 1～4, and R ₈～R ₁₀Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another, and the R of above-mentioned formula (XI) and above-mentioned formula (XII) ₁₃And R ₁₅While and R ₁₄The alkyl of representing hydrogen atom or carbonatoms 1～4 independently, and R ₁₆Expression hydrogen atom, perhaps R ₁₆The alkyl of expression carbonatoms 1～4, and R ₁₃～R ₁₅Simultaneously or represent the alkyl of hydrogen atom, halogen atom, trihalogenmethyl, cyano group, carbonatoms 1～4, the alkoxyl group of carbonatoms 1～4, the alkylthio of carbonatoms 1～4, the acyloxy of carbonatoms 1～4, the acyl amino or the three halogen methoxyl groups of carbonatoms 1～4 independently of one another.

11. as any described preparation method in the claim 1,9 and 10, in above-mentioned formula (X), R ₁₂Be chlorine atom or bromine atoms.