JPH1029981A - Production of hexahydropyridazine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain a hexahydropyridazine compound useful as an intermediate for agrochemicals/medicines in high yield at low cost by reaction of a hydrazine-lower aliphatic diacyl derivative with a dihalogenobutane under specified conditions. SOLUTION: This new compound, a hexahydropyridazine-1,2-diacyl derivative of formula III, is obtained by reaction of (A) a hydrazine-1,2-diacyl derivative of formula I (R<1> and R<2> are each a lower aliphatic alkyl) with (B) a 1,4- dihalogenobutane of formula II (X<1> and X<2> are each a halogen) in the presence of an alkali metal carbonate or hydroxide pref. in an aprotic polar solvent as reaction solvent. Another version of the objective compound, hexahydropyridazine, is obtained by reaction of an alkali hydroxide with the reaction liquor containing the compound of formula III. Thus, the objective compounds can be obtained in an industrially advantageous way as compared to conventional methods.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a hexahydropyridazine-1,2-diacyl derivative and a hexahydropyridazine useful as an intermediate material for agricultural chemicals such as benzothiazine agricultural chemicals and pharmaceuticals.

[0002]

2. Description of the Related Art Conventionally, hexahydropyridazine-1,2
As a method for producing a diacyl derivative, (A) a method of reacting a monoalkali metal salt of a hydrazine-1,2-diacyl derivative with 1,4-dibromobutane in a dimethylformamide solvent [Rocz. Chem. 47,151
1 (1973)] and (B) hydrazine-1,2-diarylacyl derivative and 1,4-dihalogenobutane in the presence of an alkali metal carbonate or hydroxide to give hexahydropyridazine-1,2-diarylacyl There is known a method for obtaining a derivative [Japanese Patent Laid-Open No. 4-240667].

As a method for producing hexahydropyridazine, for example, hexahydropyridazine obtained by reacting (C) a monoalkali metal salt of a hydrazine-1,2-diacyl derivative with 1,4-dibromobutane in a dimethylformamide solvent is used. The -1,2-diacyl derivative is once removed by distillation, then heat-treated with concentrated hydrochloric acid, the hydrolysis product and excess hydrochloric acid are distilled off under reduced pressure, and the obtained hexahydropyridazine dihydrochloride is removed. A method of heating with an alcohol solution of potassium hydroxide and finally distilling to obtain hexahydropyridazine [Rocz. Chem. 47,1
511 (1973)] and (D) reacting a hydrazine-1,2-dicarboxy derivative with 1,4-dihalogenobutane in the presence of an aprotic polar solvent in the presence of an alkali metal hydroxide to give hexahydropyridazine -1,2-
There is known a method of obtaining a dicarboxy derivative, without isolating the product, and further decarboxylating in the presence of an alkali metal hydroxide and a hydrogen-donating compound to obtain hexahydropyridazine [JP-A-7-224043]. ing.

[0004]

However, the method (A) uses a monoalkali metal salt of a hydrazine-1,2-diacyl derivative obtained by using an expensive and cumbersome metal alkali as a raw material. Therefore, the obtained hexahydropyridazine-1,2-diacyl derivative becomes expensive, and 1,2-diacetylhydrazine is reacted with 1,4-dihalogenobutane to obtain 1,2-diacetylhexahydropyridazine. However, there is a problem that the yield is extremely low, at most 21%, and it is very difficult to say that this is an industrial production method from a practical point of view.

In the method (B), the target hexahydropyridazine-1,2-diacyl derivative is limited to a hexahydropyridazine-1,2-diarylacyl derivative, and hexahydropyridazine-1,2
-Di lower aliphatic acyl derivatives are not described. All other descriptions relate to hexahydropyridazine-1,2-dicarboxy derivatives, and are described in Example 6 of JP-A-4-240407, which is the only production example of hexahydropyridazine-1,2-diarylacyl derivatives. Is 1,
1,2-Dibenzoylhexahydropyridazine is obtained in a high yield of 92% by reacting 2-dibenzoylhydrazine with 1,2-dibromobutane, but the raw material 1,2-dibenzoylhydrazine is expensive. In view of the fact that the other raw material 1,4-dibromobutane is used in an amount of 3.8 times the molar amount of 1,2-dibenzoylhydrazine, a recovery step is required. , 2-Dibenzoylhexahydropyridazine is expensive.

In the method (C), hexahydropyridazine-1, 2-hexylpyridazine-1,2-alkane is used as a starting material from a monoalkali salt of a hydrazine-1,2-diacyl derivative obtained by using an expensive and cumbersome metal alkali. It is possible to obtain the diacyl derivative, take it out of the system once, and further use the hexahydropyridazine through the reaction and recovery steps, so that the intermediate hexahydropyridazine-1,2-diacyl derivative can be taken out of the system once. In addition, there is a problem that the operation is complicated as a whole.

In the method (D), hexahydropyridazine is obtained by a relatively simple operation. However, even if the yield based on the starting material hydrazine-1,2-dicarboxy derivative is high, it is about 60%. Once the reaction solution containing the hexahydropyridazine-1,2-dicarboxy derivative, which is expensive as the raw material hydrazine-1,2-dicarboxy derivative itself, is once cooled and filtered, the reaction is carried out in the hexahydropyridazine synthesis step. However, if these operations can be omitted, it would be more industrially advantageous.In the hexahydropyridazine synthesis step, water was added as a hydrogen-donating compound into the reaction system, and after the reaction was completed, the mixture was cooled and filtered. Since the inorganic salts are removed and the filtrate is rectified to obtain hexahydropyridazine, the generated inorganic salts accompany the water partially dissolved in the filtrate, and the distillation yield of the filtrate is reduced. Is lower too as concerns the inorganic salt is deposited in the distillation still had a problem like.

Accordingly, an object of the present invention is to solve the problems of the prior art, to obtain hexahydropyridazine by a method which can be carried out industrially by a simple operation at a low cost with a good yield.
An object of the present invention is to provide a method for producing a 1,2-diacyl derivative and hexahydropyridazine.

[0009]

DISCLOSURE OF THE INVENTION To solve the problems of the prior art, the present inventors have proposed hexahydropyridazine-1,
As a result of intensive studies on the production methods of 2-diacyl derivatives and hexahydropyridazine, hydrazine-1,2-di-lower aliphatic acyl derivatives and 1,4-dihalogenobutane, which have not been substantially studied, have been aprotic. The hexahydropyridazine-1,2-diacyl derivative was found to be obtained in a high yield by a simple operation of reacting in the presence of a polar solvent in the presence of an alkali metal carbonate or hydroxide. Hexahydropyridazine-1,2-diacyl derivative reaction solution obtained in the above, it is recognized that hexahydropyridazine can be obtained in a high yield by a simple operation of reacting an alkali metal hydroxide, based on these findings The present invention has been completed.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The inventors of the present invention have proposed a hydrazine-1,2-diacyl derivative represented by the above formula (1), which has not been substantially studied, and a compound of the above formula (2). By reacting 1,4-dihalogenobutane represented by the formula (1) with a carbonate or hydroxide of an alkali metal.
Hexahydropyridazine-1,2-diacyl derivative represented by the following formula, and further adding an alkali metal hydroxide to a reaction solution containing the derivative to react to obtain hexahydropyridazine-1,2 -A novel process for the preparation of diacyl derivatives and hexahydropyridazine has been found. As described above, hexahydropyridazine-1,2-diacyl derivatives and hexahydropyridazine are compounds useful as intermediates for pesticides such as benzothiazine pesticides and pharmaceuticals.

Hereinafter, the present invention will be described in detail. The present invention provides a hydrazine-1,2-diacyl derivative represented by the formula (1), a 1,4-dihalogenobutane represented by the formula (2), and a carbonate of an alkali metal in the presence of an aprotic polar solvent. The salt or hydroxide is reacted to obtain a hexahydropyridazine-1,2-diacyl derivative represented by the formula (3), and the reaction solution containing the derivative is subjected to a physical operation such as filtration without subjecting the reaction solution to filtration. A method for producing a hexahydropyridazine-1,2-diacyl derivative and hexahydropyridazine, wherein an alkali metal hydroxide is added and reacted to obtain hexahydropyridazine.

The hydrazine-1,2-dia according to the present invention
As the sil derivative, R¹, R ^TwoAre independently low
Aliphatic alkyl groups, specifically, for example, having 1 to 6 carbon atoms
Alkyl group having a linear, branched or alicyclic structure,
Specifically, for example, methyl group, ethyl group, propyl
Group, isopropyl group, butyl group, isobutyl group,
Butyl, pentyl, hexyl or cyclohexyl
Compounds that are lower aliphatic alkyl groups such as xyl groups
More specifically, for example, 1,2-diacetyl
Hydrazine, 1,2-dipropionyl hydrazine, 1,
2-dibutyrylhydrazine, 1,2-diisobutyrylhydr
Drazine, 1,2-divaleryl hydrazine, 1,2-di
Isovaleryl hydrazine, 1,2-dipivaloyl hydra
Gin, 1,2-dihexanoylhydrazine, 1,2-di
Heptanoylhydrazine and 1,2-dicyclohexyl
Carbonylhydrazine and the like. R¹And R^TwoIs the same
The raw material is easily available and suitable
Particularly preferably, 1,2-diacetylhydrazine is safe.
Valuable and readily available.

In the present invention, as the 1,4-dihalogenobutane, X ¹ and X ² each independently represent a halogen atom,
Specifically, any compound that is a chlorine atom, a bromine atom or an iodine atom may be used. Particularly, a compound that is a chlorine atom or a bromine atom is easily available and suitable. Specifically, for example,
1,4-dichlorobutane, 1,4-dibromobutane, 1-chloro-4-bromobutane and the like can be mentioned.

The alkali metal carbonate or hydroxide used in the reaction for obtaining the hexahydropyridazine-1,2-diacyl derivative includes, for example, potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. . The molar ratio of the hydrazine-1,2-diacyl derivative, 1,4-dihalogenobutane and the alkali metal carbonate or hydroxide used in the reaction for obtaining the hexahydropyridazine-1,2-diacyl derivative is 1: (1 5):
(1 to 10), preferably 1: (1 to 3): (2 to
3).

The aprotic polar solvent used in the reaction for obtaining the hexahydropyridazine-1,2-diacyl derivative includes, for example, N, N-dimethylformamide, N, N
Examples include N-dimethylacetamide, N, N-diethylacetamide, N-methylpyrrolidone, γ-butyrolactone, dimethylsulfoxide, and the like. The amount of the solvent to be used is not particularly limited, but it is usually used in an amount of 0.5 to 30 times by weight, preferably 1 to 20 times by weight, relative to the hydrazine-1,2-diacyl derivative.

The reaction temperature in the reaction for obtaining the hexahydropyridazine-1,2-diacyl derivative is from 20 ° C. to the boiling point of the solvent, preferably from 60 ° C. to 120 ° C., more preferably from 80 ° C. to 100 ° C. The pressure is usually carried out at normal pressure, and the reaction time is 1 to 72 hours, preferably 1 to 48 hours.
Hours, more preferably 2 to 24 hours. There are no particular restrictions on the procedures for charging and heating the raw materials in the reaction for obtaining the hexahydropyridazine-1,2-diacyl derivative. For example, hydrazine-1,2-diacyl derivatives,
A method in which 1,4-dihalogenobutane, a carbonate or hydroxide of an alkali metal and a solvent are substantially simultaneously charged and then stirred and heated to a predetermined temperature, a solvent heated to a predetermined temperature under stirring, and hydrazine-1,2- In a mixture of a diacyl derivative and a carbonate or hydroxide of an alkali metal, 1,4-
A method of appropriately charging dihalogenobutane and a slurry of an alkali metal carbonate or hydroxide and a solvent and 1,4-dihalogenobutane in a mixture of a solvent and a hydrazine-1,2-diacyl derivative heated to a predetermined temperature under stirring. It is possible to implement a method in which each is separately and appropriately charged.

In the method of the present invention, hydrazine-1,
The alkali metal hydroxide was added to the reaction solution containing the hexahydropyridazine-1,2-diacyl derivative obtained by the reaction between the 2-diacyl derivative and 1,4-halogenobutane without performing physical operations such as filtration. By reacting, hexahydropyridazine can be obtained. Examples of the alkali metal hydroxide used in the reaction for obtaining hexahydropyridazine include potassium hydroxide and sodium hydroxide.

The molar ratio of the alkali metal hydroxide used in the reaction for obtaining hexahydropyridazine is hydrazine-
1,2-diacyl derivative: alkali metal hydroxide = 1:
(1 to 10), preferably 1: (2 to 5). The reaction temperature for the reaction to obtain hexahydropyridazine is 4
The reaction is carried out at a normal pressure and at a temperature of 0 ° C to the boiling point of the solvent, preferably 60 ° C to 120 ° C.
４２42 hours, preferably 2-20 hours.

[0019]

EXAMPLES The present invention will be described specifically with reference to Examples.
The present invention is not limited to these examples. Example 1 Production of 1,2-diacetylhexahydropyridazine 1,2-diacetylhydrazine was placed in a four-necked flask equipped with a reflux condenser, a stirrer, a thermometer, and a raw material supply port.
6 g (0.10 mol), 1,4-dibromobutane
7 g (0.11 mol), potassium carbonate 27.6 g (0.
20 mol) and 100 g of γ-butyrolactone solvent, and gradually heated to 80 ° C. while stirring.
The reaction was carried out at 48 ° C. for 48 hours to obtain a reaction solution containing 1,2-diacetylhexahydropyridazine. Collect a part of the reaction solution,
The resulting inorganic salt was removed by cooling and filtration, and the filtrate was subjected to gas chromatography analysis. As a result, 11.9 g (0.07 mol) of 1,2-diacetylhexahydropyridazine was produced, and the yield was 1,2. -7 based on diacetylhydrazine
0.0 mol%.

Example 2 Production of 1,2-diacetylhexahydropyridazine In a four-necked flask of the same type as in Example 1, 11.6 g (0.10 mol) of 1,2-diacetylhydrazine, 1,4
-Charge 13.3 g (0.105 mol) of dichlorobutane, 11.7 g (0.21 mol) of potassium hydroxide and 60 g of a dimethyl sulfoxide solvent, raise the temperature to 80 ° C. while stirring, and further react at 80 ° C. for 6 hours. Thus, a reaction solution containing 1,2-diacetylhexahydropyridazine was obtained. As a result of analysis in the same manner as in Example 1, 10.2 g (0.06 mol) of 1,2-diacetylhexahydropyridazine was produced, and the yield was 6 based on 1,2-diacetylhydrazine.
0.0 mol%.

Example 3 Preparation of 1,2-diacetylhexahydropyridazine In a four-necked flask of the same type as in Example 1, 5.8 g (0.05 mol) of 1,2-diacetylhydrazine, 1,4-
12.7 g (0.10 mol) of dichlorobutane, 27.6 g (0.20 mol) of potassium carbonate and 60 g of a dimethyl sulfoxide solvent were charged, the temperature was raised to 100 ° C. with stirring, and the reaction was further performed at 100 ° C. for 29 hours. , A reaction solution containing 1,2-diacetylhexahydropyridazine. As a result of analysis in the same manner as in Example 1, 6.8 g (0.04 mol) of 1,2-diacetylhexahydropyridazine was produced, and the yield was 8 based on 1,2-diacetylhydrazine.
0.0 mol%.

Example 4 Production of 1,2-diacetylhexahydropyridazine In a four-necked flask of the same type as in Example 1, 58.0 g (0.50 mol) of 1,2-diacetylhydrazine and 138.0 g of potassium carbonate were placed. (1.00 mol) and 300 g of a dimethyl sulfoxide solvent, and the mixture was stirred at 100 ° C.
And heated to 127.0 g of 1,4-dichlorobutane
(1.00 mol) was added dropwise over 1 hour.
For 24 hours to obtain a reaction solution containing 1,2-diacetylhexahydropyridazine. As a result of analyzing in the same manner as in Example 1, 68.0 g (0.40 mol) of 1,2-diacetylhexahydropyridazine was produced, and the yield was 1,
It was 80.0 mol% based on 2-diacetylhydrazine.

Example 5 Preparation of Hexahydropyridazine 56.0 g of potassium hydroxide (1.%) was obtained without filtering the reaction solution of 1,2-diacetylhexahydropyridazine obtained by reacting under the same conditions as in Example 4. 00 mol) and 10
The reaction was performed at 0 ° C. for 5 hours. After cooling and filtering to remove inorganic salts, gas chromatography analysis revealed that 34.4 g (0.40 mol) of hexahydropyridazine was produced, and the yield was 80.80 based on 1,2-diacetylhydrazine.
It was 0 mol%.

[0024]

According to the present invention, pesticides such as benzothiazine-based pesticides and hexahydropyridazine-1,2-diacyl derivatives and hexahydropyridazines useful as pharmaceutical intermediates can be easily produced in good yield. .

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hitoshi Tanazawa 8-25-1, Matsuhama, Niigata City, Niigata Prefecture Niigata Research Institute, Ltd. Niigata Research Institute (72) Inventor Chikako Ota Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa 1000 Mitsubishi Chemical Corporation Yokohama Research Laboratory

Claims (3)

[Claims] 1. A compound represented by the following formula (1): R ¹ OC—HN—NH—COR ² (1) (wherein R ¹ and R ² each independently represent a lower aliphatic alkyl group). And a hydrazine-1,2-diacyl derivative represented by the following formula (2): X ¹ -CH ₂ CH ₂ CH ₂ CH ₂ -X ² (2) wherein X ¹ and X ² are each independently Represents a halogen atom)
Wherein 1,4-dihalogenobutane represented by the following formula is reacted in the presence of an alkali metal carbonate or hydroxide: (Wherein R ¹ and R ² are the same as those in the above formula (1)). A method for producing a hexahydropyridazine-1,2-diacyl derivative represented by the formula (1): 2. The method according to claim 1, wherein an aprotic polar solvent is used as the reaction solvent. 3. A method for producing hexahydropyridazine, which comprises reacting an alkali hydroxide with a reaction solution of a hexahydropyridazine-1,2-diacyl derivative obtained by the production method according to claim 2.