JPH06316550A - Synthesis of deactivated aniline - Google Patents

Abstract

PURPOSE: To synthesize a compound such as p-trifluoromethyl-N,N- dimethylaniline in a single step by reacting dialkyl amide with heating in the presence of a base from a corresponding halogenated derivative as a starting material.

CONSTITUTION: Deactivated aniline is obtained by reacting a compound of formula (R₁ is favorably Cl or the like; R₂ is H, hydrocarbon, halogen or the like; R₃ is favorably Cl or the like; R₄ is favorably perfluoroalkyl or the like; R₅ is favorably F, Cl or the like; R₆ is a hydrocarbon chain, halogen or the like) with dialkyl amide in the presence of a base at 150 to 300°C, particularly 180 to 250°C. The process is important to particularly obtain a trifluoromethyl derivative. I.e., the process can be used for the preparation of the aniline substituted particularly at a p-position by an electron-withdrawing group.

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to the synthesis of inactivated aniline. In particular, the present invention relates to methods that include a dialkyl amination step with an amide.

[0002]

BACKGROUND OF THE INVENTION The synthesis of aniline is generally carried out with a nitro derivative, which consists of hydrogenating it. However, this method is subject to many constraints and is not always easy to apply when the product is sensitive to hydrogenolysis or produces many side reactions. Moreover, the positioning of nitro functional groups is not always easy and some syntheses require a large number of steps.

[0003]

The present invention therefore relates to a novel synthetic process which can be used in particular for the preparation of anilines in which the p-position is replaced by an electron-withdrawing group (EAG).

[0004]

The above-mentioned object is obtained by the following formula (I):

[Chemical 2] (Wherein, R ₁ represents the anion (R ₁ ^- groups as constituting a) is good leaving group, preferably selected from among bromine or chlorine atom, preferably a chlorine atom (anion Acids associated with at most a pKa value of at most 1 and advantageously at 0, preferably at -1, are considered good leaving groups), R ₂ is hydrogen, a hydrocarbon chain, halogen and Of groups that are selected from the group (EAG) that has an electron-withdrawing property due to the inductive effect rather than the resonance effect, and R ₃ is inactive, but has at least an attractive force due to the inductive effect as hydrogen and an alkyl group. R ₄ is advantageously selected from among hydrogen, hydrocarbon chains, halogens and groups which are electron withdrawing by inductive effects rather than resonance effects, and R ₅ is inactive Induced effect as much as and alkyl groups It is advantageous to be selected from among the group of at least exerting a suction force by, R ₆ is selected from among the hydrocarbon chain is an electron-withdrawing by an inductive effect, rather than the halogen and resonance effects group, provided that Group R
_At least one of ₁ , R ₆ and preferably R ₄ is electron-withdrawing by an inductive effect, and R ₂
And R ₃ and / or R ₅ and R ₆ may form at least one optionally substituted ring, optionally an aromatic ring) in the presence of a base of 150-300
Achieved by a method involving reaction with a dialkylamide at a temperature of 0 ° C, preferably 180-250 ° C (position zero is not important unless otherwise stated herein).

[0005]

DETAILED DESCRIPTION OF THE INVENTION One of the surprising features of the present invention is that there are less than two nitro groups on the same ring and the reaction proceeds even in the absence of such groups. It comes from the fact that we were able to find the conditions. Advantageously, as a result of their nature or as a result of the arrangement of the electron withdrawing groups, the anion (R ₁ ⁻ ) constitutes a better leaving group than the anion originating from the radicals R _{2 to} R ₆ .

Advantageously, the electron withdrawing group (EAG) is
Pseudohalogens and alkoxycarbonyls, light halogens (fluorine, chlorine, bromine), mostly chlorine, and preferably perhaloalkyl, more preferably trihalomethyl,
It is preferably selected from among perfluoroalkyl groups. The radicals R ₃ and R ₅ are advantageously less prominent and are preferably hydrogen, pseudohalogen or halogen, advantageously fluorine or chlorine, provided that they are not as good leaving groups as R ₁ .

Pseudohalogen means that the acid associated with the anion constitutes an anionic leaving group such that the acid has a pKa value equal to at most 1, advantageously 0, preferably -1. It should be understood as meaning a group capable of forming. The perhaloalkyl, the formula R- (CX _{2) n} -, where (III), · n is equal to at least 1, when R is not an electron withdrawing is preferably equal to 2. Each X is selected from halogen, preferably fluorine and chlorine. Y is a leaving group, preferably fluorine, chlorine, bromine or iodine. · R is C ₁ -C _10, preferably C ₁ -C _6, preferably C
Hydrocarbons, alkyl or aryl residues ₁ -C _4, preferably an electron withdrawing residue, preferably X (halogen, preferably chlorine or fluorine). X is almost always the same. n is generally at most equal to 10 and is 6 or less, preferably 4 or less, especially when the perfluoroalkyl is in the o-position.

The solvent may be any solvent which does not decompose under the experimental conditions and is inert to the reactants and is preferably polar (ie its dielectric constant ε is at least equal to 30). . When the solvent is protic, and further when the solvent is not, the solvent is preferably p-water.
It has a pKa at least equal to Ka, ie 14. Solvents are to be understood as meaning any mixture or pure substance which can be used as solvent.
However, it is preferred to carry out using either excess reactants or excess substrate as the only solvent.

Among the bases which can be used, anionic bases including carbonates are preferred. The bases used are preferably alkali metal oxides, alkali metal amides, alkali metal hydroxides and alkali metal alcoholates.

To obtain good results, it is desirable that the pKa of the base conjugate acid is at least equal to 9, advantageously 10 and preferably 12.

In the reaction system, the use of hydroxylated derivatives, in particular water, as solvent is acceptable, especially when copper is used as catalyst. Therefore, the reaction is advantageously carried out in the presence of copper. Copper is preferably introduced in the form of a cuprous salt and in an amount of 0.1 mol% to 10 mol% with respect to the substrate. Advantageously, the amounts of reactants and catalysts used are as follows, with the amount of substrate being 1. Base: 0.5-5 gram equivalents, preferably 2-4 gram equivalents Amide: 1-100 gram equivalents, preferably 5-25
Gram equivalent

The amide is preferably a dialkyl amide of a light carboxylic acid (up to 10 carbon atoms). It is possible to use a diamide such as tetramethylurea,
Tetramethylguanidine can also be used. The best result is that the dialkylamide is a dialkylformamide and the alkyl group grafted onto the nitrogen of the amide is so light that its carbon number does not exceed 6, advantageously 4 and preferably 3. Obtained when there is something. The methyl derivative is the preferred derivative.

The reaction is carried out in an autoclave under experimental conditions under the natural pressure of the reactants. Although not essential, it is preferred to carry out under an inert atmosphere, for example under a nitrogen or argon atmosphere.

The present invention is of particular importance for obtaining trifluoromethyl derivatives. In fact, contrary to all expectations, perfluoroalkyl groups, especially trifluoromethyl groups, are stable under the operating conditions of the present invention. According to the invention, it is thus possible to synthesize p-trifluoromethyl-N, N-dimethylaniline from the corresponding halogenated derivative, in particular the chlorinated derivative, in a single step. The result is that the starting material is a perfluoroalkyl functional group, which is an electron-withdrawing group, generally m- and p of a trifluoromethyl group.
A dihalogenated or trihalogenated derivative at the -position,
It is good when it is a dichloro or trichloro derivative.

In other words, of special importance, in the formula (I) R ₁ is chlorine or bromine, preferably chlorine,
₂ is fluorine, chlorine or bromine, preferably chlorine, R ₃
Is hydrogen, fluorine, chlorine or bromine, preferably chlorine,
In the synthesis when R ₄ is perfluoroalkyl, generally trifluoromethyl. However, all the compounds obtained by this step of the invention cannot be used directly. It can be said that the first or second aniline is more useful than the corresponding third aniline.

A common method for demethylating anilines, by the way, consists in using hydrobromic acid (HBr), which, together with the aniline functional group, gives the functional group which it is desired to have on the ring. There is a risk of destruction. Instable functional groups include halogenated functional groups, most often benzyl positions, ie perhalogenated groups in the α position with respect to the aromatic ring, especially perfluoroalkyl groups, most often In this case, a trifluoromethyl group may be mentioned.

For this reason, one of the objects of the invention is that the anilines, in particular the deactivated anilines, ie the acids associated with them, have a pKa equal to at most 2 and preferably equal to 1. It is to provide a method of dealkylating ones. Another object of the invention is a labile functional group as described above, for example a perfluoroalkyl group,
It is generally to provide a method of the type described above which does not compromise the trifluoromethyl functionality. Yet another object of the invention is to provide a method of the above type which does not affect the substituents in the m-position with respect to aniline.

These objects, as well as others which will become apparent from the following description, are achieved by a method of N-dealkylating an advantageously deactivated mono- or dialkylated aniline, which is Steps: b) Including halogenations known per se with free-radical halogenating agents. This halogenation is carried out under conditions known to involve free radicals, preferably by an initiating reaction (using an electromagnetic wave of suitable wavelength, peroxide or its equivalent).

They are preferably of the formula (II)

[Chemical 3] (Here, R ₁ represents a mono- or dialkylamino group, R ₂ is a group that is electron-withdrawing by hydrogen, a hydrocarbon chain, halogen and an inductive effect rather than a resonance effect (EAG).
R ₃ is inactive, but it is advantageous that R ₃ is selected from the group that at least exerts an attractive force by an inducing effect as hydrogen and an alkyl group, and R ₄ is hydrogen or a hydrocarbon chain. , Halogen and a group which is electron withdrawing by an inducing effect rather than a resonance effect, R ₅
Is inactive, but it is advantageous that it is selected from groups that at least exert an attractive force by an inducing effect like hydrogen and an alkyl group, and R ₆ is not a hydrocarbon chain, a halogen and a resonance effect, but an inducing effect. Selected from among groups having electron withdrawing properties).

In the first step, the o- and p-positions are halogenated with a halogenating agent if there are free sites. In the second step, if the amount of halogenating agent used is limited to a stoichiometric amount (or about 10% excess relative to the stoichiometric amount for a single dealkylation), the alkyl group One of which is also not limited by the amount of halogenating agent, both alkyl groups are monohalogenated in the α-position and can be isolated, and the following structure Ar-N (- _{CH 2-x Z x -R 1} ') (- CH 2-y Z y -R 2') (III ') ( wherein, Z represents a halogen brought by halogenating agent, R _1' is An alkyl group having at most 4 carbon atoms, preferably hydrogen, R ₂ 'is an alkyl group having at most 4 carbon atoms, preferably hydrogen, and R ₁ ' and R ₂ 'are nitrogen. With can be combined to give the only group forming a ring with. Compounds of this type are described further in the specification.

This dealkylation is particularly surprising in terms of its selectivity. This is because the m-position is unaffected and the carbon of the alkyl chain in the α-position relative to the aniline functional group is substantially unaffected more than once, which saves expensive reactants and the amount of effluent. Is to reduce. Furthermore, it is also possible in a broad sense to carry out a selective mono-dealkylation of aniline.

During the work of the present invention, this halogenation occurs on the carbon of the alkyl chain directly attached to the aniline functional group and on the o- and p-positions (if they are free) with respect to the aniline functional group. Only found that it would happen.

Generally, this halogenation step is carried out in a chlorinated or simply polar solvent at a temperature of 0 to 100 ° C, preferably about 0 to 50 ° C. When using a solvent with a boiling point of 100 ° C. or lower, it is convenient to carry out under reflux and, if appropriate, under reduced pressure so as to bring the reflux temperature to the preferred range.

In general, the process involves the following steps: c) Halogenation the hydrolysis of the product of step b). The hydrolysis is known per se and is preferably carried out in the presence of an absorbent of the released acid.

In the halogenation, various halogens selected from chlorine, bromine or iodine can be introduced into the molecule. Chlorine is generally preferred for economic reasons. But when you want to bring a specific halogen to the ring,
It is appropriate to use a halogenating agent which provides this halogen. The same is true when it is desired to avoid perhalogenation in the free o- and p-positions with respect to aniline. In this case, halogenation with a halogenating agent which introduces a higher rank halogen than the halogens present in the ring is preferred, and then dehydrohalogenation is carried out by means known per se to be selective. .

Examples of solvents for this halogenation are solvents which are inert under the experimental conditions, such as, but not limited to, compounds such as carbon tetrachloride, chlorobenzene, dichlorobenzene and acetonitrile. You can Most often the halogenating agent is a molecular or elemental halogen. Apart from the halogen itself, as a halogenating agent thionyl halide or sulfuryl SO _n Cl ₂ (n is 1
Or equal to 2), phosphorus pentachloride PCl ₅ , PCl ₃ / C
1 ₂ mixtures, alkyl hypochlorite and X ₂ O (X represents halogen other than fluorine and iodine) type compounds.

When these reactants are not naturally free-radical reactants (as are thionyl halides or sulphuryls), they are present in the presence of substances or conditions which promote the formation of free radicals, in particular Hal. Used under the action of actinic radiation, which is known to promote the formation of radicals. It is possible to choose mono-dealkylation or di-alkylation between ring halogenations by selection of stoichiometric amounts. In the case of bromine, when it is stable and not so toxic, a compound corresponding to the above chlorine compound and N-bromosuccinimide (NB
S) type compounds may be mentioned. In the case of iodine, the best iodizing agent is molecular iodine.

Therefore, the derivatives obtained from 1,2-dichloro-4-trifluoromethylbenzene or p-trifluoromethylchlorobenzene are converted into 4-trifluoromethyl-2-chloro-6 by halogenation known per se.
-Converted to haloaniline and then hydrolyzed. Although it was not expected, the formula _{Ar-N (-CH 2-x} Cl x -R 1 ') (- CH 2-y Cl y -R 2') (III) ( wherein, x and y Each have a value of 0 or 1 and x
+ Y is greater than 0 and Ar represents a group derived from formula (I) by removing the group R ₁ to leave a free valence and optionally by chlorination of the free o- and m-positions. The intermediate product of)) is sufficiently stable to be isolated and constitutes a precursor to many chemical derivatives. Furthermore, their isolation from the reaction medium makes it possible to obtain high purities of fully or partially dealkylated anilines, and the compounds in which y = 1 and x = 1 are very predominant. Therefore, separation is very easy. The process according to the invention works well, in particular the pK whose conjugate acid is at most equal to 2, advantageously equal to 1 and preferably equal to 0.
This is the case for mono- or dialkylated anilines (in a broad sense) such as having a.

It was also found during the study of the present invention that it is possible according to the present invention to selectively dealkylate mono- and dialkylanilines without affecting the initial aromatic groups. This process comprises the following steps: b ') aniline and ammonia or amine (advantageously mostly secondary amine in the free or salt form) of a catalytic amount of a pyridine salt, preferably pyridine. Consisting in using a method which comprises reacting in the presence of a hydrohalide salt. This surprising reaction has the advantage that it can be made selective for dialkylanilines and even when the alkylanilines are secondary.

Here, the term "aniline" should be understood in its broadest sense. That is, it means any amine that is directly attached to the electron-deficient aromatic ring system (preferably only one). This electron deficiency is measured by the pKa of the acid associated with the aniline functionality desired to be dealkylated. Thus, aniline includes not only aniline itself, but also compounds obtained by substitution of aniline, including aniline linked to other ring systems such as naphthylamine. The lack of electrons in the ring system is due to any known cause, for example:
Presence of any type of electron-withdrawing substituent or ring (6-membered ring)
Probably because of the existence of a heteroatom in. It should also be understood that amines also include mixtures of amines such as those mentioned above. The amine may be pyridine. Pyridine is to be understood in its broadest sense, ie any molecule having a pyridine ring in which the nitrogen atom has no substituents. Thus, pyridine should be understood to include not only pyridine itself, but also compounds resulting from the substitution of pyridine, including pyridine attached to other ring systems such as quinoline. With respect to the substituents on the pyridine itself, those having a boiling point equal to at most about 200 ° C are preferred. Of course, it should be understood that pyridine also includes mixtures of pyridines as described above.

When it is desired to demethylate dimethylaniline, it is also possible to carry out mono- or di-dealkylation. Monodealkylation is present when the acid corresponding to the pyridine salt and / or the amine salt is a relatively weak acid, i.e. its pKa is at most approximately equal to 1, preferably equal to 3. Generally, pyridine hydrochloride is used alone or in the presence of amine hydrochloride. Advantageously, the amine has a pKa greater than the pKa of pyridine, preferably at least 2 units, more preferably 2.5 units.

Advantageously, step b ') comprises 150 to 220
C., preferably 180-220.degree. C. Excess amine, preferably 1 to 50 equivalents, preferably 2
It is expedient to work with an excess of pyridine equivalent to 10 equivalents (for stoichiometric amount of demethylation) of pyridine hydrochloride.

One of the most surprising and most beneficial aspects of this technique is that aniline is a perfluoroalkyl functional group,
In general, ammonolysis is not observed even with the trifluoromethyl group. The pKa of the acid associated with aniline is at most 5 and 2 for liberation,
The reaction is easier when it is preferably equal to zero.

[0034]

The following examples are illustrative of the invention and are not limiting in any way.

Examples 1-4 reactions:

[Chemical 4] p-chlorotrifluoromethylbenzene (1.29 g,
7.15 mmol), DMF (4 g) and sodium amide (0.56 g, 14.3 mmol) are introduced in this order into a jacketed Teflon autoclave (100 ml). The autoclave is sealed and the mixture is heated to 180 ° C. for 24 hours with stirring. After treating the reaction medium, p-trifluoromethyl-N, N-dimethylaniline was obtained (DC 74%, TY 77%). Effect of solvent ・ Reaction

[Chemical 5] (Where X = Br or preferably Cl) Conditions: CF ₃ -Φ-CE 0.322 g (1.79 mmol) NaNH ₂ 0.14 g (53.6 mmol) DMF 4 g Teflon product autoclave with jacket (100 m
l) The results obtained are shown in Table 1 below.

[Table 1] Temperature range: 150-230 ° C using DMF

Examples 5-9 Reaction

[Chemical 6] In a 1 liter Hastelloy autoclave 3,4-dichlorotrifluoromethylbenzene (47.1 g, 0.
212 mol), DMF (200 g) and sodium hydride pellets (25.8 g, 0.645 mol). Close the autoclave and stir the mixture 2
Heat to 10 ° C. for 3 hours. The pressure reaches 9 bar. After treating the reaction medium, 4-trifluoromethyl-2-chloro-N, N-dimethylaniline was obtained (DC92
%, CY93%). The results obtained are shown in Table 2 below.

[Table 2]

Example 10 A solution of 2-chloro-4-trifluoromethyl-N, N-dimethylaniline (14.2 g, 63.8 mmol) in carbon tetrachloride (90 ml) had sulfuryl chloride (9. 5 g, 70 mmol) are added. Experiments were conducted in the presence of a strong lamp and in the absence of light. 2 at 70 ° C
After heating for an hour, the solution is treated with excess 50% aqueous sodium hydroxide solution. The results of the HPLC analysis of the organic phase are shown in Table 3 below.

[Table 3]

Example 11 2,6-Dichloro-4-trifluoromethyl-N, N-
A mixture of dimethylaniline (4.5 g, 17.4 mmol) and 2,6-dichloro-4-trifluoromethyl-N-methylaniline (1.88 g, 6.9 mmol) was dissolved in carbon tetrachloride (60 ml). The resulting solution is treated with sulfuryl chloride (5.7 g, 42.2 mmol). The reaction mixture is cooled to 10 ° C. and then irradiated with a UV lamp for 6 hours and then treated with excess 50% aqueous sodium hydroxide solution. HPLC analysis of the organic phase showed the presence of 2,6-dichloro-4-trifluoromethylaniline (70 mol%).

Example 12 A solution prepared by dissolving 2,6-dichloro-4-trifluoromethyl-N-methylaniline (1.31 g, 5.4 mmol) in carbon tetrachloride (40 ml) was treated with sulfuryl chloride (4. 5 g, 33 mmol). The reaction mixture is cooled to 10 ° C., irradiated with a lamp for 1 hour and then treated with excess 50% aqueous sodium hydroxide solution. HPLC analysis of the organic phase showed the presence of 2,6-dichloro-4-trifluoromethylaniline (83 mol%).

Example 13 2,6-Dichloro-4-trifluoromethyl-N, N-
A theoretical amount of gaseous chlorine is introduced into a solution of dimethylaniline (3 g, 11.6 mmol) in carbon tetrachloride (60 ml). During the introduction of chlorine, the reaction mixture is cooled to 10 ° C. and illuminated by UV lamp. HPLC analysis of the organic phase after treatment showed that after 1 hour a conversion of 92% and a
A yield of 4% 2,6-dichloro-4-trifluoromethylaniline was shown.

Example 14 2,6-Dichloro-4-trifluoromethyl-N, N-
A theoretical amount of gaseous chlorine is introduced into a solution of dimethylaniline (2.25 g, 8.7 mmol) in 1,2-dichlorobenzene (65 ml). During the introduction of chlorine,
The reaction mixture is cooled to 10 ° C. and illuminated by UV lamp. HPLC analysis of the organic phase after treatment showed 99% conversion after 50 minutes and a yield of 92% 2,6-dichloro-4-trifluoromethylaniline.

Example 15 2,6-Dichloro-4-trifluoromethyldimethylaniline (8.45 mmol) was dissolved in 1,2-dichlorobenzene (65 ml) and cooled to 10 ° C. to give a theoretical amount. Introduce gaseous chlorine of. 15 by UV lamp
After irradiating the reaction medium for minutes, the light is blocked and the reaction is continued for 2 hours. HPLC analysis of the organic phase after treatment shows 98%
And a yield of 34% 2,6-dichloro-4-trifluoromethylaniline.

Example 16 1,2,3-Trichlorobenzene (0.963 g), D
MF (4 g) and sodium hydroxide (0.4 g) in that order with a jacketed Teflon autoclave (100
ml). The autoclave is sealed and the mixture is heated to 220 ° C. for 24 hours with stirring. Conversion rate is 7
It was 8%. After treating the reaction medium, a mixture of 0.517 g of dichloro-N, N-dimethylaniline is contacted with pyridine hydrochloride (5.70 g). 185 the mixture
Heat to ° C for 45 minutes. HPLC analysis of the mixture was 2,
It showed the presence of 3-dichloroaniline (95%) and 2,6-dichloroaniline (5%).

Example 17 1,2,4-Trichlorobenzene (0.766 g), D
MF (4 g) and sodium hydroxide (0.4 g) in that order with a jacketed Teflon autoclave (100
ml). The autoclave is sealed and the mixture is heated to 220 ° C. for 24 hours with stirring. Conversion rate is 8
It was 2%. After treating the reaction medium, a mixture of 0.223 g of chloro-N, N-dimethylaniline is contacted with pyridine hydrochloride (3.2 g). The mixture is heated to 185 ° C for 60 minutes. HPLC analysis of the mixture was 2,4-
The presence of dichloroaniline (96%) and 3,4-dichloroaniline (4%) was indicated.

Example 18 1,2,4,5-tetrachlorobenzene (0.919
g), DMF (4 g) and sodium hydroxide (0.4
g) are introduced in that order into a jacketed Teflon autoclave (100 ml). The autoclave is sealed and the mixture is heated to 220 ° C. for 24 hours with stirring. The conversion rate was 100%. After treating the reaction medium, 0.50 g of a mixture of trichlor-N, N-dimethylaniline is contacted with pyridine hydrochloride (5.8 g). The mixture is heated to 190 ° C for 60 minutes. HPLC analysis showed the presence of 2,4,5-trichloroaniline (100%).

Example 19 2,6-Dichlorobromobenzene (0.992 g), D
MF (4 g) and sodium hydroxide (0.4 g) in that order with a jacketed Teflon autoclave (10
0 ml). The autoclave is sealed and the mixture is heated to 220 ° C. for 24 hours with stirring. The conversion rate was 89%. After treating the reaction medium, chlor-N,
0.43 g of a mixture of N-dimethylaniline is contacted with pyridine hydrochloride (5.2 g). The mixture is heated to 190 ° C for 6
Heat for 0 minutes. HPLC analysis of the mixture showed the presence of 2,6-dichloroaniline (43%) and 2-bromo-3-chloroaniline (57%).

Example 20 Pyridine hydrochloride (4.35 g, 37.7 mmol) was added to 2,6-dichloro-4-trifluoromethyl-N, N-.
Add to dimethylaniline (0.86 g, 3.3 mmol). The mixture is heated to 185 ° C for 2 hours. HPLC
Analysis showed the presence of 2,6-dichloro-4-trifluoromethylaniline (76 mol%).

Example 21 : Mono-demethylated 2,6-dichloro-4-trifluoromethyl-N, N-
Dimethylaniline (0.86 g, 3.3 mmol) and pyridinium acetate (5 g) are introduced into a jacketed Teflon autoclave (100 ml). The autoclave is closed and the mixture is heated to 190 ° C for 2 hours. HP
LC analysis showed the presence of 2,6-dichloro-4-trifluoromethyl-N-methylaniline (yield 9 mol%).

Example 22 : Comparative Example 2,6-Dichloro-4-trifluoromethyl-N, N-
A mixture of dimethylaniline (0.810g) and dimethylamine hydrochloride (3.5g) is heated to 180 ° C for 1 hour. HPLC analysis of the mixture showed no conversion.

Example 23 2,6-dichloro-4-trifluoromethyl-N, N-
Dimethylaniline (0.745 g), pyridine hydrochloride (34 mg) and dimethylamine hydrochloride (3.24 g)
Is heated to 180 ° C. for 1 hour. HPL of the mixture
C analysis showed a 20% yield of 2,6-dichloro-4-trifluoromethylaniline. This is 3 times higher than the theoretical value if only pyridine was active.

Example 24 : Prior Art 2,6-Dichloro-4-trifluoromethyl-N, N-
Dimethylaniline (1 g) was added to a hydrobromic acid aqueous solution (47
%, 5 g) and refluxed for 5 hours. HPLC analysis of the mixture showed a conversion of 89% and a yield of 2,6-dichloro-4-trifluoromethylaniline of 55%.

Example 25 : Comparative Example This purpose is to illustrate the need for free radical properties. A solution of 2-chloro-6-nitro-N, N-dimethylaniline (0.802 g, 4 mmol) in chloroform (10 ml) is introduced into a 100 ml Teflon reactor. A solution of bromine (0.64 g, 4 mmol) in chloroform (20 ml) is added to the above solution. The mixture is stirred at room temperature for 4 hours. Analysis of the reaction mixture showed that nothing other than the starting material was present (analytical method: gas chromatography and mass spectrometry).

Example 26 : Comparison with US Pat. No. 2,887,514 This is to demonstrate that the presence of a base is necessary. Absence of base 3,4-dichloro-4-trifluoromethylbenzene (4.62 g, 21.4 mmol) and dimethylformamide (22 g, 14 molar equivalents) were added in that order to 100 m.
1 teflon autoclave with jacket. Close the autoclave and stir the mixture 2
Heat to 00 ° C. for 5 hours. Analysis by gas chromatography of the reaction medium showed a conversion of 3% for a dimethylaniline yield of 2%. Presence of base 3,4-dichloro-4-trifluoromethylbenzene (4.62 g, 21.4 mmol), dimethylformamide (22 g, 14 molar equivalent) and solid sodium hydroxide (0.856 g, 2.5 molar equivalent). ) In that order 10
Introduce into 0 ml jacketed Teflon autoclave. The autoclave is closed and the mixture is heated with stirring to 200 ° C. for 5 hours. Analysis by gas chromatography of the reaction medium showed 95% for a yield of 80% 3-chloro-4-trifluoromethyldimethylaniline.
It was shown that the conversion rate was

Example 27 : Example of Regeneration and Recycle Method for Pyridinium Compounds Pyridine hydrochloride can be prepared by methods known to those skilled in the art, for example, treatment of pyridine with a stoichiometric amount of 36% aqueous hydrochloric acid and then water. Can be easily obtained by azeotropic distillation with toluene. Method 2,6-Dichloro-4-trifluoromethyldimethylaniline (1.72 g, 6.6 mmol) in the presence of pyridine hydrochloride (8.7 g, 37.7 mmol) at 180 ° C.
Heat for 1 hour. Analysis of the reactants showed 100% conversion. The reaction medium is then cooled to 140 ° C. and o-xylene (5 ml) is added with stirring. After 2 minutes, the stirring was stopped and the two layers separated. Collect the upper layer. Analysis by gas chromatography showed 2,6-dichloro-4-trifluoromethylaniline (1.47
g, 97% yield). 20 lower layers containing methylpyridinium hydrochloride and pyridinium hydrochloride
It is regenerated by reacting ammonia at 0 ° C. The pyridine recovered by distillation can be recycled.

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Claims (15)

[Claims] 1. The following formula (I): (Wherein R ₁ is selected from the group whose anion constitutes an excellent leaving group, preferably from among bromine or chlorine atoms,
Preferably chlorine atom (equal to 1 the acid associated with the anion at most, preferably to 0, preferably considered are those showing a pKa value equal to -1, which is a good leaving), R ₂ is It is selected from hydrogen, a hydrocarbon chain, a halogen, and a group (EAG) that is electron-withdrawing by an inductive effect rather than a resonance effect, and R ₃ is inactive, but is attracted by an inductive effect as much as hydrogen and an alkyl group. It is advantageous to be selected from among groups which at least exert a force, R ₄ is selected from among hydrogen, hydrocarbon chains, halogens and groups which are electron-withdrawing by inductive effect rather than resonance effect, and R ₅ is inactive, it is advantageous to be selected from among the group of at least exerting a suction force by about the inductive effects of hydrogen and alkyl radicals, R ₆ is I is a hydrocarbon chain, halogen and resonance effects Selected from among the groups which are electron-withdrawing by an inductive effect Te.
Provided that at least one of the groups R ₁ , R ₆ and preferably R ₄ is electron withdrawing by an inducing effect) in the presence of a base at 150 to 300 ° C., preferably 180 to 250 ° C. A method comprising the step of reacting with a dialkylamide at a temperature of ° C (presence or absence of position is not important unless stated otherwise herein). 2. A process according to claim 1, wherein the reaction is carried out in the presence of copper and the copper is introduced, preferably in the form of cuprous. 3. The electron withdrawing group (EAG) is selected from alkoxycarbonyl and light halogen (fluorine, chlorine, bromine) and is most often chlorine, preferably a perfluoroalkyl group. the method of. 4. The radicals R ₃ and R ₅ are advantageously relatively insignificant and are preferably hydrogen, pseudohalogen or halogen, preferably fluorine or chlorine.
The method according to any one of 3 above. 5. The amide is preferably a lightweight carboxylic acid (1
A method according to any one of claims 1 to 4, which is a dialkylamide having 0 or less carbon atoms). 6. The dialkylamide is a dialkylformamide, the alkyl group grafted to the nitrogen of the amide preferably having no more than 6 carbon atoms, preferably 4 carbon atoms.
The method according to any one of claims 1 to 5, wherein the weight is preferably not more than 3. 7. In formula (I), R ₁ is chlorine or bromine, preferably chlorine, R ₂ is fluorine, chlorine or bromine, preferably chlorine, and R ₃ is hydrogen, fluorine, chlorine or bromine, preferably chlorine, according to claim 1 to 6 R ₄ is perfluoroalkyl, in general trifluoromethyl
The method described in any one of. 8. The process according to claim 1, which comprises the following step b) halogenation known per se with a free-radical halogenating agent. 9. The method according to claim 1, wherein the halogenation step is carried out at a temperature in the range of 0 to 100 ° C., preferably 0 to 50 ° C. 10. The halogenating agent is thionyl chloride So ₂ C.
l ₂ , phosphorus pentachloride PCl ₅ , a mixture of PCl ₃ / Cl ₂ ,
10. The method according to claim 1, which is selected from the group consisting of alkyl hypochlorite and X ₂ O (X represents halogen other than fluorine and iodine) type compounds. 11. The method according to claim 1, wherein the halogenating agent is a molecular or atomic halogen. 12. Next step b ′) Aniline and ammonia or amine in the presence of a catalytic amount of a pyridine salt, preferably pyridine hydrohalide, which is preferably at most a second 8. A process according to any of claims 1 to 7, which comprises reaction with an amine, in free form or in the form of its salt. 13. A method according to any of claims 7 to 11 wherein the amine has a pKa higher than the pKa of pyridine, preferably by at least 2 units, more preferably by 2.5 units. 14. Process b ′) is carried out at a temperature of 150 to 250 ° C., preferably 180 to 220 ° C.
The method described in any one of. 15. The following formula _{Ar-N (-CH 2-x} Cl x -R 1 ') (- CH 2-y Cl y -R 2') (III) ( wherein, x and y each is 0 or an Has a value of 1 and x
+ Y is greater than 0 and Ar represents a group derived from formula (I) by removing the group R ₁ to leave a free valence and optionally by chlorination of the free o- and m-positions. ) Intermediate compounds.