JP3028168B2 - Method for producing benzenesulfonamide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a benzenesulfonamide derivative. More specifically, the present invention relates to a method for producing [substituted pyrazinecarboxamidoalkyl] benzenesulfonamides from substituted pyrazinecarboxylic acids and aminoalkylbenzenesulfonamides.

[0002]

2. Description of the Related Art For the synthesis of [substituted pyrazinecarboxamidoalkyl] benzenesulfonamide, which is a raw material of a drug useful as a hypoglycemic agent, for example, a substituted pyrazinecarboxylic acid is prepared in acetone or dimethylformamide. Reaction of ethyl chlorocarbonate in the presence of triethylamine to form an active reaction intermediate, and then adding an aqueous solution of aminoalkylbenzenesulfonamide (Arzneim. Forsc
h. , 21 , 200 (1971)) and a method in which a substituted pyrazinecarboxylic acid is converted to an acid chloride with a chlorinating agent such as thionyl chloride and then reacted with an aminoalkylbenzenesulfonamide (Japanese Patent Publication No. 46-30191). ing. However, when these methods are used, the product may be colored, complicated operations are required, and the yield is low. Therefore, it is hard to say that the method is industrially advantageous. An object of the present invention is to provide a method for producing a high-quality benzenesulfonamide derivative in a simple and high yield.

[0003]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have reacted substituted pyrazinecarboxylic acids with aminoalkylbenzenesulfonic acids to produce [substituted pyrazinecarboxamidoalkyl] benzenesulfonamides. After intensive research on the method used, a high-quality target compound can be easily produced in high yield by appropriately selecting the order of addition of the tertiary amine used as a catalyst and the type of organic solvent used in the reaction. The present inventors have found that the present invention can be performed, and as a result of further research, the present invention has been completed. That is, the gist of the present invention is represented by the general formula (1)

[0004]

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(Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an amino group, an acetylamino group, an aryl group , A thienyl group, or a freel group, wherein the alkyl group, alkoxy group, acetylamino group, aryl group, thienyl group, and freel group may be substituted. -Carboxylic acid and general formula (2)

[0006]

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Wherein n is an integer of 1 to 6 and reacted with 4- (n-aminoalkyl) benzenesulfonamide represented by the general formula (3):

[0008]

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Wherein R ¹ , R ² , R ³ and n are as defined above, to produce 4- [n- (substituted pyrazine-2-carboxamido) alkyl] benzenesulfonamide. In the method, the compound represented by the general formula (1), the compound represented by the general formula (2), and the halogenocarbonate are dissolved in an organic solvent, and thereafter,
A tertiary amine is added dropwise to this mixed solution, or as a solvent, the compound represented by the general formula (3) has a solubility of 1% by weight or less at 0 ° C. and the general formula (3) Using a single or mixed organic solvent in which the solubility of the compound represented by the formula is 1 to 0.01 times the solubility of the compound represented by the formulas (1) and (2). The present invention relates to a method for producing 4- [n- (substituted pyrazine-2-carboxamido) alkyl] benzenesulfonamide represented by (3).

The substituted pyrazine-2-carboxylic acid as a starting compound used in the present invention is a compound represented by the general formula (1).

[0011]

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(Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an amino group, an acetylamino group, an aryl group , A thienyl group, or a freel group, wherein the alkyl group, alkoxy group, acetylamino group, aryl group, thienyl group, and freel group may be substituted.) Here, the halogen atom is Fluorine, chlorine, bromine,
Or, when the iodine atom is an alkyl group,
Having 4 straight or branched chains, for example a methyl group,
Ethyl group, propyl group, butyl group and the like, and as the alkoxy group, those having a straight or branched chain having 1 to 4 carbon atoms, for example, methoxy group, ethoxy group, propoxy group,
Butoxy group and the like. Examples of the aryl group include a phenyl group and a naphthyl group. Also,
When these alkyl group, alkoxy group, acetylamino group, aryl group, thienyl group, freel group, and the like have a substituent, examples of the substituent include a hydroxyl group, an amino group, and a halogen atom.

The compound represented by the general formula (1) is, for example, 5-methylpyrazine-2-carboxylic acid,
-Ethylpyrazine-2-carboxylic acid, 5-chloropyrazine-2-carboxylic acid, 6-methylpyrazine-2-carboxylic acid, 6-ethylpyrazine-2-carboxylic acid, 6-chloropyrazine-2-carboxylic acid, 3 -Methylpyrazine-2
-Carboxylic acid, 5,6-dimethylpyrazine-2-carboxylic acid, 5-chloro-6-methylpyrazine-2-carboxylic acid and the like. The amount of the compound represented by the general formula (1) is 1.0 to 1.5 times, preferably 1.0 time, the mol of the compound represented by the general formula (2).

The starting compound 4-
(N-aminoalkyl) benzenesulfonamide is a compound represented by the general formula (2).

[0015]

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(Wherein n represents an integer of 1 to 6) For example, 4- (2-aminoethyl) benzenesulfonamide, 4- (3-aminopropyl) benzenesulfonamide, 4- (4-amino- n-butyl) benzenesulfonamide, 4- (5-aminopentyl) benzenesulfonamide, 4- (6-aminohexyl) benzenesulfonamide and the like.

The halogenocarbonate used in the present invention includes chlorocarbonate, bromocarbonate,
And iodocarbonate. Among them, chlorocarbonate is economical, and methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, butyl chlorocarbonate and the like can be conveniently used, but ethyl chlorocarbonate is easily available and easy to handle, and is particularly preferred. The amount of the halogenocarbonate used is 1.0 to 1.5 times, preferably 1.1 times the mole of the compound represented by the general formula (2).

The tertiary amine used in the present invention is, for example, trimethylamine, triethylamine, tripropylamine, tributylamine, etc. Among them, triethylamine is particularly preferred because it is easily available and easy to handle. The used amount of the tertiary amine is 1.0 to 1.5 times, preferably 1.1 times the mole of the compound represented by the general formula (2).

The choice of the reaction solvent used in the present invention is particularly important. It is a prerequisite that the compound is inert to the reaction. On top of that, the compounds represented by the general formulas (1) and (2) are dissolved to some extent, and It must be an organic solvent that hardly dissolves the represented compound. Thus, after the end of the reaction,
The target compound represented by the general formula (3) can be easily separated simply by filtration.

That is, the organic solvent used in the present invention has a solubility of the compound represented by the general formula (3) of 0 ° C.
And the solubility of the compound represented by the general formula (3) is 1 to 0.01 times the solubility of the compound represented by the general formulas (1) and (2). You. That is, although the organic solvent in the present invention is inert to the reaction and shows some solubility to the compounds represented by the general formulas (1) and (2), It is preferable to use a compound which shows almost no solubility for the target compound of the present invention represented by the formula (1).
Thus, the target compound of the present invention represented by the general formula (3) can be easily separated only by filtration after the completion of the reaction. Examples of such organic solvents include halogenated hydrocarbon solvents, ketone solvents, ether solvents, and the like. Examples of the halogenated hydrocarbon solvent include methylene chloride, chloroform, and 1,2-dichloroethane, and examples of the ketone solvent include acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone. Examples of the ether solvent include diethyl ether and isopropyl ether. In the present invention, among them, halogenated hydrocarbon solvents are preferred, and methylene chloride is particularly preferred.
As long as the organic solvent in the present invention exhibits the above-mentioned solubility,
They may be used alone or as a mixture of two or more.

The production method of the present invention is carried out according to the following procedures using the above-mentioned starting compounds, compounds represented by the general formulas (1) and (2), halogenocarbonate and tertiary amine. Will be First, a compound represented by the general formulas (1) and (2) is suspended or dissolved in an organic solvent, and a halogenocarbonate is added dropwise with stirring to prepare a mixed solution. The dropping of the halogenocarbonate is carried out at about 10 ° C. or lower, preferably −10 ° C. or lower, in order to suppress the decomposition of the reaction intermediate.
It is performed under a temperature condition of 0 ° C. Next, after preparing a mixed solution,
In order to sufficiently produce the reaction intermediate, the reaction intermediate is usually left for 0 to 60 minutes, and then the tertiary amine is added dropwise. The reaction temperature at this time is usually about 10 ° C. or lower, preferably −10 to 0 ° C., and the reaction time is 1 to 4 hours. After completion of the reaction, desired crystals of the compound represented by the general formula (3) are obtained. Separation of the target compound from the reaction solution can be easily performed only by filtration, and a high-quality benzenesulfonamide derivative can be obtained in a high yield.

[0022]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples, but the present invention is not limited to these Examples and the like.

Example 1 In 80 ml of methylene chloride, 5.00 g of 5-methylpyrazine-2-carboxylic acid and 7.25 g of 4- (2-aminoethyl) benzenesulfonamide were dissolved, and stirred at -5 ° C. 4.32 g of ethyl chlorocarbonate was added dropwise, and after 30 minutes, 4.03 g of triethylamine was added dropwise. After completion of the reaction, the mixture was filtered, and the collected crystals were dried to give 4
-[2- (5-methylpyrazine-2-carboxamide)
Ethyl] benzenesulfonamide (melting point: 236 ° C.) was obtained. The yield was 95%.

Example 2 In 80 ml of acetone, 5.00 g of 5-methylpyrazine-2-carboxylic acid and 7.25 g of 4- (2-aminoethyl) benzenesulfonamide were dissolved. 4.32 g of ethyl carbonate was added dropwise,
After 30 minutes, 4.03 g of triethylamine was added dropwise. After the completion of the reaction, the mixture was filtered, and the collected crystals were dried to give 4- [2
-(5-Methylpyrazine-2-carboxamido) ethyl] benzenesulfonamide (melting point: 233 ° C).
56 g were obtained. The yield was 69%.

Comparative Example 1 55.2 g of 5-methylpyrazine-2-carboxylic acid and 40.5 g of triethylamine were dissolved in 400 ml of acetone, and 43.4 g of ethyl chlorocarbonate was added dropwise while cooling to -5 to 0 ° C. 30 minutes later, 80 g of 4- (2-aminoethyl) benzenesulfonamide dissolved in 400 ml of water and 40.5 g of triethylamine were simultaneously added dropwise. After 3 hours, acetone was distilled off and 51 g of 10% hydrochloric acid was used.
Was added, and the insolubles were collected by filtration. After water was distilled off from the filtrate, the mixture was diluted with 70 ml of ethanol, and the precipitated crystals were collected by filtration and dried together with the second crystals recovered from the filtrate.
4- [2- (5-Methylpyrazine-2-carboxamido) ethyl] benzenesulfonamide (melting point: 234.
6 ° C.). The yield was 38%.

Comparative Example 2 In 80 ml of acetone, 5.00 g of 5-methylpyrazine-2-carboxylic acid, 7.25 g of 4- (2-aminoethyl) benzenesulfonamide and 4.0 of triethylamine were used.
After dissolving 3 g, 4.32 g of ethyl chlorocarbonate was added dropwise while stirring at -5 ° C. After completion of the reaction, the mixture was filtered and the collected crystals were dried to obtain 6.38 g of 4- [2- (5-methylpyrazine-2-carboxamido) ethyl] benzenesulfonamide (melting point: 232 ° C.). The yield is 55
%Met.

[0027]

According to the method of the present invention, high-quality 4- [n- (substituted pyrazine-2-yl) can be obtained simply by filtration after completion of the reaction.
Carboxamido) alkyl] benzenesulfonamide can be obtained in high yield.

────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference US Pat. No. 3,669,966 (US, A) Altzneimitter-For Schung; vol. 21 (No. 2) p200-204, 204-208 (1971) Chemical Abstracts; 88: 50772 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 241/24 C07D 241/26 C07D 405 / 04 C07D 409/04 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula (1) (Wherein, R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, an amino group, an acetylamino group, an aryl group, a thienyl group) Or a freel group, wherein the alkyl group, alkoxy group,
An acetylamino group, an aryl group, a thienyl group, and a freel group may be substituted. )) And a substituted pyrazine-2-carboxylic acid represented by the general formula (2): (Where n represents an integer of 1 to 6) 4- (n
-Aminoalkyl) benzenesulfonamide to give a compound of the general formula (3) (Wherein R ¹ , R ² , R ³ and n have the same meanings as described above), and a method for producing 4- [n- (substituted pyrazine-2-carboxamido) alkyl] benzenesulfonamide represented by the formula: Dissolving the compound represented by the general formula (1), the compound represented by the general formula (2), and the halogenocarbonate in an organic solvent, and then adding a tertiary amine dropwise to the mixed solution. A method for producing 4- [n- (substituted pyrazine-2-carboxamido) alkyl] benzenesulfonamide represented by the general formula (3). 2. The substituted pyrazine-2-carboxylic acid represented by the general formula (1) described in claim 1 and 4- (n-aminoalkyl) benzenesulfonamide represented by the general formula (2). And then reacting 4- [n- represented by the general formula (3).
In the method for producing (substituted pyrazine-2-carboxamido) alkyl] benzenesulfonamide, the solubility of the compound represented by the general formula (3) is 0 ° C. as an organic solvent.
Or a mixture of 1 to 0.01 times the solubility of the compound represented by the general formula (3) and 1 to 0.01 times the solubility of the compound represented by the general formula (1) or (2) A process for producing 4- [n- (substituted pyrazine-2-carboxamido) alkyl] benzenesulfonamide represented by the general formula (3), wherein an organic solvent is used. 3. The organic solvent according to claim 1, wherein the compound represented by the general formula (3) has a solubility of 1% by weight or less at 0 ° C. and the compound represented by the general formula (3) has a solubility of the general formula (1).
And the solubility of the compound represented by (2) is from 1 to 0.01.
2. The method according to claim 1, wherein a single or mixed organic solvent is used. 4. The organic solvent according to claim 2, wherein the organic solvent is methylene chloride, chloroform or 1,2-dichloroethane.
The manufacturing method as described.