Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-10-21
2004-06-08
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S442000, C548S343100
Reexamination Certificate
active
06747175
ABSTRACT:
The present invention is targeted at a process for the synthesis of an aniline which is chlorinated on the ring and which comprises at least one carbon atom of sp
3
hybridization which is both perhalogenated and the carrier of a fluorine atom. It is targeted more particularly at the chlorination in a hydrofluoric acid medium of a precursor aniline of said chlorinated aniline.
Fluorinated molecules are playing an increasing role in pharmaceuticals and in agrochemicals. The synthesis of fluorinated derivatives is often problematic as direct fluorination reactions are generally too violent and too selective to be able to be employed. Consequently, the synthesis of fluorinated derivatives often makes use of exchanges of various substituents with fluorine and in particular exchanges of heavier halogens with fluorine.
The most widely used and the least expensive reactant in carrying out the exchange is unquestionably liquid-phase hydrofluoric acid.
Hydrofluoric acid exhibits various properties which depart from the ordinary and renders the reactions carried out within a hydrofluoric acid medium difficult to predict and in any case different from the results obtained with conventional techniques.
In particular, liquid hydrofluoric acid is a particularly aggressive medium and where numerous combinations by hydrogen bonding take place; moreover, hydrofluoric acid forms, with amines and in particular with weak amines and with aromatic heterocycles, extremely stable complexes which it is difficult to treat and to restore the free amine and the hydrofluoric acid.
Generally, an aniline bonds with four molecules of hydrofluoric acid which it will be necessary to neutralize to release the amine.
This neutralization is particularly expensive and leads to the discharging of hydrofluoric acid salts, the discharge of which is generally strictly regulated.
Currently, the chlorination of anilines takes place on the free aniline, in particular when the ring carrying the amine functional group is depleted in electrons by electron-withdrawing groups.
The hydrochloric acid given off by the chlorination of the aniline subsequently has to be neutralized to release the amine.
The problem is particularly acute in the case of anilines which carry, on a side chain, a perhalogenated and in particular perfluorinated carbon of sp
3
hybridization.
For this reason, one of the aims of the present invention is to provide a process which comprises a stage of chlorine/fluorine exchange in a hydrofluoric acid medium (with or without diluent) and which makes it possible to avoid a twofold release of the aniline, once from hydrofluoric acid and another time from hydrochloric acid.
Another aim of the present invention is to provide a process which makes possible good recovery of hydrofluoric acid bonded to anilines.
Another aim of the present invention is to provide a process of the preceding type which makes it possible to limit the saline discharges from the process.
These aims and others which will become apparent subsequently are achieved by means of the process for the synthesis of an aniline which is chlorinated on the ring and which comprises at least one carbon atom of sp
3
hybridization which is both perhalogenated and the carrier of a fluorine atom, characterized in that it comprises the stage of chlorination of a precursor aniline of the chlorinated aniline, this reaction being carried out in a hydrofluoric acid medium capable of exchanging chlorine and fluorine in the benzyl position or on a carbon carrying a chalcogen.
The term “perhalogenated carbon” should be understood as meaning a carbon of sp
3
nature which does not carry hydrogen and which comprises, in addition to its bond with the aryl or with the chalcogen, at most 2, advantageously at most 1, radicals, all the other atoms being halogens; said radicals are advantageously chosen from electron-withdrawing groups, in particular when there are 2 of them.
The present invention is of particular use for anilines which carry an electron-withdrawing group in the position para to the amine functional group. This electron-withdrawing group is advantageously an electron-withdrawing group which exerts its effect via an inductive effect and in particular groups perhalogenated on the carbon bonded to the aromatic ring of the aniline.
The hydrofluoric acid medium can either be liquid hydrofluoric acid or a hydrofluoric acid diluted in a solvent.
This hydrofluoric acid medium can be composed simply of the amine complexed by several molecules of hydrofluoric acid, generally from 2 to 5, most often 4. Generally, the HF/aniline ratio is between 2 and 10, advantageously between 4 and 8. The upper limits have only an economic meaning.
Although the aniline can be prepared in situ by decomposition of carbamoyl fluoride, this implementation is not preferred because of the risks of emission of fluorophosgene (COCl
2
). According to a preferred implementation, the optional “release” of the amine from its carbamoyl fluoride is carried out before carrying out the chlorination.
The solvents used are advantageously solvents known for making possible ionic chlorination (chlorination by an entity of the C1
+
type).
Mention may in particular be made, among the solvents which can be used, of fluorinated derivatives and chlorinated aromatic derivatives, such as, for example, monochlorobenzenes, dichlorobenzenes or trichlorobenzenes.
According to the present invention, it is possible to carry out a monochlorination or especially a dichlorination, the monochlorination occurring ortho and the dichlorination being essentially ortho-ortho′ to the aniline functional group.
The chlorination generally occurs at a temperature of between 0 and 150° C., advantageously between 20 and 120° C.
The double chlorination occurs at temperatures greater than ambient temperature and gives good results at a temperature of between 70° C. and 150° C.; the most satisfactory results are obtained between 90° C. and 140° C.
However, to obtain very good yields, it is desirable to be at a temperature greater than or equal to 100° C. (2 significant figures), preferably greater than 100° C. To further improve the yield and the selectivity, it is desirable to introduce the substrate into a reaction mass (including solvent) corresponding to the above temperature restrictions. During heating, to avoid the unfavorable effect of the intermediate temperatures below the preferred temperatures, it is even possible to envisage heating the substrate in particular and the reactants in general before introduction.
In addition, it is desirable for the chlorine to be introduced so that the medium always remains chlorinating, in other words the rate of consumption of the chlorinating agent (e.g. chlorine) is at most equal to the rate of introduction into the medium of said chlorinating agent. For example, the fact of introducing chlorine so that it is stoichiometrically in excess with respect to the desired reaction constitutes an operating parameter which improves both the yield and the selectivity. This stoichiometric excess is advantageously produced throughout virtually the entire reaction.
In order to avoid side reactions, it is desirable, as soon as sparging of chlorine ceases, to suddenly cool the reaction mixture. This cooling is advantageously carried out at least partially by the removal of the hydrofluoric acid under reduced pressure.
According to an advantageous embodiment of the reaction, the substrate and the chlorine are introduced gradually and simultaneously over a heel of solvent or of reaction mass, brought to and maintained at the favorable temperature.
The presence of Lewis acid, such as boron trifluoride, although favoring the reaction, is not necessary. The molar amount of optional Lewis acid is advantageously between 10
−4
and 10
−1
with respect to the substrate.
The pressure at which the reaction is carried out is advantageously either atmospheric pressure or a pressure greater than atmospheric pressure, preferably autogenous pressure.
The chlorinating agent is advantageousl
Guidot Gilbert
Kempf Hubert
Saint-Jalmes Laurent
Davis Brian J.
Rhodia Chimie
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