Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic halides
Reexamination Certificate
2003-10-17
2004-12-21
Zucker, Paul A. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic halides
Reexamination Certificate
active
06833476
ABSTRACT:
A subject matter of the present invention is a process for the synthesis of fluorinated compounds using, as fluorine source, the carbamoyl fluoride which is in equilibrium with the isocyanate and the hydrofluoric acid.
The present invention is targeted more particularly at the synthesis of compounds simultaneously exhibiting a perfluorinated carbon, or in any case a perhalogenated carbon, and an isocyanate functional group, in particular an isocyanate functional group deriving from an aniline functional group.
The perhalogenated carbon, generally a perfluorinated carbon, is a carbon of aliphatic nature, that is to say that it has sp
3
hybridization.
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 part of the molecule carrying the isocyanate functional group, at most 2 radicals, advantageously at most 1 radical, all the other atoms being halogens; said radicals are advantageously chosen from electron-withdrawing groups, this being the case in particular when there are 2 of them. Although not perhalogenated stricto sensu, carbons carrying two halogens and one hydrogen are capable of being treated like the perhalogenated compounds in the strict sense. However, they are more sluggish. Carbons carrying exchangeable or exchanged halogens are also denoted by the term “halophoric carbon(s)”.
During recent decades, and more specifically during the last decade, compounds carrying a perhalogenated and in particular perfluorinated aliphatic atom have become increasingly important in the field of agrochemistry and of pharmaceuticals. This is because these perfluorinated products, generally comprising a perfluoromethyl or perfluoroethyl radical, have physiological properties which render the molecules of which they are composed particularly active.
Consequently, numerous proposals for processes resulting in said products have blossomed. Generally, the fluorinating agent is liquid hydrofluoric acid, while the intermediate substrate or the starting substrate are isocyanates.
Mention may thus be made, in the case of anilines carrying trifluoromethyl groups, of the Occidental Chemical Corporation patent No. EP-A-129 214 and the patent of the predecessor in law of the Applicant Company, namely the European patent filed on behalf of Rhône-Poulenc Spécialités Chimiques and granted under the number EP-B-152 310.
More recently, a European patent on behalf of Hoechst A. G. was published under the number EP-A-639 556.
These documents describe various alternative treatment forms by the hydrofluoric acid route and are often a good means of appreciating the limitations of this route.
According to this technique, the starting point is the protection of the amine functional group by an isocyanate functional group, for example by phosgenation. The carbon which will have to be in a perfluorinated form in the final stage is then chlorinated, generally by the free radical route. Finally, the chlorinated compound thus obtained is subjected to a stage of chlorine/fluorine exchange in an anhydrous hydrofluoric acid medium.
Two alternative forms have to date been explored in releasing the amine from the carbamoyl fluoride obtained after the exchange; these two alternative forms are: the release of the amine by means of heating in the presence of a large excess of hydrofluoric acid to give fluorophosgene or alternatively hydrolysis in a hydrofluoric acid medium by a relatively small amount of water.
The technique using the decomposition of carbamoyl fluorides to fluorophosgene has the undoubted disadvantage of resulting in the concomitant release of fluorophosgene, the toxicity of which is much greater than that of phosgene proper, which was used as a poison gas during the First World War.
Another disadvantage of this technique is the increased consumption of hydrofluoric acid, which is a relatively expensive reactant since it has to be used in large excess.
The other techniques described, namely techniques using the in situ hydrolysis of the carbamoyl fluoride, give yields which are far from being excellent.
These low yields put a serious strain on the cost price of the final product and thus on the profitability of the complete operation.
Furthermore, the use of very large excesses of hydrofluoric acid involves subsequent recovery for economic reasons or for environmental reasons, when the industrial plant is situated inland, which recovery can be in particular:
either a recycling, as less costly, and a subsequent dehydration, which renders the recovery extremely disadvantageous as regards the cost price of the operation;
or a neutralization, followed by a recovery in value of the salts thus obtained.
Finally, during the study which led to the present invention, it was shown that, even when the aromatic ring of the molecule is depleted in electrons, the reactivity of the carbamoyl fluorides is very high and results in multiple byproducts which are injurious to the conversion yield, that is to say to the selectivity of the conversion. One of the possible routes remaining open which allows easy access to the aniline is the return to the isocyanate. Thus, during the study which led to the present invention, it was shown that it is possible to proceed from the carbamoyl fluoride to the fluorinated isocyanate, provided that particularly strict procedures are adhered to.
This part of the study has formed the subject matter of an international patent application filed in France under the number PCT/FR00/01912 under priority of the French application filed under the number 9908647. These applications are published.
This technique, although it represented a significant advance, still involved the recycling of large amounts of hydrofluoric acid. This is why the study was continued to examine whether it was possible to use the discovery according to which the carbamoyl fluoride was not the source of a large number of byproducts when it was in the presence of a significant amount of isocyanate functional groups.
This is why one of the aims of the present invention is to provide a fluorinating process which does not require a large excess of hydrofluoric acid. Another aim of the present invention is to provide a process which makes it possible to achieve high conversion yields and high reaction yields.
Another aim of the present invention is to provide a process of the preceding type which makes it possible to avoid the release, or at least to limit the release, of fluorophosgene.
These aims, and others which will become apparent subsequently, are achieved by means of a process for the treatment of a derivative carrying a perhalogenated carbon, advantageously in the benzyl or allyl position or carried by an atom exhibiting a free doublet, advantageously a chalcogen, by means of a carbamoyl fluoride, advantageously an aromatic carbamoyl fluoride (that is to say, the nitrogen atom of which is connected to an aromatic ring), characterized in that said derivative carrying a perhalogenated carbon and said carbamoyl fluoride are subjected to a temperature at least equal to 70° C., advantageously at least equal to 90° C., and in that, at said temperature of at least 70° C., the ratio Q of; on the one hand, the sum of the hydrofluoric acid (HF) and of the carbamoyl fluorides to, on the other hand, the sum of the exchangeable halogens, of the isocyanate functional groups and of the carbamoyl fluorides is maintained, throughout the duration of the reaction, at a value at most equal to 1.2, advantageously to 1; indeed even 0.9 in the final third of the final exchange.
The above ratio Q can be expressed as written below:
HF
+
carbamoyl fluoride (s)
exchangeable halogens
+
isocyanate
+
carbamoyl fluorides
This ratio is targeted at all the entities present in the reactor, whether they are in the gas phase or whether they are in (the) liquid phase(s). If, in the case where the operation is being carried out in an open (unclosed) reactor, the amount of HF in the gas phase cannot be easily determined, only the HF
Guidot Gilbert
Kempf Hubert
Saint-Jalmes Laurent
Schanen Vincent
Rhodia Chimie
Zucker Paul A.
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