JPH041159A - Production of 2,6-dihalogenoaniline - Google Patents

Abstract

PURPOSE:To readily obtain the subject compound useful as an intermediate of medical drug or agricultural chemicals with one process in high yield by reacting 2,6-dihalogenobenzoyl halide with hydroxylamines with using a non- protonic polar solvent. CONSTITUTION:2,6-dihalogenobenzoyl halide expressed by formula I (X is halogen), e.g. 2,6-dichlorobenzoyl chloride is reacted with hydroxylamine or salt of the hydroxylamine, e.g. hydroxylamine hydrochloride in a non-protonic polar solvent, e.g., sulfolane or N-methylpyrrolidone and adding an alkaline substance such as NaHCO3 for neutralizing by-produced hydrogen chloride, as necessary, at preferably a temperature from 100 deg.C to boiling point of used solvent for preferably 0.5-10hr, then a crystal of the aimed compound expressed by formula II is able to be recovered by a sublimation method. Besides, in the above- mentioned method, adoption of a special atmosphere such as an inert gas atmosphere is not needed.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing 2°6-dihalogenoaniline, which is useful as an intermediate for pharmaceuticals and agricultural chemicals.

[Prior art and its problems] The following methods (1) and (2) have been proposed as methods for producing 2.6-dichloroaniline.

(1) A method of chlorinating sulfanilamide to form 3,5-dichlorosulfanilamide and then desulfonylamidation (Parmatsiya, 34(4),
(pp. 35-42) (2) 3.5-'; A method in which chloro-1-bromobenzene is nitrated, and then the nitro group is reduced to an amino group and debrominated (Japanese Unexamined Patent Publication No. 169447/1982) 2.2°6.6 by reacting with ammonia in the presence of sulfuric acid
-Titrachlorocyclohexanimine and further dehydrochlorination method (JP-A-111789, 1-
117852) However, the above method (1) has the drawbacks of a large number of steps and a low yield. Also, the above (2
The method of ) not only requires a large number of steps, but also involves the use of 2 -Nitro-3,5-dichloro-1=bromobenzene (b) is produced as a by-product, which has the disadvantage of requiring its separation.

The following method (3) has also been proposed.

(3) Chlorination of cyclohexanone and 2. 2. 6
However, this method (3) also has a large number of steps, and the yield of each step is 80%.
~87%, so the overall yield is 50~70%. Hydrochloric acid is generated, and it is difficult to purify the imine from the solid obtained by solvent extraction, and repeated recrystallization etc. further reduces the yield. Since hydrolysis is likely to occur in this method, the solvent must be sufficiently dried, resulting in poor operability.

That is, the above-mentioned methods (1), (2), and (3) proposed as methods for producing dichloroaniline all require multiple steps, so the operations are complicated and the overall yield is low. This method is still unsatisfactory as an industrial production method, as it is necessary to remove by-products after each step.

By the way, a method using a Rossen rearrangement reaction of benzohydroxamic acid is known as a method for producing aniline.

This reaction is a one-step reaction, but since the raw material benzohydroxamic acid needs to be synthesized by reacting a benzoic acid derivative such as ethyl benzoate with hydroxylamine, it ends up being a two-step reaction, reducing the number of steps. In most cases, the problem is that the operation becomes complicated. For example, Japanese Patent Application Publication No. 4
Publication No. 9-13127 discloses an example of obtaining an aniline derivative from benzohydroxamic acid using a nitrile, a basic solvent, or a mixture thereof as a reaction medium.
A pre-step to react ethyl benzoate with hydroxylamine to obtain benzohydroxamic acid is necessary, resulting in a two-step reaction. Furthermore, the reaction to obtain the aniline derivative from benzohydroxamic acid must be carried out in a closed system purged with nitrogen, and the yield is low, making it impractical for mass production.

In order to avoid the complexity of a multi-step reaction, a method of directly synthesizing an aniline derivative in polyphosphoric acid from a benzoic acid derivative, which is a precursor of benzohydroxamic acid, and hydroxylamine is also being considered (Chem, Revs,
58 p. 374 (1954)).

However, in the case of synthesizing aniline by reacting benzoyl chloride, a benzoic acid derivative, with hydroxylamine, the yield is as low as 51%, which is not only impractical;
Since polyphosphoric acid is used as a solvent, post-processing such as separation of the product is complicated. This document also describes an example in which a benzoic acid derivative (for example, 2,6-cyhalogenobenzoyl chloride) having two or more substituents (excluding -COOR and -COX) on its benzene ring is used as a starting material. It has not been.

[Object of the Invention] An object of the present invention is to provide a novel method that eliminates the drawbacks of the above-mentioned conventional techniques and can produce 2,6-dihalogenoaniline in a high yield in one step.

[Means for achieving the objective] As a result of various studies to achieve this objective, we found that 2,6 expressed by the general formula (I) OX (wherein X is the same or different halogen atom) -By reacting cyhalogenobenzoyl halide and hydroxylamine or its salt in an aprotic polar solvent, a compound represented by the general formula (n) (wherein X is the same or different halogen atom) is obtained. It has been found that 2,6-dihalogenoaniline can be obtained in high yield in one step.

The present invention has been made based on the above findings, and the present invention relates to a 2,6-cyhalogenobenzoyl halide represented by the general formula (I) (wherein X is the same or different halogen atom). and hydroxylamine or a salt thereof are reacted in an aprotic polar solvent. , and a method for producing 6-cyhalogenisoaniline.

The present invention will be explained in detail below.

In the present invention, 2°6-cyhalogenobenzoyl halide represented by general formula (I) and hydroxylamine or a salt thereof are used as reaction reagents.

In general formula (I) showing one of the reaction reagents, 2,6-cyhalogenobenzoyl halide, X is the same or different halogen atom (chlorine, bromine, iodine, fluorine), so 2 of general formula (I) The following are exemplified as the 6-cyhalogenobenzoyl halide.

(i) 2. 6-cyclopenzoyl chloride, 2゜6-dibromobenzoyl chloride, 2,6-diiodobenzoyl chloride, 2,6-cyfluoropenzoyl chloride, etc. (11) 2-chloro-6-bromobenzoyl chloride,
2-chloro-6-iotobenzoyl chloride, 2-chloro-6-fluorobenzoyl chloride, 2-bromo-6
-Iothobenzoyl chloride etc. (iii) 2. 6-cyclopenzoyl bromide,
The other reaction reagent, such as 2.6-dibromobenzoyl bromide, 2,6-diiodobenzoyl bromide, and 2,6-cyfluoropenzoyl bromide, is hydroxylamine or a salt thereof. Examples of hydroxylamine salts include hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine nitrate, hydroxylamine phosphate, hydroxylamine-〇-sulfonic acid, hydroxylamine oxalate,
Examples include hydroxylamine acetate, hydroxylamine propionate, etc. Inorganic acid salts of hydroxylamine,
It may be any organic acid salt.

In the reaction, hydroxylamine or a salt thereof is preferably used in an amount of 1 to 2 moles per mole of 2,6-dihalogenobenzoyl halide represented by general formula (I). The reason for this is that if the amount of hydroxylamine or its salt is less than 1 mole, the reaction will not be completed, whereas if it exceeds 2 moles, a large amount of hydroxylamine or its salt will not participate in the reaction, which is not economical. be.

In the present invention, an aprotic polar solvent is used as the solvent. Examples of aprotic polar solvents include sulfolane (tetrahydrothiophene-1°1-dioxide),
Examples include N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. Among these, sulfolane and N-methylpyrrolidone are particularly preferably used. The amount of solvent used is 2゜6 represented by general formula (I)
-0.0% per 1 part by weight of dihalogenobenzoyl halide.
A range of 1 to 10 parts by weight is preferred. The reason is that if the solvent is less than 0.1 part by weight, side reactions are likely to occur.
- On the other hand, if it exceeds 10 parts by weight, the reaction will be slow and the reaction time will be longer.

The reaction is carried out by mixing 2,6-cyhalogenobenzoyl halide and hydroxylamine or a salt thereof in the above-mentioned aprotic polar solvent.

The reaction temperature depends on the reaction time, but is preferably from 100°C to the boiling point of the solvent used. This is because if the reaction temperature is less than 100°C, the reaction will be slow, and if it exceeds the boiling point of the solvent used, problems such as decomposition of the solvent may occur. The reaction time depends on the reaction temperature, but is preferably 0.5 to 10 hours, particularly preferably 1 to 10 hours.
It's 7 hours.

After the reaction is completed, for example, the reaction mixture is washed with water, extracted with a solvent such as ether, dehydrated and treated with activated carbon, the solid matter is filtered off, and the solvent is distilled off from the mother liquor to obtain the target substance 2. , 6-dihalogenoaniline crystals can be obtained.

As described above, according to the method of the present invention, 2,6-cyhalogenobenzoyl halide, which is a reaction reagent, and hydroxylamine or its salt are mixed without using a special atmosphere such as an inert gas atmosphere. By reacting in an aprotic polar solvent, the target substance 2,6-dihalogenoaniline can be obtained in a high yield in one step. Since additives such as catalysts are not required during this reaction, it is easy to recover the target substance after the reaction is completed, which also contributes to improving the yield of the target substance. However, in order to neutralize hydrogen chloride produced as a by-product during the reaction, an alkaline substance may be added to the reaction system as necessary. Examples of alkaline substances include sodium hydrogen carbonate, sodium carbonate,
Examples include sodium hydroxide, potassium hydroxide, and tertiary organic amines. The amount of these alkaline substances added is preferably equal to or less than the mole of the reaction reagent.

Further, according to the present invention, during the reaction, measures such as (1) increasing the reaction temperature, (2) reducing the pressure, (3) blowing inert gas, (4) lengthening the reaction time, 2.6
- By promoting the sublimation of dihalogenoaniline, 2.6
- Cyhalogenisoaniline can also be easily recovered.

In addition, when recovering 2,6-dihalogenoaniline by a sublimation method, addition of an alkaline substance such as sodium hydrogen carbonate should be avoided.

[Examples] Next, the present invention will be explained in more detail with reference to Examples, but it goes without saying that the present invention is not limited to the following Examples.

[Example 1] In an eggplant flask equipped with a cooling tube, 2.09 g (9.98 mmol) of 2,6-cyclopenzoyl chloride and 0.0 g of hydroxylamine hydrochloride were added. 84g (12 mmol),
Sodium bicarbonate 0. 84 g (10 mmol) and 10 g of sulfolane were added, and the mixture was heated and stirred at 180° C. for about 2 hours.

After the reaction, 50 ml of water was added, and after neutralization with sodium hydrogen carbonate, extraction was performed using 50 ml of ether. After washing the ether solution with water, add 0.5 g of Glauber's salt and 0.5 g of activated carbon.
After adding 2 g of the solution and stirring, the solid matter was filtered off, and the ether was distilled off from the mother liquor to obtain 1.44 g (8.89 mmol) of needle-shaped crystals. As a result of analysis using a gas chromatograph mass spectrometer, it was confirmed that the obtained substance was 2,6-dichloroaniline. The yield of 2,6-dichloroaniline based on 2,6-dichlorobenzoyl chloride is 89.
It was 1%.

[Example 2] 2,6-cyclopenzoyl chloride 2.09 g (9.98 mmol) and hydroxylamine hydrochloride 0.89 g (12.8 mmol) were placed in an eggplant flask equipped with a cooling tube.
, 5 g of sulfolane was added, heated to 180°C, and stirred for about 5 hours. Formation of needle-like crystals was observed in the upper part of the reaction vessel and in the cooling tube, and as a result of gas chromatographic analysis, the needle-like crystals were a mixture of 2,6-dichloroaniline and sulfolane. By washing this with water and drying it, 2
0.23 g (1.42 mmol) of ゜6-dichloroaniline was obtained. Furthermore, as a result of extracting the reaction solution in the same manner as in Example 1, 1.23 g of 2,6-dichloroaniline (
7.59 mmol) was obtained. Therefore, total 1.46g
(9.01 mmol) of 2.6-dichloroaniline was obtained, and the yield of 2.6-dichloroaniline based on the raw material 2.6-dichlorobenzoyl chloride was 90.3%.

[Example 3] The same method as Example 2 was carried out except that hydroxylamine hydrochloride was changed to 1.4 g (20.1 mmol). 0.76 g (4.70 mmol) from the needle crystals formed in the upper part of the reaction vessel and the cooling tube, and 0.76 g (4.70 mmol) from the reaction solution.
68g (4.20 mmol), total 1.44g (8
, 90 mmol) of 2°6-dichloroaniline was obtained. 2 for 2,6-dichlorobenzoyl chloride,
The yield of 6-dichloroaniline was 89.2%.

[Example 4] The reaction and treatment were carried out in the same manner as in Example 1 except that N-methylpyrrolidone was used instead of sulfolane, and 2,6
-Dichloroaniline was obtained. The yield of 2,6-dichloroaniline based on 2.6-dichlorobenzoyl chloride was 53.8%.

[Comparative Example 1] The reaction and treatment were carried out in the same manner as in Example 1 except that 2,6-dichlorotoluene was used instead of sulfolane, but no production of 2,6-dichloroaniline was observed.

[Effects of the Invention] As described above, according to the present invention, by reacting 2,6 dihalogenobenzoyl halide with hydroxylamine or its salt in an aprotic polar solvent,
It is possible to produce <2.6-cyhalogenisoaniline with a yield of <2.6-cyhalogenisoaniline through a simple process.

Claims (3)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) 2,6-dihalogenobenzoyl halide represented by (in the formula, X is the same or different halogen atom) and hydroxylamine or a salt thereof in an aprotic polar solvent. General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) (In the formula, X is the same or different halogen atom A method for producing 2,6-dihalogenoaniline represented by (2) The method according to claim (1), wherein the aprotic polar solvent is sulfolane or N-methylpyrrolidone. (3) The method according to claim (1), wherein 2,6-dihalogenoaniline is recovered by a sublimation method.