JP2609966B2 - Method for producing 2-substituted benzo [b] thiophenes and intermediates thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing mercaptobenzaldehyde, and to a method for producing 2-mercaptobenzaldehyde.
The present invention relates to a method for producing 2-substituted benzo [b] thiophene using mercaptobenzaldehyde as a raw material. Mercaptobenzaldehyde and 2-substituted benzo [b] thiophenes are useful compounds as intermediates for pharmaceuticals, agricultural chemicals, functional polymers and the like.

[0002]

2. Description of the Related Art Heretofore, several methods for producing mercaptobenzaldehyde have been known. For example, the following method can be used.

(A) Method using 2,2'-dithiosalicylic acid as a raw material

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(B) Method using 2-nitrobenzaldehyde as a raw material

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(C) Method using thiosalicylic acid as a raw material

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(D) A method using 4-methylmercaptobenzaldehyde as a raw material

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However, such a known method for producing mercaptobenzaldehyde has disadvantages such as a high raw material cost, a long number of steps, and a low yield, and therefore cannot be said to be an industrially advantageous method.

On the other hand, conventionally, as a method for producing 2-substituted benzo [b] thiophene, for example, the following method has been known as an example of producing 2-acetylbenzo [b] thiophene.

(1) A method of reacting butyl [b] thiophene with butyllithium and subsequently reacting with N, N-dimethylacetamide

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(2) A method of reacting sodium salt of 2-mercaptobenzaldehyde with chloroacetone in the presence of sodium hydroxide

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(3) A method in which thiosalicylic acid is reduced with lithium aluminum hydride to form 2-mercaptobenzyl alcohol salt, subsequently reacted with chloroacetone to form a sulfide, and then cyclized with pyridine-sulfuric anhydride.

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However, such known methods are:
Each has the following disadvantages.

The method (1) is not industrially advantageous because benzo [b] thiophene used as a raw material is expensive.

The method (3), like the method (1), is not industrially advantageous because it uses raw material costs and expensive auxiliary raw materials.

The method (2) has a problem in the production method and stability of 2-mercaptobenzaldehyde or its alkali metal mercaptide used as a raw material.

[0016]

DISCLOSURE OF THE INVENTION In view of the above situation, the present inventors have intensively studied to provide a method for easily and economically producing mercaptobenzaldehyde. As a result, as shown in the following reaction formula, in the presence of a polar solvent, by reacting an alkali metal hydrosulfide or an alkali metal sulfide with a halobenzaldehyde, it has been found that the intended mercaptobenzaldehyde can be easily obtained. The inventions described in 1 to 4 have been achieved.

Embedded image (In the formula, Z represents Cl or Br, and M represents an alkali metal.)

In addition, in view of the above situation, the present inventors have found that under industrial handling conditions and under ordinary handling conditions,
-Serious research was conducted to provide a method for producing substituted benzo [b] thiophene. As a result, as shown in the following reaction formula, 2-halobenzaldehyde represented by the general formula (III), which can be obtained easily and inexpensively, is reacted with an alkali metal hydrosulfide or an alkali metal sulfide in the presence of a polar solvent. In one step with 2-mercaptobenzaldehyde or its alkali metal mercaptide,
Subsequently, it has been found that the desired 2-substituted benzo [b] thiophene can be produced by a so-called one-pot reaction by reacting the halo compound represented by the general formula (I). Reached.

Embedded image (Wherein X and Z each represent Cl or Br,
M represents an alkali metal, Y is _-CH 3, -OH, -O
Na, _-OK, a -OCH 3, _-OC 2 _{H 5} group shown. )

That is, the gist of the invention described in claims 1 to 4 is a method for producing mercaptobenzaldehyde, which comprises reacting an alkali metal hydrosulfide or an alkali metal sulfide with a halobenzaldehyde in the presence of a polar solvent. . The method for producing mercaptobenzaldehyde according to the present invention is a completely novel method which has never been seen before, and is characterized by using halobenzaldehyde which is industrially available at low cost as a raw material and reacting it with an alkali metal hydrosulfide or an alkali metal sulfide. At least, it can be easily manufactured.

The mercaptobenzaldehyde obtained in the present invention includes 2-mercaptobenzaldehyde and 4-mercaptobenzaldehyde.
Mercaptobenzaldehyde and the like can be mentioned, and examples of the halobenzaldehyde used as a raw material for obtaining the same include 2-chlorobenzaldehyde, 2-bromobenzaldehyde, 4-chlorobenzaldehyde and 4-bromobenzaldehyde.

Examples of the alkali metal sulfide include sodium hydrogen sulfide and potassium hydrogen sulfide, and examples of the alkali metal sulfide include sodium sulfide and potassium sulfide.

The amount of the alkali metal hydrosulfide or alkali metal sulfide used in the present invention is usually 0.8 to 2.5 moles, preferably 1. moles, per mole of the halobenzaldehyde.
It is in the range of 0 to 2.0 times mol. When the amount of the alkali metal hydrosulfide or the alkali metal sulfide used is less than 0.8 mole, unreacted halobenzaldehyde increases, while when it exceeds 2.5 mole, side reactions increase. , The yield decreases.

The reaction between the halobenzaldehyde and the alkali metal hydrosulfide or the alkali metal sulfide is carried out in the presence of a polar solvent, but the polar solvent used is not particularly limited, and N, N-dimethylformamide, N, N N
-Dimethylacetamide, acetamide, formamide, N-methyl-2-pyrrolidone, ethylene glycol, diethylene glycol, dimethylsulfoxide, sulfolane, acetonitrile and the like. In particular, N,
Good results are obtained when N-dimethylformamide, N-methyl-2-pyrrolidone or the like is used. The appropriate amount of the solvent used is 0.5 to 30 times by weight based on the halobenzaldehyde.

As the solvent for this reaction, the above-mentioned polar solvents can be used alone, but from an economic viewpoint, a mixed system with other solvents is also possible. Other solvents used include water; lower alcohols such as methanol, ethanol, propanol and isopropanol; aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene; halogenated hydrocarbons such as methylene chloride and chloroform; Hydrocarbons such as pentane, hexane, cyclohexane, heptane and the like can be mentioned. In this case, the proportion of the polar solvent in the total solvent is 10 to 100% by weight, preferably 30 to 100% by weight.

The reaction temperature between the halobenzaldehyde and the alkali metal hydrosulfide or the alkali metal sulfide varies depending on the type of the solvent used and the mixing ratio, and cannot be specified unconditionally.
Usually, it is in the range of 10 to 120C, preferably 20 to 100C. When the reaction temperature is lower than 10 ° C., the reaction rate is low. On the contrary, when the reaction temperature is higher than 120 ° C., the yield decreases due to side reactions, which is not preferable. The reaction time is usually 0.5 to
The range is 10 hours.

Since the mercaptobenzaldehyde obtained by the present invention is easily oxidized, if a reducing agent such as sodium thiosulfate, sodium dithionite, sodium pyrosulfite, sodium pyrosulfate and hydroquinone is added to the reaction system, Oxidation of the generated mercaptobenzaldehyde can be suppressed, and the yield can be improved. The amount of the reducing agent added is 0.5 to the solvent.
10% by weight is an appropriate amount. If the amount is less than 0.5% by weight, the effect of the addition of the reducing agent is not obvious, and even if the amount exceeds 10% by weight, the effect corresponding thereto is not recognized.

The thus obtained mercaptobenzaldehyde can be easily obtained, for example, by an operation such as extraction.

Next, an embodiment of the present invention according to claims 5 to 10 relates to a method for producing a 2-substituted benzo [b] thiophene, and 2-mercaptobenzaldehyde or an alkali metal mercaptide thereof obtained by the above-mentioned method. And then reacting a halo compound represented by the general formula (I) to obtain a 2-substituted benzo [b] thiophene.

That is, the gist of the invention according to claims 5 to 10 is that a 2-halobenzaldehyde represented by the general formula (III) is reacted with an alkali metal hydrosulfide or an alkali metal sulfide in the presence of a polar solvent. 2-substituted benzo [b] thiophene represented by the general formula (II), characterized by reacting with 2-mercaptobenzaldehyde or an alkali metal mercaptide thereof and subsequently reacting a halo compound represented by the general formula (I) It is a manufacturing method.

In obtaining 2-mercaptobenzaldehyde or an alkali metal mercaptide thereof, the embodiments of the invention described in claims 1 to 4 can be applied as they are.

The 2-mercaptobenzaldehyde or its alkali metal mercaptide obtained according to the first to fourth aspects of the present invention can be isolated as it is, but as described above, is a compound which is easily oxidized. Therefore, from an industrial point of view, it is preferable to transfer the reaction solution to the next step without isolation, without isolation.

That is, when the resulting reaction solution of 2-mercaptobenzaldehyde or its alkali metal mercaptide is subsequently reacted with the halo compound represented by the general formula (I), the desired compound represented by the general formula (II) )) To obtain a 2-substituted benzo [b] thiophene. At that time, a base may be added as necessary.

The halo compounds represented by the general formula (I) include chloroacetone, bromoacetone, chloroacetic acid,
Examples thereof include sodium chloroacetate, potassium chloroacetate, bromoacetic acid, sodium bromoacetate, methyl chloroacetate, ethyl chloroacetate, and ethyl bromoacetate.

The amount of the halo compound represented by the general formula (I) is usually 0.5 to 2.0 moles per mol of the 2-halobenzaldehyde of the general formula (III) used as a raw material.
Preferably it is in the range of 0.6 to 1.5 moles. When the use amount of the halo compound is less than 0.5 times mol, the yield decreases, and when the use amount exceeds 2.0 times mol, no effect commensurate with it is obtained, so that it is economically disadvantageous. Becomes

As the base to be added, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate such as sodium carbonate and potassium carbonate; a metal alcoholate such as sodium methylate and sodium ethylate are used. Can be. Sodium hydroxide is preferred from an economic standpoint. However, when an excess alkali metal hydrosulfide or alkali metal sulfide remains at the end of the reaction between the 2-halobenzaldehyde and the alkali metal hydrosulfide or alkali metal sulfide, the excess alkali metal hydrosulfide or alkali metal sulfide becomes a base. In some cases, it is not necessary to use an additional base.

The reaction temperature of 2-mercaptobenzaldehyde or its alkali metal mercaptide with the halo compound represented by the general formula (I) is usually in the range of 0 to 80 ° C, preferably 5 to 50 ° C. When the reaction temperature is lower than 0 ° C., the reaction rate is low, and when the reaction temperature is higher than 80 ° C., the yield decreases due to side reactions. The reaction time is usually 0.5 to 6
Time range.

Thus, the 2-substituted benzo [b] thiophene represented by the general formula (II) produced by the one-pot reaction includes 2-acetylbenzo [b] thiophene and 2-benzo [b] thiophenecarboxylic acid. And 2-benzo [b] thiophenecarboxylic acid methyl ester, 2-benzo [b] thiophenecarboxylic acid ethyl ester, and the like. Isolation of the 2-substituted benzo [b] thiophene from the reaction solution can be usually performed by adding water to the reaction solution, extracting the solution, and performing crystallization or acid precipitation.

[0037]

According to the present invention, the desired mercaptobenzaldehyde can be easily obtained in good yield by reacting halobenzaldehyde with an alkali metal hydrosulfide or an alkali metal sulfide. This is also an advantageous method.

Further, using the obtained 2-mercaptobenzaldehyde as a raw material, the desired 2-substituted benzo [b] is obtained.
Since thiophene can be obtained at low cost and by a simple operation, so-called one-pot reaction, the industrial value is extremely large.

Example 1 70% sodium hydrosulfide in a 300 ml four-necked flask equipped with a stirrer, thermometer and condenser under a nitrogen atmosphere.
8 g (0.11 mol), 2-bromobenzaldehyde 1
8.50 g (0.10 mol) and 50 g of N, N-dimethylformamide were charged and stirred at 60 ° C. for 2 hours. After the reaction, the reaction solution was cooled to room temperature, 200 g of water was added, and the reaction solution was neutralized with concentrated hydrochloric acid. Then, 100 g of methylene chloride
And extracted to obtain a methylene chloride solution containing 2-mercaptobenzaldehyde. When this solution was quantified by high performance liquid chromatography, 8.98 g of 2
-Mercaptobenzaldehyde had formed. The yield based on 2-bromobenzaldehyde was 65.1%.

Examples 2 to 4 Mercaptobenzaldehyde was obtained in the same manner as in Example 1 except that the molar ratios of halobenzaldehyde, solvent, alkali metal hydrosulfide or alkali metal sulfide shown in Table 1 were changed. Table 1 shows the obtained mercaptobenzaldehyde and the yield.

[0041]

[Table 1]

Example 5 2-mercaptobenzaldehyde was obtained in the same manner as in Example 2, except that the solvent was changed to a mixed solvent of 20 g of N-methyl-2-pyrrolidone and 30 g of cyclohexane. The yield based on 2-chlorobenzaldehyde was 58.8%.

Example 6 2-mercaptobenzaldehyde was obtained in the same manner as in Example 2 except that 2.5 g of sodium dithionite was added as a reducing agent during the reaction between 2-chlorobenzaldehyde and sodium hydrosulfide. The yield based on 2-chlorobenzaldehyde was 60.6%.

Example 7 70% sodium hydrosulfide in a 300 ml four-necked flask equipped with a stirrer, thermometer and condenser under a nitrogen atmosphere.
8 g (0.11 mol), 2-chlorobenzaldehyde 1
4.05 g (0.10 mol), N-methyl-2-pyrrolidone 20 g and cyclohexane 30 g were charged and stirred at 60 ° C. for 2 hours to obtain a reaction solution containing 2-mercaptobenzaldehyde. Subsequently, the reaction solution was cooled to 20 ° C., and at the same temperature 10.18 g of chloroacetone (0.1%).
1 mol) was added dropwise and stirred for 1 hour. Then, 8.3 g (0.10 mol) of a 48% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour to carry out a cyclization reaction.

After the completion of the reaction, 80 g of water and 70 g of cyclohexane were added, and the mixture was subjected to heat extraction and separation at 60 ° C. to obtain 120 g of a cyclohexane layer. 3 g of activated carbon was added to the cyclohexane layer, activated carbon treatment was performed at 60 ° C., followed by cooling, crystallization, filtration and drying to obtain 9.2 g of 2-acetylbenzo [b] thiophene as pale yellowish white crystals. The yield based on 2-chlorobenzaldehyde was 52.3%.

Examples 8 to 10 2-acetylbenzo [b] thiophene was obtained in the same manner as in Example 7, except that the molar ratio of 2-halobenzaldehyde and NaSH shown in Table 2 and the solvent were used. Table 2 shows the yield based on 2-halobenzaldehyde.

[0047]

[Table 2]

Example 11 60% sodium sulfide was placed in a 300 ml four-necked flask equipped with a stirrer, a thermometer and a cooler under a nitrogen atmosphere.
6 g (0.12 mol), 2-chlorobenzaldehyde 1
4.05 g (0.10 mol) and 50 g of N, N-dimethylformamide were charged, 0.5 g of hydroquinone was added as a reducing agent, and the mixture was stirred at 60 ° C. for 2 hours to obtain a reaction solution containing 2-mercaptobenzaldehyde. . Subsequently, the reaction solution was cooled to 25 ° C., and 12.81 g (0.11 mol) of sodium monochloroacetate was added at the same temperature, followed by stirring for 1 hour. Then, 8.3 g (0.10 mol) of a 48% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour to carry out a cyclization reaction.

After completion of the reaction, 200 g of water was added, and acid precipitation with concentrated hydrochloric acid, filtration and washing with water were performed to obtain crude 2-benzo [b] thiophenecarboxylic acid. This crude 2-benzo [b] thiophenecarboxylic acid was recrystallized in a mixed solvent of 80 g of methanol and 40 g of water to obtain 8.5 g of pale yellowish white powder of 2-benzo [b] thiophenecarboxylic acid. The yield based on 2-chlorobenzaldehyde was 47.8%.

Example 12 A reaction solution containing 2-mercaptobenzaldehyde was obtained in the same manner as in Example 11. Subsequently, this reaction solution was added to 25
After cooling to ℃, methyl monochloroacetate 1 at the same temperature
1.94 g (0.11 mol) was added dropwise and stirred for 1 hour. Then, 8.3 g of a 48% aqueous sodium hydroxide solution
(0.10 mol), and the mixture was stirred for 1 hour to carry out a cyclization reaction.

After completion of the reaction, 200 g of water was added, followed by precipitation, filtration and washing with water to obtain crude 2-benzo [b] thiophenecarboxylic acid methyl ester. The crude 2-benzo [b] thiophenecarboxylic acid methyl ester was recrystallized in a mixed solvent of 65 g of methanol and 80 g of water to obtain 2-yellow-white crystals.
8. Benzo [b] thiophenecarboxylic acid methyl ester
1 g was obtained. The yield based on 2-chlorobenzaldehyde was 47.4%.

Claims (10)

(57) [Claims] 1. A method for producing mercaptobenzaldehyde, comprising reacting an alkali metal hydrosulfide or an alkali metal sulfide with halobenzaldehyde in the presence of a polar solvent. 2. The method of claim 1, wherein the alkali metal sulfide is sodium bisulfide and the alkali metal sulfide is sodium sulfide. 3. The method according to claim 1, wherein the polar solvent is N, N-dimethylformamide and / or N-methyl-2-pyrrolidone. 4. The method according to claim 1, which is performed in the presence of a reducing agent. 5. A 2-halobenzaldehyde is reacted with an alkali metal hydrosulfide or an alkali metal sulfide in the presence of a polar solvent to form 2-mercaptobenzaldehyde or its alkali metal mercaptide, and then represented by the following general formula (I). A method for producing a 2-substituted benzo [b] thiophene represented by the following general formula (II): XCH ₂ COY (I) (wherein, X represents Cl or Br, Y represents —CH ₃ ,
-OH, -ONa, -OK, -OCH ₃ or -OC,
It represents the ₂ H ₅ group. ) (In the formula, Y is the same as described above.) 6. The method according to claim 5, wherein the halo compound represented by the general formula (I) is chloroacetone or bromoacetone. 7. The method according to claim 5, wherein the 2-halobenzaldehyde is 2-chlorobenzaldehyde. 8. The method according to claim 5, wherein the alkali metal sulfide is sodium bisulfide and the alkali metal sulfide is sodium sulfide. 9. The method according to claim 5, wherein the polar solvent is N, N-dimethylformamide and / or N-methyl-2-pyrrolidone. 10. The method according to claim 5, which is performed in the presence of a reducing agent.