JPH07267950A - Process for producing 5-chloro-N- (4,5-dihydro-1H-imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine or acid addition salt thereof - Google Patents

Abstract

(57) [Summary] (Modified) [Structure] 5-chloro-2,1,3-benzothiadiazol-4-amine and 1-acyl-2-imidazolidinone are reacted in the presence of phosphorus oxychloride. To obtain a compound represented by the following general formula (III), which is refluxed in alcohol or treated with an acid or a base to decompose, and represented by the following formula (IV): 5-chloro-N-
(4,5-Dihydro-1H-imidazol-2-yl)
-2,1,3-Benzothiadiazol-4-amine or a method for producing an acid addition salt thereof. (However, in the formula, R has a lower alkyl group or a lower alkoxy group.) [Effect] The above-mentioned production method uses industrial raw materials that are inexpensive and easily available, and is simpler with a shorter reaction process than conventional techniques. The target product can be obtained in high yield by the operation.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 5-chloro-N- (4,5-dihydro-1H-imidazol-2-yl) -2,1,3-benzo having excellent therapeutic effect as a muscle relaxant. The present invention relates to a novel method for producing thiadiazol-4-amine and acid addition salts thereof.

[0002]

BACKGROUND OF THE INVENTION 5-Chloro-N-, which has been used as an excellent central muscle relaxant with few side effects, has hitherto been used.
(4,5-Dihydro-1H-imidazol-2-yl)
As a method for producing -1,2,3-benzothiadiazol-4-amine and an acid addition salt thereof, a method described in JP-B-54-42983 represented by the following reaction formula (A) and the following reaction formula (B) , (C) and (D)
The method described in JP-B-33718 or the method described in JP-B-56-2071 represented by the following reaction formula (E) is known.

[0003]

[Chemical 5]

[0004]

[Chemical 6]

[0005]

[Chemical 7]

[0006]

[Chemical 8]

[0007]

[Chemical 9]

[0008]

However, the above-mentioned methods (A) to (D) require a large number of reaction steps in order to obtain the starting intermediate of the starting material from the amine derivative of the formula (I), There is a drawback that the operation is complicated and the total yield is naturally low. Further, the method (E) also has a problem that a reaction step for obtaining a raw material intermediate from a corresponding amine derivative is long and a by-product is easily generated during chlorination.

Further, in the methods (A) and (C), highly toxic raw materials such as phosgene and thiophosgene are used, and in all the methods, raw materials that produce a bad odor or a strong odor are required. It wasn't a satisfying method.

Therefore, the above-mentioned 5-chloro-N- (4,5-
Dihydro-1H-imidazol-2-yl) -2,1,
Development of an industrially advantageous production method, which uses 3-benzothiadiazol-4-amine or an acid addition salt thereof in a short reaction process, is simple in operation, uses safe and easily available raw materials, and can be obtained in high yield Was wanted.

[0011]

Means and Actions for Solving the Problems As a result of intensive studies to achieve the above object, the present inventor has found that 5-chloro-2,1,3-benzothiadiazole represented by the following formula (I). -4-amine and 1-acyl-2-imidazolidinone represented by the following general formula (II) are reacted in the presence of phosphorus oxychloride to obtain a compound represented by the following general formula (III). Of 5-chloro-N- (4,5-dihydro-1H-imidazol-2-yl) -2,1 represented by the following formula (IV) by refluxing in alcohol or treating with acid or base to decompose. , 3-
The inventors have found that benzothiadiazol-4-amine or an acid addition salt thereof can be obtained in a high yield by using a raw material that is easy to operate in a shorter reaction step, is safe and easily available, and has completed the present invention. .

[0012]

[Chemical 10] (However, in the formula, R means a lower alkyl group or a lower alkoxy group.)

That is, according to the present invention, 5 in the above formula (I) is used.
-Chloro-2,1,3-benzothiadiazol-4-amine is reacted with 1-acyl-2-imidazolidinone of the above general formula (II) in phosphorus oxychloride to give a compound of the above general formula (III) To give 5-chloro-N- (4,5-dihydro-1H of the above formula (IV) by decomposing it by refluxing in alcohol or treating with acid or base.
-Imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine can be obtained in a shorter reaction step and in a higher yield as compared with the prior art. At this time, an alcohol is added to the phosphorus-containing intermediate product obtained by simply distilling phosphorus oxychloride under reduced pressure without isolating and purifying the compound of the above formula (III) obtained by usual post-treatment, By refluxing and decomposing and performing the two steps in the same reaction vessel, the target compound of the above formula (IV) can also be obtained in a simpler operation and higher yield as compared with the conventional techniques.

Further, the compound of the general formula (II) can be easily obtained from inexpensive ethylene urea by a known method, and the other raw material compounds are also inexpensive and easily available. Therefore, the method of the present invention is very effective as an industrial production method of the target compound.

Therefore, according to the present invention, 5-chloro-2,1,3-benzothiadiazol-4-amine of the above formula (I) is oxidized with 1-acyl-2-imidazolidinone of the above general formula (II). The reaction is carried out in phosphorus chloride, and the above general formula (II
5-chloro-N- (4,5-dihydro-1H of the above formula (IV), characterized in that the compound of I) is obtained, which is refluxed in alcohol or treated with acid or base to decompose.
-Imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine or a method for producing an acid addition salt thereof is provided.

The present invention will be described in more detail below. In the method for producing the above-mentioned formula (IV) which is the object compound of the present invention, 5-chloro-2,1,3-benzothiadiazol-4-amine represented by the following formula (I) which is a starting material is a compound of Zhur. Obshchei. Khim. 27, 157
It can be easily synthesized according to the method described in 0-1575 (1957).

[0017]

[Chemical 11] On the other hand, 1-acyl-2 represented by the following general formula (II)
-Examples of imidazolidinone include 1-acetyl-2
-Imidazolidinone, 1-propionyl-2-imidazolidinone, 1-n-butyryl-2-imidazolidinone, 1-ethoxycarbonyl-2-imidazolidinone and the like, but from the economical aspect Especially 1-acetyl-2
-Imidazolidinone is preferred, these can be easily synthesized by reacting ethylene urea with the corresponding acid anhydride or halogenated carbonate.

[0018]

[Chemical 12] (However, in the formula, R means a lower alkyl group or a lower alkoxy group.)

The compound of the above formula (I) and the above general formula (I
In the case of reacting with the compound of I), the mixing ratio is 0.9 mol to 2 mol of the latter, preferably 1 to 1 mol of the former.
It can be 1.5 mol.

The reaction is carried out in the presence of phosphorus oxychloride, where the phosphorus oxychloride used serves both as reaction reagent and reaction solvent. The amount of phosphorus oxychloride used is appropriately selected, but it is preferably about 15 to 20 times the amount of the compound of the above formula (I).

The reaction conditions can be appropriately selected, but the reaction temperature is from room temperature to the boiling point of phosphorus oxychloride, preferably 50 to 70.
The reaction time is 24 to 72 hours at 40 ° C., preferably 40 to 5 hours.
It is about 0 hours.

After the reaction is performed as described above, water is added to the phosphorus-containing intermediate product obtained by distilling phosphorus oxychloride from the reaction product under reduced pressure, followed by hydrolysis to add a caustic soda solution or the like. After being made alkaline, the separated organic matter is extracted with an organic solvent such as chloroform, and the obtained compound of the general formula (III) is refluxed in alcohol or treated with an acid or a base to decompose, and then the compound of the above formula (IV ) May be obtained, but alcohol is added to the phosphorus-containing intermediate product obtained by simply distilling off phosphorus oxychloride under reduced pressure, the mixture is refluxed and decomposed, and two steps are carried out in the same reaction vessel. Thus, the target compound of the above formula (IV) can also be obtained.

When the compound of the above-mentioned general formula (III) or its phosphorus-containing intermediate product is refluxed in alcohol or treated with an acid or a base to decompose to obtain the target compound of the above-mentioned formula (IV), the alcohol is a fat. Group lower alcohols can be preferably used, and the object is sufficiently achieved by simply refluxing for 2 to 24 hours in a lower alcohol such as methyl alcohol, ethyl alcohol or n-propyl alcohol. The amount of the alcohol used is preferably about 15 to 20 times the amount of the compound of the general formula (III) or the phosphorus-containing intermediate product. When an acid is used, mineral acid or acetic acid is preferably used, and when a base is used, caustic soda, caustic potash, ammonia and the like are preferably used.

The above formula (IV) obtained as described above
5-chloro-N- (4,5-dihydro-1H-imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine can be purified by a conventional method,
If necessary, an acid addition salt such as hydrochloric acid can be prepared by a known method.

[0025]

Industrial Applicability The production method of the present invention comprises 5 of the above formula (I).
-Chloro-2,1,3-benzothiadiazol-4-amine was reacted with 1-acyl-2-imidazolidinone of the above general formula (II) in phosphorus oxychloride to give the compound of the above general formula (III). The resulting product is refluxed in alcohol or treated with an acid or a base and decomposed to give 5-chloro-N- (4,5-dihydro-1H of the above formula (IV).
-Imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine and a method for producing an acid addition salt thereof, which uses an inexpensive and easily available industrial raw material,
The target product can be obtained in a high yield by a simple operation with a shorter reaction step compared to the conventional techniques.

[0026]

EXAMPLES The present invention will now be specifically described with reference to examples, but the present invention is not limited to the following examples.

Example 1 1.29 g (7.0 mmol) of 5-chloro-2,1,3-benzothiadiazol-4-amine and 1-acetyl-2-imidazolidinone.
99 g (7.73 mmol) of phosphorus oxychloride 13 ml
And was stirred at 60 ° C. for 48 hours. After the reaction,
The phosphorus oxychloride was completely removed under reduced pressure and the residue was washed with water 2
0 ml was added, and the mixture was made alkaline with a caustic soda solution under ice cooling. The separated organic matter is extracted with chloroform three times,
The extract was washed twice with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 1.86 g of 5-chloro-.
N- (1-acetyl-2-imidazolin-2-yl)-
2,1,3-Benzothiadiazol-4-amine was obtained (yield 90%, melting point 193-195 ° C.).

1.86 g of the obtained acyl derivative was dissolved in 40 ml of methyl alcohol and refluxed for 8 hours. After completion of the reaction, methyl alcohol was concentrated to 1/3 and left standing in a refrigerator overnight, and the precipitated crystal was collected by filtration and dried to give the desired product, 5-chloro-N- (4,5-dihydro). -1H-Imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine (1.44 g) was obtained (yield 91%, melting point 221-223 ° C).

This product completely matched the melting point, thin layer chromatography, and various spectral data with the standard product separately synthesized by a known method. Further, its hydrochloride was obtained according to a conventional method. The melting point of this hydrochloride is 275-282 ° C.
Met.

Example 2 1.0 g (5.39 mmol) of 5-chloro-2,1,3-benzothiadiazol-4-amine and 1-acetyl-2-imidazolidinone.
76 g (5.94 mmol) of phosphorus oxychloride 10 ml
And was stirred at 60 ° C. for 48 hours. After the reaction,
Phosphorus oxychloride was completely removed under reduced pressure, 30 ml of methyl alcohol was added to the obtained residue, and the mixture was refluxed for 3 hours. Thereafter, methyl alcohol was distilled off under reduced pressure, 20 ml of water was added to the obtained residue, and the mixture was made alkaline with a caustic soda solution under ice cooling. The separated crystals were collected by filtration, washed with water, dried and recrystallized from methyl alcohol to give the desired product, 5-chloro-N- (4,5-dihydro-1H-imidazol-2-yl)-. 1.13 g of 2,1,3-benzothiadiazol-4-amine was obtained (yield 83%, melting point 221-223 ° C).

This product completely matched the melting point, thin layer chromatography and various spectral data with the standard product synthesized separately by a known method. The melting point of the hydrochloride was 275 to 282 ° C.

Example 3 1.2 g (6.47 mmol) of 5-chloro-2,1,3-benzothiadiazol-4-amine and 1.01 g (7.11 g) of 1-propionyl-2-imidazolidinone. 12 mmol phosphorus oxychloride
It was suspended in ml and stirred at 60 ° C. for 42 hours. After the reaction was completed, phosphorus oxychloride was completely removed under reduced pressure, 20 ml of water was added to the residue, and the mixture was made alkaline with a caustic soda solution under ice cooling. The separated organic matter was extracted three times with chloroform, the extract was washed twice with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 1.73 g of 5-chloro-N- (1 -Propionyl-2-imidazoline-2-
Yl) -2,1,3-benzothiadiazol-4-amine was obtained (yield 86%, melting point 211-212 ° C.).

1.73 g of the obtained acyl derivative was dissolved in 40 ml of methyl alcohol and refluxed for 20 hours. After the reaction was completed, methyl alcohol was concentrated to 1/3 and left in a refrigerator overnight, and the precipitated crystals were collected by filtration, dried,
5-chloro-N- (4,5-dihydro-1H-
1.35 g of imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine was obtained (yield 96%,
Mp 221-223 ° C).

This product had completely the same melting point, thin layer chromatography and various spectral data as those of the standard product separately synthesized by a known method. The melting point of the hydrochloride was 275 to 282 ° C.

Example 4 1.2 g (6.47 mmol) of 5-chloro-2,1,3-benzothiadiazol-4-amine and 1.12 g of 1-ethoxycarbonyl-2-imidazolidinone (7. (11 mmol) was suspended in 12 ml of phosphorus oxychloride and stirred at 60 ° C. for 40 hours. After the reaction was completed, phosphorus oxychloride was completely removed under reduced pressure, 20 ml of water was added to the residue, and the mixture was made alkaline with a caustic soda solution under ice cooling. The separated organic matter was extracted three times with chloroform, the extract was washed twice with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 2.03 g of 5
-Chloro-N- (1-ethoxycarbonyl-2-imidazolin-2-yl) -2,1,3-benzothiadiazol-4-amine was obtained (yield 96%, melting point 133-13).
5 ° C).

2.03 g of the obtained acyl derivative was dissolved in 40 ml of methyl alcohol and refluxed for 24 hours. After the reaction was completed, methyl alcohol was concentrated to 1/3 and left in a refrigerator overnight, and the precipitated crystals were collected by filtration, dried,
5-chloro-N- (4,5-dihydro-1H-
1.46 g of imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine was obtained (yield 93%,
Mp 221-223 ° C).

This product completely matched the melting point, thin layer chromatography and various spectral data with the standard product synthesized separately by a known method. The melting point of the hydrochloride was 275 to 282 ° C.

Claims (1)

[Claims] 1. The following formula (I): 5-chloro-2,1,3-benzothiadiazol-4-amine represented by the following general formula (II) (In the formula, R means a lower alkyl group or a lower alkoxy group.) 1-acyl-2-imidazolidinone represented by the following general formula (III) [Chemical 3] (Wherein R has the same meaning as described above), and the compound is refluxed in alcohol or treated with an acid or a base to decompose the compound, and the compound of the following formula (IV): 4] 5-chloro-N- (4,5-dihydro-1 represented by
H-imidazol-2-yl) -2,1,3-benzothiadiazol-4-amine or a method for producing an acid addition salt thereof.