JPH08231537A - Production of 2-substituted benzo(b)thiophene - Google Patents

Abstract

PURPOSE: To obtain the subject compound by reacting a 2-halogenobenzaldehyde compound with an alkali metallic sulfide and sulfur or an alkali metallic polysulfide and then reacting the resultant reactional mixture with a monohalogenoacetone, etc., in a specific solvent. CONSTITUTION: A compound of formula I [X<1> is a halogen; X<2> is a halogen, nitro, cyano or H; (n) is 1-4] is reacted with an alkali metallic sulfide and sulfur or an alkali metallic polysulfide in an ethylene glycol-based solvent of the formula R<1> -O-(CH2 CH2 O)m -R<2> (R<1> and R<2> are each H, an alkyl or an aryl) having 62-30000 molecular weight (e.g. polyethylene glycol 400) at ambient temperature to 80 deg.C to provide a reactional mixture, which is then reacted with a compound of the formula XCH2 R (X is a halogen; R is an acyl, an alkoxycarbonyl, a phenoxycarbonyl or cyano) at 0-80 deg.C to afford a compound of formula II useful as a synthetic intermediate for an antiinflammatory agent from the readily available raw material in good yield according to simple operations.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an industrial process for producing 2-substituted benzo [b] thiophenes useful as synthetic intermediates for anti-inflammatory agents.

[0002]

2. Description of the Related Art Conventionally, a 2-substituted benzo [b] thiophene has been obtained by reacting 2-halobenzaldehyde with an alkali metal hydrosulfide or an alkali metal sulfide in the presence of a polar solvent. A method is known in which mercaptobenzaldehyde or a salt thereof is reacted with monohalogenoacetone or the like (JP-A-5-155881). However, in this method, when 2-chlorobenzaldehyde is used as a raw material, the yield is only about 50%.

Further, after reacting 2-halogenobenzaldehyde with an alkali metal sulfide and sulfur or an alkali metal polysulfide in an aprotic polar solvent,
The reaction mixture is reacted with monochloroacetone to give 2-
A method for obtaining acetylbenzo [b] thiophene is known (JP-A-6-157513). However, this method has a drawback in that the yield is reduced when sodium sulfide containing water is used. However, industrially, since sodium sulfide is usually sold in a water-containing state, it is necessary to dehydrate this water-containing alkali metal sulfide at a high temperature in advance, which causes problems such as complicated operation. Was there.

[0004]

The problem to be solved by the present invention is to use easily available raw materials and
Moreover, it is an object of the present invention to provide a method for producing a 2-substituted benzo [b] thiophene which is suitable for industrial practice and which can produce a target product with a high yield.

[0005]

Means for Solving the Problems The inventors of the present invention have made extensive studies on an industrial production method of 2-substituted benzo [b] thiophene in order to solve the above-mentioned problems, and found that a 2-halogenobenzaldehyde compound and an alkali sulfide. When reacting a metal and sulfur, or an alkali metal polysulfide, and reacting the reaction mixture with monohalogenoacetone, etc., surprisingly, when an ethylene glycol-based solvent is used as the solvent, the alkali metal sulfide or the alkali polysulfide used. The metal may be either anhydrous or hydrated, and further the reaction mixture obtained by the reaction of the 2-halogenobenzaldehyde compound with an alkali metal sulfide or an alkali metal polysulfide is reacted with monohalogenoacetone as it is. To easily obtain a 2-substituted benzo [b] thiophene in good yield. It found that the, and have completed the present invention based on this finding.

That is, the present invention provides a method for producing a 2-substituted benzo [b] thiophene shown in the following items (1) and (2).

(1) General formula

[0008]

Embedded image (In the formula, X ¹ represents a halogen atom, X ² represents a halogen atom, a nitro group, a cyano group, or a hydrogen atom, and n represents an integer of 1 to 4.)

The compound represented by (hereinafter sometimes simply referred to as "2-halogenobenzaldehyde") is reacted with an alkali metal sulfide and sulfur or an alkali metal polysulfide, and the reaction mixture and the general formula

[0010]

[Chemical 6] (In the formula, X represents a halogen atom, and R represents an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a cyano group.)

When a 2-substituted benzo [b] thiophene is produced by reacting with a compound represented by the following formula, an ethylene glycol solvent is used as a solvent.

[0012]

[Chemical 7] (In the formula, X ² , n, and R have the same meanings as described above.)

A method for producing a 2-substituted benzo [b] thiophene represented by:

(2) The ethylene glycol solvent has a molecular weight of 62 to a number average molecular weight of 30,000 and has a general formula

[0015]

[Chemical 8](In the formula, R¹ And R²Are independently hydrogen atom, alkyl group,
Represents an aryl group, and m represents a positive integer. )

The method for producing a 2-substituted benzo [b] thiophene according to item (1), which is a compound represented by: and / or a propylene oxide adduct of the compound.

The present invention will be described in detail below.

In the method of the present invention, 2-halogenobenzaldehydes are reacted with an alkali metal sulfide and sulfur or an alkali metal polysulfide in an ethylene glycol solvent, and the reaction mixture is represented by the general formula (Formula 7). After the desired 2-substituted benzo [b] thiophene is produced by reacting with a compound, water is added to the reaction mixture to make the pH of the aqueous layer basic and the desired product is extracted with an appropriate solvent. It is separated and taken out.

The ethylene glycol solvent used in this reaction has a molecular weight of from 62 to 3
It may be a compound represented by the general formula (Formula 8) and / or a propylene oxide adduct of the compound, in the range of 0000, and specific examples of the substituents R ¹ and R ^{2 in} the formula are hydrogen. In addition to the atoms, examples thereof include an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group and a butyl group, an aryl group such as a phenyl group, and a β-hydroxypropyl group.

Examples of the ethylene glycol solvent represented by the general formula (Formula 8) include ethylene glycols, specifically, ethylene glycol, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol t-butyl. Methyl ether (1-t-butoxy-2-methoxyethane),
Ethylene glycol t-butyl ethyl ether (1-t
-Butoxy-2-ethoxyethane), ethylene glycol diphenyl ether, propylene oxide adduct of ethylene glycol, etc .; diethylene glycols, specifically, for example, diethylene glycol, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol t-butyl methyl ether, diethylene glycol dibutyl ether, Diethylene glycol propylene oxide adduct, etc .; Triethylene glycols, specifically, for example, triethylene glycol, triethylene glycol dimethyl ether, propylene oxide adduct of triethylene glycol, etc .;
Polyethylene glycols having a number average molecular weight in the range of 190 to 30,000, specifically, polyethylene glycol 200 (number average molecular weight 190 to 210), polyethylene glycol 300 (number average molecular weight 285 to 31).
5), polyethylene glycol 400 (number average molecular weight 3
80-420), polyethylene glycol 600 (number average molecular weight 570-630), polyethylene glycol 1
000 (number average molecular weight 950 to 1050), polyethylene glycol 2000 (number average molecular weight 1800 to 220)
0), polyethylene glycol 6000 (number average molecular weight 7400 to 9000), polyethylene glycol 200
00 (number average molecular weight 18,000 to 25,000); and the like, and propylene oxide adducts of polyethylene glycols whose number average molecular weight falls within the range of 190 to 30,000. The ethylene glycol-based solvent may be used alone or in combination of two or more kinds. Of the above ethylene glycol-based solvents, those that are solid at room temperature can be used as a solvent by dissolving when mixed with other ethylene glycol-based solvents, or by melting at the reaction temperature to form a liquid. The preferable range of the molecular weight (including the case of being represented by the number average molecular weight) is 285 to 2200.

Further, in the method of the present invention, another inert solvent may be mixed with the above ethylene glycol solvent as a reaction solvent. As another inert solvent,
For example, aromatic hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene, and dichlorobenzene, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), N, N-diethylacetamide (DEAC). , Dimethyl sulfoxide (DM
SO), aprotic polar solvents such as sulfolane, and the like. Here, if the mixing ratio of another inert solvent is too high, the reaction rate may decrease, so that the mixing ratio is preferably 50% by volume or less.

In the method of the present invention, the amount of the solvent to be used is not limited as long as it can stir the reaction system, but it is usually 50 ml with respect to 1 mol of 2-halogenobenzaldehyde.
It is used in the range of up to 4000 ml, preferably 100 ml to 3000 ml.

The 2-halogenobenzaldehydes represented by the general formula (Formula 5) used in the method of the present invention include fluorine atom, chlorine atom at the 2-position of benzaldehyde,
Benzaldehydes in which a halogen atom such as a bromine atom or an iodine atom (hereinafter, the halogen atom is synonymous with each other) is substituted may be used, and a halogen atom, a nitro group, or One or more optional substituents such as a cyano group may be introduced. Examples of such 2-halogenobenzaldehydes include 2-fluorobenzaldehyde, 2-chlorobenzaldehyde, 2-bromobenzaldehyde,
2-chloro-5-nitrobenzaldehyde, 2-bromo-5-nitrobenzaldehyde, 2-fluoro-5-nitrobenzaldehyde, 2-chloro-5-cyanobenzaldehyde, 2-bromo-5-cyanobenzaldehyde, 2-fluoro-5 -Cyanobenzaldehyde, 2,
5-dichlorobenzaldehyde, 2,5-dibromobenzaldehyde, 2,5-difluorobenzaldehyde,
2-bromo-5-chlorobenzaldehyde, 2-fluoro-5-chlorobenzaldehyde and the like can be exemplified.

In the method of the present invention, examples of the alkali metal sulfide that can be used when the alkali metal sulfide is reacted with 2-halogenobenzaldehyde together with sulfur include sodium sulfide and potassium sulfide. As the alkali metal sulfide, either anhydrous alkali metal sulfide or water-containing alkali metal sulfide may be used. Industrially easily available materials can be used as they are as raw materials. The water content of the alkali metal sulfide may be 60% or less, preferably 50% or less, particularly preferably 20 to 50%. Examples of such an alkali metal sulfide having a water content of 60% or less include anhydrous sodium sulfide, 60% sodium sulfide, sodium sulfide pentahydrate (Na ₂ S.5H ₂ O), and the like, which are commercially available. .

The amount of alkali metal sulfide used in this reaction is 2
-Normally 0.5 per mole of halogenobenzaldehydes
It is selected in the range of 10 to 10 mol, preferably 1.0 to 3.5 mol, and the amount of sulfur used is 0.5 mol to 10 mol, preferably 1. It may be in the range of 0 mol to 3.5 mol.

In this reaction, sulfur and 2-
The halogenobenzaldehydes may be charged to the reaction vessel and the reaction may be started by adding alkali metal sulfide to the reaction vessel. Alternatively, sulfur and alkali metal sulfide may be charged to the reaction vessel in advance and 2-halogeno- The reaction may be started by adding benzaldehydes, and in any case, the reaction reagent previously charged in the reaction vessel is stirred at room temperature to 80 ° C. for about 0 to 3 hours in advance, and each is then stirred. The rest of the reaction reagents may be added and reacted. Further, all the reaction reagents may be charged into the reaction vessel from the beginning and used for the reaction.

In the method of the present invention, the alkali metal polysulfide used when the 2-halogenobenzaldehyde is reacted with the alkali metal polysulfide has the general formula

[0028]

[Chemical 9] (In the formula, M represents an alkali metal such as sodium or potassium, and x represents an integer of 2 or more, preferably 3 to 8
Is. )

Any compound represented by the following may be used. Examples of such a compound include sodium polysulfide, specifically sodium disulfide, sodium trisulfide, sodium tetrasulfide, and sodium polysulfide (sodium disulfide, trisulfide). Examples thereof include a mixture of sodium, sodium tetrasulfide, and higher-order sodium polysulfide, and potassium polysulfide corresponding to these sodium polysulfides.
As the alkali metal polysulfide, either anhydrous alkali metal polysulfide or water-containing alkali metal polysulfide may be used. The water content of the alkali metal polysulfide may be 60% or less, preferably 50% or less, particularly preferably 20%.
A range of up to 50% is suitable. Industrially easily available materials can be used as they are as raw materials. Here, the amount of the alkali metal polysulfide used is usually selected in the range of 0.5 to 10 mol, preferably 1 to 3.5 mol per mol of the 2-halogenobenzaldehyde. In addition, sulfur may be added in the reaction using the alkali metal polysulfide. In this reaction, 2-halogenobenzaldehydes may be first dissolved and charged in an ethylene glycol solvent, and the reaction may be carried out by adding an alkali metal polysulfide to the solution. It is preferable to employ a method in which 2-halogenobenzaldehydes are added and reacted in a pure ethylene glycol solvent. Further, all the reaction reagents may be charged into the reaction vessel from the beginning and used for the reaction.

The reaction temperature in the method of the present invention is such that, even when 2-halogenobenzaldehydes are reacted with an alkali metal sulfide and sulfur, the 2-halogenobenzaldehydes and an alkali metal polysulfide are present in the presence or absence of sulfur. In any case, the reaction can be arbitrarily selected within the range of 0 ° C to the boiling point of the solvent, but the range of 0 ° C to 80 ° C is preferable. The end point of the reaction can be confirmed by examining the disappearance of 2-halogenobenzaldehydes by, for example, gas chromatography, and the reaction time is usually 3 to 24 hours.

Then, the reaction mixture obtained as described above is reacted with the compound represented by the general formula (Formula 6).

The acyl group of the substituent R in the general formula (Formula 6) is, for example, an aliphatic acyl group having 2 to 5 carbon atoms (eg, acetyl group, propionyl group, butyryl group,
Valeryl group, etc.) and arylcarbonyl group (eg, benzoyl group, naphthoyl group, etc.), and this acyl group may be substituted with an alkyl group, an alkoxy group, a halogen atom or the like as long as it does not inhibit the reaction.

The compound represented by the general formula (Formula 6) which has such an acyl group as the substituent R in the general formula (Formula 6) and can be used in this reaction, for example, has a carbon number as the acyl group of the substituent R. As those having 2 to 5 aliphatic acyl groups, chloroacetone, 1-chloro-2-butanone,
1-chloro-2-pentanone, 1-chloro-2-hexanone, bromoacetone, 1-bromo-2-butanone, 1
-Bromo-2-pentanone, 1-bromo-2-hexanone and the like are specifically, for example, 2-chloroacetophenone (phenacyl chloride) or 2-chloro as those having an arylcarbonyl group as the acyl group of the substituent R. Acetonaphthone, 2-chloro-2'-methylacetophenone, 2-bromoacetophenone (phenacyl bromide), 2-bromoacetonaphthone, 2-bromo-2'-
Methyl acetophenone, 2-iodoacetophenone, 2
-Iodoacetonaphthone and 2-iodo-2'-methylacetophenone can be exemplified.

The alkoxycarbonyl group of the substituent R in the general formula (Formula 6) is, for example, an alkoxycarbonyl group whose alkoxy moiety is an alkyloxy group having 1 to 6 carbon atoms (eg, methoxycarbonyl group, ethoxycarbonyl group, Propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, ter
t-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, amyloxycarbonyl group, isoamyloxycarbonyl group, tert-amyloxycarbonyl group, sec-isoamyloxycarbonyl group, hexyloxycarbonyl Groups, isohexyloxycarbonyl groups, pentyloxycarbonyl groups, hexyloxycarbonyl groups, etc.) and alkoxycarbonyl groups whose alkoxy moieties are aralkyloxy groups (eg, benzyloxy groups, phenethyloxy groups, etc.) (eg benzyloxycarbonyl groups, phenethyl groups) Oxycarbonyl group, etc.)
However, these alkoxycarbonyl groups may be substituted with an alkyl group, an alkoxy group, a halogen atom or the like as long as the reaction is not hindered.

The compound represented by the general formula (Formula 6) which has such an alkoxycarbonyl group as the substituent R in the general formula (Formula 6) and can be used in this reaction is a monohalogenoacetic acid ester compound, specifically Is a monohalogenoacetic acid (for example, monochloroacetic acid, monobromoacetic acid, monoiodoacetic acid, etc.), and an alkoxy group, a carbon atom which may be substituted with a halogen atom or the like if it does not inhibit the reaction.
6 alkyl alcohols (eg methyl alcohol, ethyl alcohol, propyl alcohol ester, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentyl alcohol, isopentyl alcohol,
Neopentyl alcohol, amyl alcohol, isoamyl alcohol, tert-amyl alcohol, sec-isoamyl alcohol, hexyl alcohol, or isohexyl alcohol, 2-chloroethyl alcohol, ethylene glycol monomethyl ether, etc.) or an alkyl group unless the reaction is inhibited. , Aralkyl alcohols such as alkoxy groups, benzyl alcohols optionally substituted with halogen atoms, phenethyl alcohols (eg benzyl alcohol, 4-chlorobenzyl alcohol, 4-methoxybenzyl alcohol, 4-methylbenzyl alcohol, phenethyl alcohol) , 4-chlorophenethyl alcohol, 4-methoxyphenethyl alcohol, 4-methylphenethyl alcohol, etc.). More specifically, methyl monochloroacetate, ethyl monochloroacetate, propyl monochloroacetate, isopropyl monochloroacetate, butyl monochloroacetate, pentyl monochloroacetate, hexyl monochloroacetate, benzyl monochloroacetate, phenethyl monochloroacetate, methyl monobromoacetate, ethyl monobromoacetate, monobromoacetate. Propyl acetate, isopropyl monobromoacetate,
Butyl monobromoacetate, Pentyl monobromoacetate, Hexyl monobromoacetate, Benzyl monobromoacetate, Phenethyl monobromoacetate, Methyl monoiodoacetate, Ethyl monoiodoacetate, Propyl monoiodoacetate, Isopropyl monoiodoacetate, Butyl monoiodoacetate, Pentyl monoiodoacetate, Hexyl monoiodoacetate, Monoiodoacetate Benzyl, phenethyl monoiodoacetate, monochloroacetic acid methoxyethyl ester, monochloroacetic acid 2-chloroethyl, monochloroacetic acid 4-chlorobenzyl, monochloroacetic acid 4-methylbenzyl, monochloroacetic acid 4-
Monohalogenoacetic acid ester compounds such as methoxybenzyl, 4-chlorophenethyl monochloroacetate, 4-methylphenethyl monochloroacetate and 4-methoxyphenethyl monochloroacetate can be exemplified.

When the substituent R in the general formula (Formula 6) is a phenoxycarbonyl group, the phenoxy moiety may be substituted with an alkyl group, an alkoxy group, a halogen atom or the like as long as it does not inhibit the reaction. The compound represented by the general formula (Formula 6) which has such a phenoxycarbonyl group as the substituent R in the general formula (Formula 6) and can be used in this reaction includes the monohalogenoacetic acid and, for example, phenol or 4- Ester compounds with chlorophenol, 4-methoxyphenol, 4-methylphenol, etc., specifically phenyl monochloroacetate, phenyl monobromoacetate, phenyl monoiodoacetate, 4-chlorophenyl monochloroacetate, 4-methylphenyl monochloroacetate, monochloroacetate 4 -Monohalogenoacetic acid ester such as methoxyphenyl The can be exemplified.

Examples of the compound represented by the general formula (Chemical Formula 6) in which the substituent R is a cyano group that can be used in the reaction include monohalogenoacetonitrile compounds, specifically, chloroacetonitrile, bromoacetonitrile, iodoacetonitrile and the like. I can do things.

The amount of the compound represented by the general formula (Formula 6) used is usually 0.5 to 10 mol, preferably 1 to 2 mol per 1 mol of 2-halogenobenzaldehyde. Just go.

The reaction temperature in this reaction is not particularly limited, but in view of the exothermic reaction, it is preferably carried out in the range of 0 to 80 ° C. while cooling. The time required for the reaction varies depending on the starting materials used, the solvent and the reaction temperature, but it is usually in the range of 1 to 16 hours. Depending on the raw material compound used, the reaction rate of the intramolecular ring-closure reaction that occurs subsequent to the substitution reaction may be slow.In such a case, for example, alkali metal alcoholates such as sodium methylate, sodium ethylate, potassium methylate, etc. The reaction rate can be increased by adding such a strong base, and the 2-substituted benzo [b] thiophene that is the target ring-closure product can be rapidly obtained.

In this reaction, a method of adding the compound represented by the general formula (Formula 6) to the reaction mixture obtained above,
And the reaction proceeds smoothly by any of the methods of adding the reaction mixture to the compound represented by the general formula (Formula 6),
From the viewpoint of convenience of operation, it is preferable to carry out the reaction continuously in the same container by adding the compound represented by the general formula (Formula 6) to the reaction container containing the reaction mixture obtained in the first reaction.

In this reaction, water and a solvent that separates from water (for example, a solvent such as xylene or toluene) are added to the reaction mixture obtained above, and if desired, a phase transfer catalyst is also used in a two-phase system. The reaction can also be carried out.

In the method of the present invention, the target compound thus obtained is taken out from the reaction mixture by a usual method such as solvent extraction, and then a mixed solvent of water such as xylene, cyclohexane or alcohol is used. 2) of higher purity
-Substituted benzo [b] thiophenes can be obtained.

When the substituent at the 2-position of the 2-substituted benzo [b] thiophene produced by the method of the present invention [the substituent represented by R in the general formula (Formula 7)] is an alkoxycarbonyl group or a cyano group. Can be isolated or hydrolyzed by a conventional method without isolation to give benzo [b] thiophene-2-carboxylic acid easily, and further, this benzo [b] thiophene-2 can be obtained.
-Carboxylic acid is added to
2 by heating at 0-300 ° C and decarboxylation treatment
It is also possible to lead to benzo [b] thiophene, which has no substituent at the position. Further, particularly when the substituent at the 2-position is a cyano group, benzo [b] thiophene-2-carboxylic acid amide can be produced by appropriately changing the hydrolysis conditions.

[0044]

INDUSTRIAL APPLICABILITY In the method of the present invention, by using an ethylene glycol-based solvent as a solvent, either an anhydride or a hydrous material can be used as a raw material alkali metal sulfide or alkali metal polysulfide. The operability was improved because a complicated operation such as dehydration treatment of alkali metal or alkali metal polysulfide was previously performed. Commercially available hydrous alkali metal sulfide or anhydrous alkali metal sulfide, or water-containing alkali metal polysulfide or anhydrous alkali metal polysulfide can be used as it is, so that the availability of the raw materials is increased. In addition, since the yield of 2-substituted benzo [b] thiophenes is as high as that of the conventional method in spite of improved operability and availability of raw materials, it is industrially possible to produce 2-substituted benzo [b] thiophenes. It is extremely suitable as a manufacturing method.

[0045]

The present invention will be described in more detail with reference to the following examples.

EXAMPLE 1 78 g (0.6 mol) of 60% sodium sulfide, 28.8 g (0.9 mol) of sulfur and 225 ml of polyethylene were placed in a 1-liter 4-diameter flask equipped with a stirrer, a thermometer and a reflux condenser. Glycol 400 (PEG made by Dai-ichi Kogyo Seiyaku Co., Ltd.
400) was charged and the reddish brown reaction mixture obtained by stirring at room temperature for 1 hour was added with 2-chlorobenzaldehyde 70.
3 g (0.5 mol) was added dropwise, and the mixture was stirred at 60 to 65 ° C for 6 hours. Next, after adding 250 ml each of xylene and water,
50.9 g (0.55 mol) of chloroacetone was added dropwise at 30 ° C or lower, and the mixture was stirred at 35 to 40 ° C for 3 hours. After the reaction was completed, 25 g of 48% sodium hydroxide was added to the reaction mixture, and the mixture was stirred at 30 ° C or lower for 0.5 hours. Next, 250 ml of xylene and 250 ml of water were added, and xylene extraction was performed.
The obtained xylene layer was washed twice with water and then concentrated. The concentrated residue was recrystallized from cyclohexane to obtain 72 g of 2-acetylbenzo [b] thiophene (yield: 81.7%, purity: 99%).

Examples 2 to 7 2-Acetylbenzo [b] thiophene was produced in the same manner as in Example 1 except that the type of ethylene glycol solvent used was changed (the amount used was 225 ml). The results are shown in (Table 1).

[0048]

[Table 1]

Comparative Example Instead of the polyethylene glycol of Example 1, N, N-
Example 1 except that 225 ml of dimethylacetamide was used.
I went in the same way. As a result, the yield of 2-acetylbenzo [b] thiophene was 45%.

Example 8 Example 8 was repeated except that 0.6 mol of anhydrous sodium sulfide was used instead of 60% sodium sulfide.
As a result, the yield of 2-acetylbenzo [b] thiophene was 65.5%.

Example 9 51.2 g (0.36 mol) of anhydrous sodium trisulfide and 135 ml of polyethylene glycol 400 (Daiichi Kogyo Seiyaku Co., Ltd.) were placed in a 1 liter 4-diameter flask equipped with a stirrer, a thermometer and a reflux condenser. Polyethylene glycol, PEG
400) was charged and stirred at room temperature for 1 hour. To this mixture, 42.2 g of 2-chlorobenzaldehyde (0.3
Mol) was added dropwise, and the mixture was stirred at 60 to 65 ° C for 6 hours. Next, after adding 135 ml of xylene and water, respectively, 30.5 g (0.33 mol) of chloroacetone was added dropwise at 30 ° C or lower,
It stirred at 35-40 degreeC for 0.5 hour. After the reaction was completed, 12 g of 48% sodium hydroxide was added to the reaction mixture, and the temperature was 30 ° C.
Stirred below for 0.5 hours. Next, xylene and water (135 ml each) were added, and xylene extraction was performed. The obtained xylene layer was washed twice with water and then concentrated. The concentrated residue was recrystallized from cyclohexane to obtain 30.7 g of 2-acetylbenzo [b] thiophene (yield: 58%, purity: 99.
5%).

Example 10 14.1 g of anhydrous sodium sulfide (0.1 ml) was placed in a 200 ml four-dimensional flask equipped with a stirrer, a thermometer and a reflux condenser.
8 mol), 11.6 g (0.36 mol) of sulfur, and 45 ml of polyethylene glycol 400 (PEG 400 manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) were charged, and when stirred at room temperature, heat was generated and the liquid temperature rose to 45 ° C. . After the fever is over
2-chloro-5-nitrobenzaldehyde 27.8 g
(0.15 mol) with slight heating at 70-75 ° C 1
Dropwise over 0 minutes. After that, the mixture was stirred at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, 16.3 g (0.15 mol) of methyl chloroacetate was added dropwise with stirring under self-heating for 10 minutes, and then stirred at 55-60 ° C for 1.5 hours. Next, 8.1 g of sodium methoxide (0.15
Mol) was added at the same temperature and stirred for 30 minutes, and the reaction solution was analyzed by gas chromatography. As a result, 85% by area of 5-nitrobenzo [b] thiophene-2-carboxylic acid methyl ester was formed. After stirring this for an additional 1 hour, 40 ml of water and 6 g of 48% sodium hydroxide
Was added, and the mixture was heated and stirred at 95 ° C. for 1.5 hours for hydrolysis. After completion of the reaction, the mixture was diluted with 100 ml of water, 100 ml of toluene was added, and extraction operation was carried out at 75 ° C. to remove neutral components. Transfer the water layer into a 1 liter beaker and stir 9
22.1 g (0.21 mol) of 5% sulfuric acid was added dropwise. The precipitated crystals were filtered and dried to obtain 23.4 g of 5-nitrobenzo [b] thiophene-2-carboxylic acid (yield 70
%).

Example 11 26.3 g (0.1%) of 2,5-dichlorobenzaldehyde instead of 2-chloro-5-nitrobenzaldehyde
5 mol), 11.3 g (0.15 mol) of chloroacetonitrile instead of methyl chloroacetate, polyethylene glycol 400 (PEG 40 manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd.)
0) instead of polyethylene glycol 400 (Daiichi Kogyo Seiyaku Co., Ltd. PEG 400) and polyethylene glycol 2000 (Daiichi Kogyo Seiyaku Co., Ltd. PEG 20)
(00) was mixed in a weight ratio of 5: 1 with 45 ml of a mixed solvent, the amount of sodium methoxide used was changed to 4.1 g, and after the sodium methoxide was added, the mixture was heated with stirring at 70 ° C. for 3 hours to complete the reaction. The reaction up to the formation of the ring-closed body was carried out in the same manner as in Example 10 except for the above. The reaction mixture is added to water 400
It was poured into 300 ml of toluene, extracted with 300 ml of toluene, and the toluene layer was washed twice with 400 ml of water. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and 22.0 g of 5-chloro-2-
Cyanobenzo [b] thiophene was obtained (yield 76.0).
%).

Example 12 2 instead of 2-chloro-5-nitrobenzaldehyde
-21.1 g (0.15 mol) of chlorobenzaldehyde, 30.2 g (0.18 mol) of sodium sulfide pentahydrate in place of anhydrous sodium sulfide, and 23.2 g (0.1% of phenacyl chloride) in place of methyl chloroacetate. 15 mol), and polyethylene glycol 200 (Daiichi Kogyo Seiyaku Co., Ltd. PEG 20) instead of polyethylene glycol 400 (Daiichi Kogyo Seiyaku Co., Ltd. PEG 400).
0) and polyethylene glycol 20000 (Daiichi Kogyo Seiyaku Co., Ltd. PEG 20000) in a weight ratio of 100: 1.
45 ml of the mixed solvent mixed in step 2 was used, the amount of sodium methoxide used was changed to 6.0 g, and 2-chlorobenzaldehyde g (0.15 mol) was added dropwise to the other reaction reagents without dropping. 70 after adding sodium methoxide
Example 10 except that the reaction was completed by heating and stirring at 3 ° C for 3 hours.
The reaction up to the formation of the ring-closed body was carried out in the same manner as in. The reaction mixture was poured into 400 ml of water, extracted with 300 ml of toluene, and then the toluene layer was washed twice with 400 ml of water. The organic layer was dried over anhydrous sodium sulfate and then concentrated to give 30.0 g of 2-
Benzoylbenzo [b] thiophene was obtained (yield 84
%).

Claims (2)

[Claims] 1. A general formula: (In the formula, X ¹ represents a halogen atom, X ² represents a halogen atom, a nitro group, a cyano group, or a hydrogen atom, and n represents an integer of 1 to 4.) and an alkali metal sulfide. And sulfur or an alkali metal polysulfide to react with the reaction mixture and the general formula: (Wherein, X represents a halogen atom, R represents an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a cyano group.)
In the production of a -substituted benzo [b] thiophene, an ethylene glycol-based solvent is used as a solvent, and the general formula: (In the formula, X ² , n, and R have the same meanings as described above.) A method for producing a 2-substituted benzo [b] thiophene. 2. The ethylene glycol solvent has a molecular weight of 62.
~ Number average molecular weight of 30,000 and general formula:(In the formula, R¹ And R²Are independently hydrogen atom, alkyl group,
Represents an aryl group, and m represents a positive integer. )
Compound, and / or propyleneoxy of the compound
A 2-substituted benzo [b] thiol according to claim 1, which is a bis-adduct.
Offen manufacturing method.