JPH02169579A - Production of anilinopyridazine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate for agricultural chemicals, etc., in high yield while suppressing the formation of by-products such as isomers by reacting a 3,6-dihalogeno-4-pyridazine with an aniline compound in the presence of an acid. CONSTITUTION:The objective compound of formula II (R<1> and R<2> are H, halogen, lower alkyl, lower alkoxy or phenoxy) can be produced by charging a reactor with a compound of formula I (R is lower alkyl; X is halogen) (e.g. 3,6-dichloro-4-methylpyridazine), 0.01-2mol (based on 1mol of the compound of formula I) of an acid having a dissociation constant (PK value) of >2.2 at 25 deg.C (e.g. hydrochloric acid or methanesulfonic acid) and preferably an organic solvent (e.g. n-hexane), adding an aniline compound (e.g. o-fluoroaniline) to the mixture e.g. by dropping, stirring the mixture and reacting the components at 50-100 deg.C.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a method for producing pyridazine derivatives.

For more details, see 6, which has high utility value as an intermediate for agricultural chemicals, etc.
-An improved method for producing aniso2-3-halogeno-4-alkylpyridazines is provided.

[Conventional technology]

General formula (II) (wherein R represents a lower alkyl group, R1 and Hl are each independently a hydrogen atom, a halogen atom, a lower alkyl group,
6-, which represents a lower alkoxy group or a substituted or unsubstituted phenoxy group, and X represents a halogen atom)
Aniso2-3-halogen-4-alkylpyridazines are compounds useful as intermediates for agricultural chemicals, and are described, for example, in JP-A-60-185768 or JP-A-60-18576.
According to No. 9, compounds of formula (I) derived from compounds of formula (n)
) (In the formula, R3 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a phenoxy group, n represents an integer of 1 to 5, and R4 represents a lower (halo)alkenyl group or a lower (halo) It is known that pyridazine derivatives represented by ), which represent an alkynyl group, are highly active as herbicides.

By the way, 6-aniso-3-halogeno- of formula (II)
4-alkylpyridazines (hereinafter abbreviated as AXAP)
is conventionally produced by condensing 3,6-dihalogeno-4-alkylpyridazine represented by formula (I) (wherein R represents a lower alkyl group and X represents a halogen atom) with aniline. It is known that it can be done.

For example, JP-A-58-77866 discloses a method of condensing 3,6-dichloro-4-methylpyridazine with aniline without a solvent or in a solvent. , potassium carbonate, triethylamine, etc.). Specifically, n of 3,6-dichlor 4-methylpyridazine
- Equimolar amount of aniline is added dropwise to the butanol solution under reflux, heated under reflux for 1 hour, cooled, drained into water, the resulting crystals are collected by filtration, and recrystallized from ethanol to improve the yield. 6-anilino-3-chloro-4-methylpyridazine was obtained at 47.3χ.

[Problem to be solved by the invention]

As mentioned above, 3,6-dihalogeno-4-alkylpyridazine and anilines are directly heated and condensed in a solvent to form the formula (I
In method I) for producing AXAP, the yield of AXAP is low. In addition, based on studies by the present inventors, in the reaction of 3,6-dihalogeno-4-alkylpyridazine with anilines, in addition to the target 6-anilino-3halogeno-4-alkylpyridazine, the isomer 3-anilino-4-alkylpyridazine is produced. It was found that large amounts of -4-alkyl-6-valogenobilitadine and 3,6-pisanilino-4-alkylpyridazine were produced as by-products, and that compounds other than these were also produced as by-products.

Incidentally, as a result of additional tests by the present inventors, 3,6-dichloro4-
In the method of reacting methylpyridazine and aniline under reflux in n-butanol, as is clear from the comparative example described below, as a result of analyzing the reaction solution by high performance liquid chromatography, 3,6-dichloro-4-methyl Although the conversion rate of pyridazine is high at around 90%, the isomers 3-anilino-6-chloro-4-methylpyridazine and 3,6-
It was found that a total of more than 50% of pisanilino-4-methylpyridazine and other side products were formed as by-products, while the production of the desired 6-aniso2-3-chloro-4-methylpyridazine was only about 30%. Furthermore, when the reaction temperature is lowered to 70 to 80°C in order to suppress by-products such as 3,6-bisanilino, the reaction becomes extremely slow and takes an extremely long time to complete. It was found that this method did not result in a significant improvement in the yield of anilino-reactive.

In this way, the known method of directly heating and condensing 3,6-dihalogeno-4-alkylpyridazine and anilines in an organic solvent produces many by-products such as isomers, and the target compound AX
The yield of AP is low, and it is difficult to say that this method is industrially satisfactory.

[Means to solve problems]

In view of the current state of the prior art as described above, the present inventors have proposed 3.
A method for efficiently producing an anilinopyridazine derivative represented by the general formula (n) by condensing 6-dihalogeno-4-alkylpyridazine and aniline was intensively investigated.

As a result, by carrying out the reaction in the presence of an acid such as hydrochloric acid or sulfuric acid in advance, the reaction proceeds smoothly under mild conditions, and moreover, it is possible to proceed smoothly with the 3-anilino form and the 3.6-
The by-product of bisanilinino bodies can be significantly suppressed, and as a result, 6-
It has been found that this leads to improvements in the selectivity and yield of the anilino compound.

For example, when equimolar amounts of 3,6-dichloro-4-methylpyridazine and aniline were reacted in n-butanol in the presence of hydrochloric acid at a molar ratio of 0.1, the reaction proceeded smoothly at 75°C. It was found that the yield of 6-anilino compound was improved to about 65%.

The present invention has been made based on this knowledge. That is, the present invention provides compounds of the formula (I) (wherein R represents a lower alkyl group and X represents a halogen atom) by reacting 3,6-dihalogeno-4 alkylpyridazine with anilines. In the formula, R and X have the same meaning as in formula (I), and R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a substituted or unsubstituted phenoxy group. The method for producing an anilinopyridazine derivative represented by formula (H) is characterized in that the reaction is carried out in the presence of an acid.

The method of reacting a 3.6-cyhalogenoviridazine compound and aniline in the presence of an acid has not been previously known and is a novel method.

3,6-dihalogeno-4 of formula (I) used in the present invention
-Alkylpyridazine specifically includes 36-dichloro-4-methylpyridazine, 3,6-dibromo-4-methylpyridazine, 3,6-dichloro-4-ethylpyridazine, 3,6-dipromo-4-ethylpyridazine, 3.
6-dichloro-4-lopropylpyridazine, 3.6-
Dipromo-4-n-propylpyridazine, 3,6-dichloro-4-iso-propylpyridazine, 36-dipromo-4-iSO-propylpyridazine, 3,6-dichloro-4-n-butylpyridazine, 3.6-dipromo-4-
tert-butylpyridazine, 3,6-dipromo-4-
Examples include tert-butylpyridazine.

Specifically, the anilines used in the present invention include aniline, 0-fluoroaniline, toiodoaniline, P
-Fluoroaniline, 0-chloroaniline, toiodoaniline, ρ-chloroaniline, 0-bromoaniline, m
-Pulmoaniline, p-bromoaniline, o-iodoaniline, toiodoaniline, p-iodoaniline, o-
Toluidine, lateral-toluidine, ρ-toluidine, d-trifluoromethylaniline, trifluoromethylaniline, p-trifluoromethylaniline, 0-ethylaniline, toiodoaniline, p-ethylaniline, o-
n-propylaniline, m-n-propylaniline, p
-n-propylaniline, 0-isopropylaniline,
Toisobrobylaniline, p-isopropylaniline,
o-n-butylaniline, m-n-phthylaniline, ρ
-n-Butylaniline, 〇-Tertiary diptylaniline, ρ-Tertiary diptylaniline 0
- Anisidine, p-anisidine, 0-phenetidine, tophenetidine, ρ-phenetidine, on-propoxyaniline, In-propoxyaniline, p-n-propoxyaniline, 0-inpropoxyaniline, toisoproboxyaniline, p-in Propoxyaniline, o-n
-butoxyaniline, m-n-butoxyaniline, ・p
-n-butoxyaniline, 〇--tert-butoxyaniline, tertiary-butoxyaniline, p-tert-butoxyaniline, 0-phenoxyaniline, -phenoxyaniline, p-phenoxyaniline, p-(4-chlorophenoxy ) Aniline, p-(4-methylphenoxy)aniline, p-(4-trifluoromethylphenoxy)aniline, tho(2-chloro-4-trifluoromethylphenoxy)aniline, 2.4-difluoroaniline, 2.6 -difluoroaniline, 3,4-difluoroaniline, 3.
5-difluoroaniline, 2,4-dichloroaniline,
2.6-dichloroaniline, 3.4-dichloroaniline, 3.5-dichloroaniline, 2.4-dibromoaniline, 2.6-dibromoaniline, 3.4-dibromoaniline, 3.5-dibromoaniline, 2 .4-diethylaniline, 3.4-shotoaniline, 3.5-diethylaniline, 4-bromo-2-chloroaniline, 2-chloro-4-fluoroaniline, 3-chloro-4-fluoroaniline, 2,4 -xylidine, 2.6-xylidine, 3
, 4-xylidine, 3.5-xylidine, 2.4-diethylaniline, 2.6-diethylaniline, 4-ethyl-2-methylaniline, 4-isopropyl-2-methylaniline, 4-tert-butyl- 2-methylaniline, 2
．． 4-dimethoxyaniline, 2.6-dimethoxyaniline, 3.4-dimethoxyaniline, 3.5-dimethoxyaniline, 2,4-jethoxyaniline, 2,6-jethoxyaniline, 4-ethoxy-2-methoxyaniline , 4-inpropoxy-2-methoxyaniline, 4-tert-butoxy-2-methoxyaniline, 2-methoxy-4
-Phenoxyaniline, 4-fluoro-2-methylaniline, 4-fluoro-3-methylaniline, 2-fluoro-4-methylaniline, 3-fluoro-4-methylaniline, 3-fluoro-2-methoxyaniline, 4 -Fluoro-3-methoxyaniline, 2-fluoro-4-methoxyaniline, 3-fluoro-4-methoxyaniline, 4-fluoro-2-phenoxyaniline, 4-fluoro-3-phenoxyaniline, 2-fluoro-4- Phenoxyaniline, 3-fluoro-4-phenoxyaniline, 4-chloro-2-methylaniline, 4-chloro-3
-methylaniline, 2-chloro-4-methylaniline,
3-chloro-4-methylaniline, 4-chloro-2-methoxyaniline, 4-chloro-3-methoxyaniline,
2-chloro-4-methoxyaniline, 3-chloro-4-
Examples include methoxyaniline, 3-chloro-2-phenoxyaniline, 4-chloro-3-phenoxyaniline, 2-chloro-4-phenoxyaniline, and 3-chloro-4-phenoxyaniline.

Although it is possible to react the 2(+) 3,6-dihalogeno-4-alkylpyridazine and aniline without a solvent in the method of the present invention, it is usually carried out in an organic solvent or in combination with an organic solvent and water. carried out in a mixed solvent of The organic solvent used is not particularly limited as long as it is inert to the reaction.

Specifically, n-hexane, n-hebutane, benzene,
Hydrocarbon solvents such as toluene, xylene or ethylbenzene, aromatic hydrocarbon solvents such as chlorobenzene, 0-dichlorobenzene, toluene, 0-chlorotoluene or p-chlorotoluene, methanol, ethanol, n-
Proper tool, isoproper tool, n-butanol, isobutanol, secondary butanol, tertiary butanol,
Alcohol solvents such as pentanol or heptatool, ether solvents such as diisopropyl ether, dioxane or tetrahydrofuran, ester solvents such as ethyl acetate or butyl acetate, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol Polyhydric alcohol solvents such as diethyl ether, diethylene glycol, propylene glycol or glycerin, carboxylic acid solvents such as acetic acid or propionic acid, nitromethane,
Nitrogen-containing solvents such as nitroethane, nitropropane, nitrobenzene, formamide, N,N-dimethylformamide, acetonitrile, pyridine, picoline, quinoline, N-methylpyrrolidone or N,N''-dimethylimidazolidinone, carbon disulfide, dimethylsulfoxide A wide range of solvents can be mentioned, such as sulfur-containing or phosphorus-containing solvents such as triethyl phosphate or tributyl phosphate.Of course, the solvents specifically illustrated here are just examples, and the solvents used in the method of the present invention It is clear that the organic solvents are not limited to these.Although these organic solvents are usually used alone, there is no problem in using two or more solvents in combination.

When using a solvent, the amount used is not particularly limited, but in consideration of the volumetric efficiency of the reaction, etc., it is usually the total amount of the raw materials 3,6-dihalo Geller-4-alkylpyridazine and anilines. It is preferably 20 times or less by weight.

In the method of the present invention, if one of the raw materials, aniline, is used in excess, 3,6-bisanilino may be substituted with anilines in the 3- and 6-position halogen atoms of 3,6-dihalogeno-4-alkylpyridazine. Since this increases by-products in the body and leads to a decrease in the yield of the target compound AχAP, the amount used should be at most 1.5 molar ratio, preferably at most 1.2 molar ratio with respect to formula%. , there is no particular restriction on the lower limit of usage, but
From an economic standpoint, it is preferable to use it in a molar ratio of 0.8 or more to 3,6-dihalogeno-4-alkylpyridazine.

Generally, approximately equimolar amounts of 3,6-dihalogeno-4-alkylpyridazine and aniline are used.

In the present invention, A
This achieves an improvement in the yield of XMP.

The acid used has a dissociation constant of PK at 25°C.
Inorganic or organic acids with a value of less than 2.2 are preferred.

A reaction in the presence of an acid with a dissociation constant greater than 2.2 in terms of PK value, for example a weak acid such as acetic acid, will not achieve the object of the present invention.

Specific examples of acids used in the present invention include inorganic acids such as hydrogen chloride (or hydrochloric acid), sulfuric acid, hydrobromic acid, hydriodic acid, perchloric acid, periodic acid, or phosphoric acid; Methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfone M, p4 luenesulfonic acid, p-chlorobenzenesulfonic acid, 0-nitrobenzenesulfonic acid, p-
Examples include aliphatic or aromatic sulfonic acids such as nitrobenzenesulfonic acid or naphthalenesulfonic acid, or fatty acids such as trifluoroacetic acid or trichloroacetic acid.

Of course, the above-mentioned conditions are not limited to the acids exemplified here, as long as the conditions are satisfied with an acid having a dissociation constant and PK value of less than 2.2. These acids are usually used alone, but it is also possible to use two or more kinds of acids in combination.

If the amount of acid used is too small, the object of the present invention cannot be achieved, and if too large is used, side reactions other than those mentioned above are likely to be induced.
0.0 for 6-dihalogeno-4-alkylpyridazine.
The molar ratio ranges from 0.01 to 2, preferably from 0.02 to 1, which achieves the object of the present invention.

The acid used in the present invention is preferably added at the beginning of the reaction between 3,6-cyhalogenoviridazine and aniline, preferably in advance.

In the present invention, the order of charging raw materials, acids, and solvents is not particularly limited. An example of a specific embodiment is as follows.

After charging 3.6-dihalogeno-4-alkylpyridazine, an acid, and a solvent, aniline is added either all at once or dropwise, and the mixture is heated and reacted with stirring.

The reaction temperature is preferably 50° C. or above and below the boiling point of the solvent, preferably 100° C. or below. The end point of the reaction can be easily determined by means such as thin layer chromatography or high performance liquid chromatography.

〔Example〕

The present invention will be explained in detail below with reference to Examples. The analysis conditions for high performance liquid chromatography (internal standard method) in Examples are as follows.

<High performance liquid chromatography analysis conditions> Example 1 16.3 g (0.1 mol) of 3,6-dichloro-4-methylpyridazine, 53-n-butanol, and 1.0 g (0.1 mol) of concentrated hydrochloric acid were placed in a 100 d4 flask. , 01 mol) was charged, and the temperature was raised to 50'C while stirring to dissolve. this?
9.3 g (0.1 mol) of aniline was added dropwise to liquid 8, the temperature was raised to 75°C, and the reaction was carried out at the same temperature for 8 hours. As a result of the analysis, the reaction results were as follows.

was added dropwise over 1 hour. Thereafter, the reaction was continued under reflux for an additional hour. The obtained reaction solution was analyzed by high performance liquid chromatography, and the reaction results were as follows.

Next, most of the solvent was distilled off from the reaction solution under reduced pressure, and then it was discharged into 30 Od of water. -4-methylpyridazine 12.8g
I got it. Yield 58.3χ (vs. 3,6-dichloro#-methylpyridazine) Melting point: 175.5-176.5°C Comparative Example 1 (Method of Synthesis Example in JP-A-58-77866) 1
00d4 A Tulo flask was charged with 16.3 g (0.1 mol) of 3,6-dichloro-4-methylpyridazine and 50 d of n-butanol, and 9.3 g (0.0 mol) of aniline was charged under heating under reflux.
, 1 mol) Comparative Example 2 The reaction was carried out in the same manner as in Example 1 except that no hydrochloric acid was added, and the reaction results were as follows.

Examples 2 to 8, Comparative Example 3 Table 1 shows the results of reacting 3,6-dichloro-4-methylpyridazine with aniline by changing the type and amount of acid used, reaction temperature, and time in Example 1. Shown in 1.

(Left below) Example 9 16.3 g (0.1 mol) of 3,6-dichloro-4-methylpyridazine, 1 aniline in a 100 d4 flask
0.2 g (0.11 mol), ethanol 60. d and P-) luenesulfonic acid hydrate 1.9 g (0,01
mol) and the temperature was raised to 80°C while stirring. After that, the reaction was allowed to proceed at the same temperature for 7 hours, and after cooling to room temperature, the reaction solution was separated and analyzed by high performance liquid chromatography. As a result, the conversion rate of 3.6-dichloro-4-methylpyridazine was 98.7χ. Yes, 6-aniso2-3-chloro-4
The yield of -methylpyridazine was 68.5x (vs. 3,6-dichloro-4-methylpyridazine).

Example 10 19.2 g (0.1 mol) of 3,6-dipromo-4-methylpyridazine, 9 aniline in a 100d4 Turow flask
．． 3 g (0.1 mol), 50 d of n-butanol and 0.96 g (0.01 mol) of methanesulfonic acid,
The temperature was raised to 70°C while stirring, and the reaction was continued at the same temperature for 4 hours. After that, it was cooled to room temperature, and a portion of the reaction solution was collected and analyzed by high-performance liquid chromatography. As a result, the yield of 6-aniso2-3-bromo-4-methylpyridazine was 69.2χ
(vs. 3,6-dipromo-4-methylpyridazine).

Example 11 The reaction was carried out in the same manner as in Example 1, except that 20.5 g of 3,6-dichloro-4-tertiary butylpyridazine was used instead of 3,6-dichloro-4-methylpyridazine. As a result of analyzing the reaction solution by high performance liquid chromatography, 6-aniso2-3-chloro-4-butylpyridazine was produced at a yield of 73.8χ.

Examples 12 to 16 Reactions were carried out in the same manner as in Example 1, except that 0.1 mol of various substituted anilines was used instead of aniline. The results are shown in Table-2.

(Left below) [Effects of the Invention] According to the method of the present invention, the reaction between 3,6-dihalogeno-4-alkylpyridazine and anilines not only proceeds smoothly under mild conditions, but also improves the efficiency of conventional methods. In comparison, by-products such as isomers can be suppressed.

Therefore, it leads to an improvement in the yield of the target 6-aniline pyridazine derivative, and is of great industrial significance.
This is a method for producing an alininoviridazine derivative.

Patent applicant: Mitsui Toatsu Chemical Co., Ltd.

Claims (1)

[Claims] 1. Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a lower alkyl group and X represents a halogen atom.) 3 , 6-dihalogeno-4-pyridazine and anilines are reacted to form the formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R represents a lower alkyl group and X represents a halogen atom. , R^1 and R^2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenoxy group.) 6-anilino-
6-anilino-3-halogeno-4- of formula (II) in a method for producing 3-halogeno-4-lower alkylpyridazines, characterized in that the reaction is carried out in the presence of an acid.
A method for producing lower alkylpyridazines. 2. The manufacturing method according to claim 1, wherein the acid is an inorganic or organic acid having a dissociation constant at 25° C. and a PK value of less than 2.2. 3. The acid is hydrogen chloride (or hydrochloric acid), sulfuric acid, hydrobromic acid,
2. The method according to claim 1, wherein the inorganic acid is selected from hydriodic acid, perchloric acid, periodic acid, or phosphoric acid. 4. The manufacturing method according to claim 1, wherein the acid is an aliphatic sulfonic acid or an aromatic sulfonic acid. 5. The manufacturing method according to claim 1, wherein the acid is trifluoroacetic acid or trichloroacetic acid. 6. The amount of acid used is 3,6-dihalogeno-4 of formula (I)
- The method according to claim 1, wherein the molar ratio is in the range of 0.01 to 2 per mole of lower alkylpyridazine.