JP2003277370A - Method for producing heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing benzothiazoles or the like by which the objective product in high purity is obtained with good suitability to the production. <P>SOLUTION: (1) The method for producing the heterocyclic compound represented by general formula (II) comprises chlorosulfonylating a heterocyclic compound represented by general formula (I). (2) The method for producing the heterocyclic compound represented by general formula (II) comprises sulfonating the compound represented by general formula (I), and chlorinating the sulfo group of the sulfonated product. (In the formulas, A is N-R<SP>2</SP>, an oxygen atom or a sulfur atom; X is a halogen atom; R<SP>1</SP>is a hydrogen atom or a substituent; R<SP>2</SP>is a hydrogen atom or an alkyl group which may has a substituent; and n is an integer of 0-3). <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing benzimidazoles, benzoxazoles and benzothiazoles which are useful as synthetic intermediates for photographic additives, sensitizing dyes, dyes, electronic materials, pharmaceuticals and the like.

[0002]

BACKGROUND OF THE INVENTION 2-Halo-6-chlorosulfonylbenzimidazoles, 2-halo-6-chlorosulfonylbenzoxazoles and 2-halo-6-chlorosulfonylbenzothiazoles have reactive sites at the 2- and 6-positions. Although it is an intermediate useful for synthesizing various functional compounds, a method for producing a highly pure product by an industrially advantageous method is not known, and for example, Ukr. Khim. Zh. (Russ.E
d. ), 43 (5), 518 (1977), the amino group was diazotized and then converted to a chlorosulfonyl group.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrial production method of benzimidazoles, benzoxazoles and benzothiazoles, which has high production suitability and can obtain the desired product with high purity. .

[0004]

The objects of the present invention have been achieved by the following means. (1) A method for producing a heterocyclic compound represented by the following general formula (II), which comprises chlorosulfonylating a heterocyclic compound represented by the following general formula (I) with chlorosulfuric acid. General formula (I)

[0005]

[Chemical 5]

(In the general formula (I), A represents NR ² , an oxygen atom or a sulfur atom, and X represents a halogen atom.
¹ represents a hydrogen atom or a substituent. R ² represents a hydrogen atom or an alkyl group which may have a substituent. n represents an integer of 0 to 3. ) General formula (II)

[0007]

[Chemical 6]

(In the general formula (II), A represents N—R ² , an oxygen atom or a sulfur atom, and X represents a halogen atom.
¹ represents a hydrogen atom or a substituent. R ² represents a hydrogen atom or an alkyl group which may have a substituent. n represents an integer of 0 to 3. )

(2) A method for producing a heterocyclic compound represented by the following general formula (II), characterized in that the heterocyclic compound represented by the following general formula (I) is sulfonated and then chlorinated. . General formula (I)

[0010]

[Chemical 7]

(In the general formula (I), A represents NR ² , an oxygen atom or a sulfur atom, and X represents a halogen atom.
¹ represents a hydrogen atom or a substituent. R ² represents a hydrogen atom or an alkyl group which may have a substituent. n represents an integer of 0 to 3. ) General formula (II)

[0012]

[Chemical 8]

(In the general formula (II), A represents NR ² , an oxygen atom or a sulfur atom, and X represents a halogen atom.
¹ represents a hydrogen atom or a substituent. R ² represents a hydrogen atom or an alkyl group which may have a substituent. n represents an integer of 0 to 3. )

(3) A method for producing a heterocyclic compound represented by the general formula (II) according to (1) or (2), wherein A is a sulfur atom. (4) In the isolation and purification step of the compound represented by the general formula (II), crystallization with a solvent containing an alcoholic solvent, the general formula (II)
At least one step of recrystallization in a solvent containing a solid alcoholic solvent containing the compound described, and washing with a solvent containing a solid alcoholic solvent containing the compound of the general formula (II) (1), (2) characterized in that
Alternatively, the method for producing the heterocyclic compound represented by the general formula (II) according to (3).

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The manufacturing method of the present invention will be described in detail below. The heterocyclic compound represented by the general formula (I) used in the present invention and the heterocyclic compound represented by the general formula (II) produced by the method of the present invention will be described. In the general formulas (I) and (II), A represents NR ² , an oxygen atom, or a sulfur atom, and preferably a sulfur atom. X represents a halogen atom, preferably a chlorine atom or a bromine atom, and more preferably a chlorine atom. R ¹ represents a hydrogen atom or a substituent. Examples of the substituent include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl group (eg, methyl, ethyl), aryl group (eg, phenyl, naphthyl), cyano group, carboxyl group, alkoxycarbonyl. Group (eg methoxycarbonyl), aryloxycarbonyl group (eg phenoxycarbonyl), substituted or unsubstituted carbamoyl group (eg carbamoyl, N-phenylcarbamoyl, N, N-dimethylcarbamoyl), alkylcarbonyl group (eg acetyl), aryl Carbonyl group (eg benzoyl), nitro group, substituted or unsubstituted amino group (eg amino,
Dimethylamino, anilino), acylamino group (eg acetamide, ethoxycarbonylamino), sulfonamide group (eg methanesulfonamide), imide group (eg succinimide, phthalimide), imino group (eg benzylideneamino), hydroxy group, alkoxy group ( For example, methoxy), aryloxy group (for example, phenoxy), acyloxy group (for example, acetoxy),
Alkylsulfonyloxy group (eg methanesulfonyloxy), arylsulfonyloxy group (eg benzenesulfonyloxy), sulfo group, substituted or unsubstituted sulfamoyl group (eg sulfamoyl, N-phenylsulfamoyl), alkylthio group (eg methylthio) , Arylthio groups (eg phenylthio) alkylsulfonyl groups (eg methanesulfonyl), arylsulfonyl groups (eg benzenesulfonyl), heterocycles and the like. Further, the substituents may be further substituted, and when there are a plurality of substituents, they may be the same or different. Further, adjacent substituents may form a ring.

R ¹ is preferably a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, an alkylthio group or an arylthio group.

R ¹ is more preferably a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group.

More preferably, R ¹ is a hydrogen atom,
Alternatively, it is an alkyl group, and a hydrogen atom is particularly preferable.

R ² is a hydrogen atom or an alkyl group which may have a substituent, preferably a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, and more preferably a hydrogen atom or an alkyl group having 1 to 12 carbon atoms. It is an alkyl group, more preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and may include a branch or ring structure. As the substituent of R ² , those mentioned as the substituent of R ¹ can be applied, and preferably a halogen atom, an alkyl group, an aryl group, a cyano group,
A carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a substituted or unsubstituted carbamoyl group,
Alkylcarbonyl group, arylcarbonyl group, acylamino group, sulfonamide group, imide group, alkoxy group, aryloxy group, acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, sulfo group, substituted or unsubstituted sulfamoyl group, alkylthio A group, an arylthio group, an alkylsulfonyl group, an arylsulfonyl group, or a heterocycle. Further, the substituents may be further substituted, and when there are a plurality of substituents, they may be the same or different. Further, adjacent substituents may form a ring.

The substituent of R ² is more preferably an aryl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a substituted or unsubstituted carbamoyl group, an alkylcarbonyl group, an arylcarbonyl group, an acylamino group, Alternatively, it is a sulfo group.

The substituent for R ² is more preferably an aryl group, an alkoxycarbonyl group or an aryloxycarbonyl group.

N represents an integer of 0 to 3, preferably 0
To an integer of 2 and more preferably 0.

Next, specific examples of the compound represented by formula (I) of the present invention are shown below, but the present invention is not limited thereto.

[0024]

[Chemical 9]

[0025]

[Chemical 10]

[0026]

[Chemical 11]

Next, the method for producing the compound represented by the general formula (II) will be described in detail. General formula (I) as a raw material
Benzimidazoles, benzoxazoles, and benzothiazoles represented by are easily available,
Various synthetic methods are known, for example, 2-position halogenation of 2-position unsubstituted azols (for example, J. Organom).
et. Chem. , 588 (2), 155 (1999)
2) halogenation of an azo group substituted at the 2-position with an amino group (for example, Tetrahedro).
n, 52 (1), 23 (1996)), 2
2-Halogenation of Azols Substituted with a Mercapto Group at the Position (eg, Bull. Chem. Soc. Jp.
n. , 65 (11), 3163 (1992); Me
d. Chem. , 35 (4), 705 (1992)) and 2-position halogenation of an azo group substituted at the 2-position with a hydroxy group (for example, Synth. Commu.
n. , 26 (17), 3323 (1996)) and the like, which are easily available.

The chlorosulfonylation of the compound represented by the general formula (I) with chlorosulfuric acid will be described. This reaction may be carried out with or without a solvent, preferably without a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but examples thereof include a halogen-based solvent (for example, carbon tetrachloride, chloroform 1,2-dichloroethane, dichloromethane) and an alkane-based solvent (for example, hexane, cyclohexane), and two or more kinds. You may use together. The amount of chlorosulfuric acid used is preferably 1 to 20 mol, more preferably 2 to 15 mol, and still more preferably 2 to 10 mol, per 1 mol of the compound of the general formula (I). This reaction is preferably carried out at 20 to 200 ° C, more preferably 60 to 180 ° C,
More preferably, it is 80 to 150 ° C. The reaction time varies depending on the reaction temperature and the like, but it is preferably 1 to 20 hours, more preferably 2 to 15 hours.

The sulfonation of the compound represented by the general formula (I) will be described. As the sulfonating agent, sulfuric acid, fuming sulfuric acid, sulfur trioxide, chlorosulfuric acid, fluorosulfuric acid, amidosulfuric acid and the like can be used, and sulfuric acid, fuming sulfuric acid, sulfur trioxide and chlorosulfuric acid are preferable, and fuming sulfuric acid is more preferable. The concentration of fuming sulfuric acid is preferably 10 to 80%, more preferably 15 to
60%. The amount of the sulfonating agent used is preferably 1 to 20 mol, more preferably 1 to 15 mol, and further preferably 2 to 10 mol, relative to 1 mol of the compound represented by the general formula (I). This reaction may be carried out with or without a solvent, preferably without a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but a halogen-based solvent (for example,
Carbon tetrachloride, chloroform 1,2-dichloroethane, dichloromethane, tetrachloroethane), carboxylic acid type solvent (for example, propionic acid acetate), acid anhydride (for example, acetic anhydride), ester type solvent (for example, ethyl acetate, butyl acetate), Examples include ether solvents (eg, diethyl ether, dibutyl ether), nitryl solvents (eg, acetonitrile), sulfur dioxide and the like, and two or more kinds may be used in combination. This reaction is preferably carried out at −20 to 200 ° C., more preferably 0 to 150 ° C., further preferably 0 to 100 ° C. The reaction time varies depending on the reaction temperature and the like, but it is preferably 0.5 to 8 hours, more preferably 0.5 to 4 hours.

Further, this reaction may be carried out in the presence of additives such as vanadyl sulfate, BF ₃ , sodium sulfate, ammonium nitrate and boric acid.

In this reaction, 15 to 60% fuming sulfuric acid is used in an amount of 2 to 10 mol per mol of the compound represented by the general formula (I).
It is preferably carried out at 0 to 100 ° C. without a solvent.

The chlorination of the sulfo group in the next step will be described. After sulfonation of the compound represented by the general formula (I),
The sulfonic acid or its salt may be isolated before being subjected to chlorination, or the sulfonation may be carried out as it is without isolation, and the latter is preferred. Chlorinating agents for sulfo groups include thionyl chloride, phosphorus pentachloride, phosphorus trichloride,
Examples thereof include phosphorus oxychloride, chlorosulfuric acid and benzotrichloride, with thionyl chloride being preferred. You may use 2 or more types together. The amount of the chlorinating agent used is preferably 1 to 20 mol, more preferably 1 to 15 mol, and further preferably 2 to 10 mol, relative to 1 mol of the compound represented by the general formula (I). This reaction may be carried out with or without a solvent, preferably without a solvent. The solvent is not particularly limited, but halogen type solvents (for example, carbon tetrachloride, chloroform 1,2-dichloroethane, dichloromethane, tetrachloroethane), sulfuric acid, ester type solvents (for example, ethyl acetate, butyl acetate), ether type solvents (for example, Diethyl ether, dibutyl ether) and nitrile solvent (for example, acetonitrile) are mentioned, and two or more kinds may be used in combination. This reaction is preferably carried out at −20 to 200 ° C., more preferably 0 to 150 ° C., further preferably 20 to 120 ° C. The reaction time varies depending on the reaction temperature and the like, but it is preferably 0.5 to 8 hours, more preferably 0.5 to 4 hours.

In this reaction, 2 to 1 mol of the compound represented by the general formula (I) is used without isolation of the compound represented by the general formula (I).
It is preferable to add 10 mol of thionyl chloride and carry out at 20 to 120 ° C.

A method for isolating the compound represented by the general formula (II) will be described. After completion of the reaction, it is preferable to add the reaction solution to a solvent containing an alcoholic solvent for crystallization. The alcohol solvent used here is a liquid at 60 ° C. or lower, preferably an alcohol having 1 to 12 carbon atoms, and more preferably an alcohol having 1 to 8 carbon atoms.
More preferably, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 2-methyl-
2-Butanol and 2-ethyl-1-hexanol, with 2-propanol being particularly preferred. An alcohol solvent and another solvent can be used in combination. The solvent used in combination is not particularly limited, but water or an organic solvent can be used. As the organic solvent, for example, ketones (eg acetone, methyl ethyl ketone etc.), esters (eg ethyl acetate, methyl acetate, butyl acetate etc.), aliphatic hydrocarbons (eg n-pentane, n-hexane, cyclohexane etc.) , Aromatic hydrocarbons (eg toluene, xylene, chlorobenzene etc.), ethers (eg diethyl ether, tetrahydrofuran, dioxane etc.), amides (N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl- 2-pyrrolidone, etc.), dimethyl sulfoxide, sulfolane, acetonitrile, acetic acid and the like. As the solvent used in combination, preferably water, acetone, methyl ethyl ketone, ethyl acetate,
n-hexane, cyclohexane, toluene, xylene,
Tetrahydrofuran, N, N-dimethylacetamide,
Acetonitrile and acetic acid are preferred, and water and acetone are more preferred. Moreover, you may use together 2 or more types of solvents. When sufficient purity cannot be obtained in the crystallization step, a high purity product can be obtained by recrystallizing and / or washing a solid containing the compound of the general formula (II) with a solvent containing an alcohol solvent. it can. The solvent including the alcohol solvent used here may be the same as that used in the crystallization step. Also. For example, after a crude product of the compound represented by the general formula (II) is obtained by a general method such as a series of operations of extraction, washing, and concentration, or crystallization by addition to a poor solvent, recrystallization and / or Alternatively, the compound of the general formula (II) having a sufficient purity may be obtained by a washing operation.

[0035]

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

<Example 1> Synthesis of 2-chloro-6-chlorosulfonylbenzothiazole. 128 g (0.75 mol) of 2-chlorobenzothiazole was added dropwise to 351 g (3.0 mol) of chlorosulfuric acid while stirring under ice cooling so that the internal temperature was 20 ° C or lower. After the completion of dropping, the mixture was stirred at an internal temperature of 130 ° C for 8 hours. The completion of the reaction is H
It was confirmed by PLC. 2-L propanol 1.5L, water 1.
While stirring 5 kg of the mixture, the reaction solution was heated to an internal temperature of 20 ° C.
It dripped over 2 hours so that it might become the following. The generated precipitate was collected by filtration under reduced pressure, and the precipitate was mixed with 2-propanol / water =
Washed with 1/1: 150 ml. This was air-dried for 1 hour, 150 ml of acetone was added, and the mixture was stirred at 30 ° C. for 0.5 hour. While stirring, add 50 parts of 2-propanol.
0 ml was added and the mixture was stirred at room temperature for 0.5 hours and at 4 to 10 ° C. for 0.5 hours, and then crystals were collected by filtration under reduced pressure. This crystal was mixed with 2-propanol / n-hexane = 1/1: 50 ml.
After that, it was washed with water and dried to obtain 40 g of crystals of 2-chloro-6-chlorosulfonylbenzothiazole. HPLC area purity 98.7%, yield 20%. The target structure is ¹ H-N
Confirmed by MR. ¹ H-NMR (300 MHz: solvent CDCl ₃ internal standard: TMS) δ ppm 8.16 (s, 2H) 8.55 (s, 1H)

Example 2 Synthesis of 2-chloro-6-chlorosulfonylbenzothiazole. 2-chlorobenzothiazole 1 was added to 444 g of 60% fuming sulfuric acid (SO ₃ conversion: 3.3 mol) while stirring under ice cooling.
15 g (0.68 mol) was added dropwise over 35 minutes at an internal temperature of 20 to 40 ° C. After dropping, the internal temperature is 40-4
The mixture was stirred at 5 ° C for 2 hours. The completion of the reaction was confirmed by HPLC. The temperature of the reaction solution was raised to 55 ° C, and thionyl chloride was added dropwise over an interval of 45 minutes at an internal temperature of 50 to 60 ° C. After the completion of dropping, the mixture was stirred at 65 ° C for 1 hour. The completion of the reaction was confirmed by HPLC. While stirring a mixture of 0.8 L of 2-propanol and 0.8 kg of ice, the reaction solution was added dropwise over 2 hours so that the internal temperature was 20 ° C or lower. The generated precipitate was collected by filtration under reduced pressure, and the precipitate was 2-propanol / water = 1 /
1: Washed with 150 ml. This was air dried for 1 hour, 250 ml of acetone was added, and the mixture was stirred at 30 ° C. for 0.5 hour. While stirring, add 750 of 2-propanol.
After adding ml, the mixture was stirred at room temperature for 0.5 hours and at 4 to 10 ° C for 0.5 hours, and then the crystals were collected by filtration under reduced pressure. This crystal was mixed with 2-propanol / n-hexane = 1/1: 100 ml.
After that, it was washed with water and dried to obtain 82 g of 2-chloro-6-chlorosulfonylbenzothiazole crystals. HPLC area purity 98.1%, yield 45%. The target structure is ¹ H-N
Confirmed by MR (same as above).

[0038]

Industrial Applicability The chlorosulfonyl compounds of benzimidazoles, benzoxazoles and benzothiazoles, which are useful as synthetic intermediates for photographic additives, sensitizing dyes, dyes, electronic materials, pharmaceuticals, etc., are industrially advantageous. It became possible to manufacture it with high purity by the method.

Claims (3)

[Claims] 1. A process for producing a heterocyclic compound represented by the following general formula (II), which comprises chlorosulfonylating a heterocyclic compound represented by the following general formula (I) with chlorosulfuric acid. . General formula (I) (In the general formula (I), A is N-R ^2, .R ² .X representing an oxygen atom or a sulfur atom .R ¹ represents a halogen atom represents a hydrogen atom or a substituent is a hydrogen atom or a substituent, Represents an alkyl group optionally having n. N represents an integer of 0 to 3.) General formula (II) (In the general Formula (II), A is N-R ^2, .R ² .X representing an oxygen atom or a sulfur atom .R ¹ represents a halogen atom represents a hydrogen atom or a substituent is a hydrogen atom or a substituent, Represents an alkyl group which may have n, and n represents an integer of 0 to 3.) 2. A heterocyclic compound represented by the following general formula (II), characterized in that the heterocyclic compound represented by the following general formula (I) is sulfonated and then the sulfo group is chlorinated. Production method. General formula (I): (In the general formula (I), A is N-R ^2, .R ² .X representing an oxygen atom or a sulfur atom .R ¹ represents a halogen atom represents a hydrogen atom or a substituent is a hydrogen atom or a substituent, Represents an alkyl group which may have n. N represents an integer of 0 to 3.) General formula (II) (In the general Formula (II), A is N-R ^2, .R ² .X representing an oxygen atom or a sulfur atom .R ¹ represents a halogen atom represents a hydrogen atom or a substituent is a hydrogen atom or a substituent, Represents an alkyl group which may have n, and n represents an integer of 0 to 3.) 3. In the step of isolating and purifying the compound represented by the general formula (II), crystallization with a solvent containing an alcoholic solvent, a solid alcoholic solvent containing a compound containing the compound represented by the general formula (II) is used. 2. At least one step of recrystallization and washing with a solvent containing a solid alcoholic solvent containing a compound represented by the general formula (II) is included.
Alternatively, a method for producing the heterocyclic compound represented by the general formula (II) described in 2 above.