JPH01117849A - Production of 2,6-dihaloaniline derivative - Google Patents

Abstract

PURPOSE:To obtain the above compound useful as an intermediate for medicines or agricultural chemicals in high yield and purity in a short process using an inexpensive raw material, by dehydrohalogenating 2,2,6,6- tetrahalocyclohexanimine derivative as a raw material. CONSTITUTION:A 2,2,6,6-tetrahalocyclohexanimine derivative expressed by formula I [R is H, alkyl or (substituted) aromatic group; X is halogen: is dehydrohalogenated in the presence or absence of a basic catalyst, such as NaOH, or by thermal decomposition to afford the aimed compound expressed by formula III useful as a medicine or agricultural chemical, especially as an intermediate for substituted phenylacetic acids expressed by formula II (R<1> and R<4> are lower alkyl, lower alkoxy or halogen having an atomic number of up to 35 or CF3; R<2> and R<3> are H or groups except CF3 in R<1> and R<4>; R<5> and R<6> are H, lower alkyl or benzyl). Furthermore, a solvent, such as chlorobenzene, is used to efficiently advance the dehydrohalogenating reaction.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (1): (wherein R is a hydrogen atom, a linear or branched alkyl group, or a substituted or unsubstituted aromatic group, and The present invention relates to a method for producing a 2,8-dihaloaniline derivative represented by (X represents a halogen atom).

For more details, see 2. 2, [Regarding a novel method for producing 2,6-dihaloaniline derivatives by dehydrohalogenating 1,8-tetrahalocyclohexanimine derivatives.

[Problems to be solved by conventional technology and invention]

2.6-Dihaloaniline derivatives are used as pharmaceuticals and agricultural chemicals, especially those with the general formula (■): (wherein R1 is a lower alkyl group, a lower alkoxy group, a halogen atom with an atomic number of up to 35, or a trifluoromethyl group. , R
2 and R3 each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom with an atomic number of up to 35, and R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom with an atomic number of up to 35. Alternatively, it is useful as an intermediate for substituted phenylacetic acid represented by a trifluoromethyl group, and R5 and R6 each represent a hydrogen atom, a lower alkyl group, or a benzine group (see Japanese Patent Publication No. 42-23418).

2.8-dihaloaniline derivatives are synthesized according to various conventionally known procedures.

For example, N-acetylsulfanyl chloride is halogenated to yield 2,6-cycloN-acetylsulfanyl chloride, and the resulting 2,6-dihalo-N-acetylsulfanyl chloride is hydrolyzed to desulfonate and deacetate. 2,6-dihaloaniline and iodobenzene obtained by deriving 2,8-dihaloaniline,
A method has been disclosed in which a 2,6-dihaloaniline derivative is obtained by condensing a halide such as bromobenzene in the presence of copper powder and potassium carbonate at high temperature by Ullmann reaction (see Japanese Patent Publication No. 42-23418). .

This method requires several steps to obtain 2,6-dihaloaniline, resulting in lower yields and increased amounts of waste.Also, in order to obtain 2,6-dihaloaniline derivatives, expensive iodo compounds are required. The problem is that the cost of the product increases because of the need for There are some problems.

2. The present invention is very useful as an intermediate for pharmaceuticals and agricultural chemicals.
The object of the present invention is to provide an excellent method for producing 6-dihaloaniline derivatives using inexpensive raw materials in short steps and with high yield and high purity.

[Means for solving problems]

However, as a result of intensive studies in view of the problems of the prior art, the present inventors found that when 2,2.6.8-tetrahalocyclohexanimine derivatives are dehydrohalogenated, 2,6-
Dihaloaniline derivatives can be used, especially when N is used as a solvent.
When using amides such as N-dimethylformamide and N,N-dimethylacetamide, aliphatic nitrile compounds such as chlorobenzene, nitrobenzene, cyanobenzene, acetonitrile and propionitrile, and abrotic polar solvents such as dimethyl sulfoxide, The present invention was completed by discovering that the dehydrohalogenation reaction proceeds efficiently.

That is, the present invention provides 2.2. I3.6-Tetrahalocyclohexanimine derivative is dehydrohalogenated in the presence or absence of a catalyst (
I): (wherein R represents a hydrogen atom, a linear or branched alkyl group, or a substituted or unsubstituted aromatic group, and X represents a halogen atom) .

〔Example〕

The 2,2.8.6-tetrahalocyclohexanimine derivatives used as starting materials in the present invention are easily obtained by halogenation of cyclohexanone, which is an inexpensive raw material and easily available. It can be easily obtained by dehydration condensation of 6-titrahalocyclohexanone and a primary amine or ammonia. Also, 2.2.8.6
The halogen atom of -titrahalocyclohexanone is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like.

The 2,6-cyhaloaniline derivative, which is the target compound of the present invention, can be produced by the reaction formula: (wherein, R is a hydrogen atom, a linear or branched alkyl group, or a substituted or unsubstituted aromatic group, and X represents a halogen atom).

Examples of the base catalyst include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; sodium carbonate, potassium carbonate, and magnesium carbonate. , anodic or alkaline earth metal carbonates such as calcium carbonate; alkali metal or alkaline earth metal oxides such as magnesium oxide or calcium oxide; organic bases such as triethylamine, pyridine, dimethylaniline, aniline, etc. Examples include amines. When a suitable base catalyst is used, the reaction proceeds under milder conditions and with high selectivity. The amount of the catalyst used is preferably 1.0 to 2.4 mol per 1 mol of 2.2.6.6-titrahalocyclohexanimine, and the reaction time is within the range of 2 to 8 hours. It is preferable to have one. The reaction temperature at this time is 50 to 120
Preferably it is ℃.

Furthermore, the present invention allows efficient dehydrohalogenation by thermal decomposition even in the absence of a catalyst. The reaction temperature at this time is preferably 50 to 150°C, more preferably 90 to 130°C. For example, 2.2
．． B, When the halogen atom of the B-tetrahalocyclohexanimine derivative is a chlorine atom, the reaction temperature is 50°C.
Below 150°C, no reaction occurs at all, and when the temperature exceeds 150°C, side reactions rapidly increase, resulting in 3 chlorine atoms per molecule.
A 2-chloroaniline derivative is produced by individual elimination. This by-product is difficult to separate from the target product, and in order to separate and purify it, a significant decrease in yield is inevitable. Furthermore, if the reaction temperature is less than 90°C, the reaction rate is slow; if it exceeds 130°C, side reactions tend to increase. In this case 2, 2,
The catalytic action of the 6,6-tetrahalocyclohexanimine derivative or the product 2,6-cyhaloaniline derivative itself, that is, the 2,6-cyhaloaniline derivative itself is an amine and is basic, so it acts as an organic base catalyst. It is thought that dehydrohalogenation is promoted.

The 2.2,6,6-tetrahalocyclohexanimine derivative is dehydrohalogenated with a base or heat to form a quinone structure, and then converted into 2.2 by prototropy.
It becomes a 6-cyhaloaniline derivative. The 2,2.8.6-titrahalocyclohexanimine derivative is sterically very crowded and is easily hydrolyzed in the presence of water, so it is preferable to carry out the reaction in a non-aqueous system. However, when a solvent is used in the reaction, it is easier to dehydrohalogenate if a polar solvent is used, so it is necessary to dry the solvent sufficiently before the reaction to prevent hydrolysis.

The solvent used in the present invention is a very important factor in the dehydrohalogenation reaction.

Specific examples of the solvent include N,N-dimethylformamide,
Aliphatic amides such as N,N-dimethylacetamide and hexamethylphosphonylamide; Aromatic polar solvents such as chlorobenzene, nitrobenzene, cyanobenzene, and anisole; Aliphatic nitriles such as acetonitrile and propionitrile; Abrotics such as dimethyl sulfoxide Examples include polar solvents. In the present invention, the reaction can be carried out in a molten state without using a solvent, but it is generally carried out in an organic solvent in order to facilitate temperature control and improve reaction selectivity and yield.

The present invention will be explained in more detail below based on production examples and examples, but the present invention is not limited thereto.

Production Example 1 90 g (0.39 mol) of 2.2.8.6-titrachlorocyclohexanone, 200 g of toluene and 81 g (0.43 mol) of titanium tetrachloride were placed in a 1 g glass reactor.
was cooled to 5° C. in a water bath, and 145 g (1.58 mol) of aniline was gradually added dropwise to this solution while stirring. At that time, the dropping rate of aniline was adjusted so that the reaction temperature was 5 to 20°C. After the addition of aniline was completed, aging was carried out at room temperature for 2 hours.

After the reaction was completed, the reaction solution was transferred into 300 g of cold water (10° C.) with stirring to hydrolyze titanium tetrachloride. Of the reaction mixture separated into a toluene layer and an aqueous layer, the toluene layer was concentrated under reduced pressure to obtain 120 g of a black solid. This solid was recrystallized in methanol to obtain 108 g of N-phenyl-2,2,8,8-tetrachlorocyclohexaneimine in the form of yellow needles (yield: 89.8%, p: 71. 8-72.8°C). The analysis results by 'H-NMR, IR and elemental analysis are shown below.

'+1-N0R (solvent = CDCI3, internal standard: TM
S) δ ppm: 7.27 (511,
-, N@), 2.85 (411%t-,
3rd and 5th positions cu2), 2.10 (211, q, 4th position CI+2) IR (KBr tablet) νN, c: 1885 (ell-1) Elemental analysis C (%) H (%) N (%) CI ( %) Actual value 4B, 29 3.47 4.51 45.38
Theoretical value 4B, 34 3.57 4.50 45.
59 Example 1 100 sr (0.32 mol) of N-phenyl-2,2,8,8-tetrachlorocyclohexaneimine obtained in Production Example 1 and 500 g of chlorobenzene were placed in a 1 g glass reactor, without stirring. and heated in an oil bath. At that time, the reaction was carried out for 5 hours while controlling the reaction temperature to be 100°C. After the reaction, the organic layer was cooled to 25° C. and washed with 300 g of 10% sodium hydroxide aqueous solution, dried over anhydrous sodium sulfate, and chlorobenzene was distilled off under reduced pressure to obtain a black solid N-femol. 84.7 g of 6-dichloroaniline was obtained (yield: 85%, mp
: 49.5-50.7°C). The purity of the obtained N-phenyl-2,B-dichloroaniline was 92.1% as measured by gas chromatography, and n1 was determined in the same manner in the examples described below.

In addition, after purifying the obtained N-phenyl-2,8-dichloroaniline by recrystallization in methanol, 'II-
The results of NMR, IR and elemental analysis are shown below.

1H-NMR (solvent: CDCl!s, internal standard: TM
S) δ ppl: 7.53 ~ 6.55 (
8H, ■, Nucleus), 5.83 (LHLS, NH
) IR (KBr tablet) νNH3380 (cm') Elemental analysis C (%) H (%) N (%) C# (%) Actual value
80.53 3.81 5.88 29.78 Theoretical value 80.48 3.89 5.92 29.70 N-phenyl-2,6- obtained in Examples 2 to 29 below
Regarding dichloroaniline, the same analysis results as in Example 1 were obtained.

Example 2 In Example 1, 40 g of sodium carbonate was used as a catalyst.
The reaction was carried out in the same manner as in Example 1, except that (0, H mol) was used and the reaction temperature was controlled at 95°C, and 3 g of N-phenyl-2,8-dichloroaniline 6B was obtained (yield:
87%, purity: 95.1%).

Examples 3 to 1O The reaction was carried out in the same manner as in Example 2 except that 500 g of the solvent shown in Table 1 was used instead of chlorobenzene in Example 2 to obtain N-phenyl-2°6-dichloroaniline. The measurement results of each yield and purity are shown in Table 1.

Table 1 Examples U to 24 The reaction was carried out in the same manner as in Example 6 except that the catalyst shown in Table 2 was used in the bag shown in Table 2 instead of sodium carbonate. I got dichloroaniline. The measurement results of each yield and purity are shown in Table 2.

[Margin below]

Table 2 Examples 25 to 29 The reaction was carried out in the same manner as in Example 1 except that the reaction temperature shown in Table 3 was used instead of 100°C in Example 1, and N-phenyl-2, 6-dichloroaniline was obtained. The measurement results of each yield and purity are shown in Table 3.

Table 3 Examples 30 to 34 In Example 1, N-phenyl 2,2,6,6-tetrachlorocyclohexaneimine was replaced with 2 shown in Table 4.
．． The reaction was carried out in the same manner as in Example 1 except that 2.8.6-tetrahalocyclohexanimine derivatives were used, and 2, An 8-dihaloaniline derivative was obtained.

Table 4 shows the structural formula, yield, and purity measurement results for each 2,6-dihaloaniline derivative.

[Margin below]

Table 4 [Effects of the invention] The present invention provides 2,6
The effect is that dihaloaniline derivatives can be produced in a short process using inexpensive raw materials with high yield and high purity.

Claims (1)

[Claims] 1 General formula (I) characterized by dehydrohalogenating a 2,2,6,6-tetrahalocyclohexanimine derivative in the presence or absence of a catalyst: ▲Mathematical formula, chemical formula , tables, etc. ▼ (I) 2,6- (wherein R represents a hydrogen atom, a linear or branched alkyl group, or a substituted or unsubstituted aromatic group, and X represents a halogen atom) A method for producing a dihaloaniline derivative. 2. A method for producing a 2,6-dihaloaniline derivative according to claim 1, wherein the dehydrohalogenation is carried out by thermal decomposition. 3. The method for producing a 2,6-dihaloaniline derivative according to claim 1, wherein the catalyst is a base catalyst. 4. 2,6-dihaloaniline according to claim 3, wherein the base catalyst is at least one selected from the group consisting of alkali metal or alkaline earth metal carbonates, oxides and hydroxides, and organic bases. Method for producing derivatives. 5. Claims 1 and 2, wherein the halogen atom of the 2,2,6,6-tetrahalocyclohexanimine derivative is a fluorine atom, chlorine atom, bromine atom, or iodine atom.
4. A method for producing a 2,6-dihaloaniline derivative according to item 1, 3 or 4. 6 N,N-dimethylformamide, N,N as a solvent
-2,6- according to claim 1, 2, 3, 4 or 5 using dimethylacetamide, chlorobenzene, nitrobenzene, cyanobenzene, acetonitrile, propionitrile or dimethyl sulfoxide. A method for producing a dihaloaniline derivative.