Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonate esters
Reexamination Certificate
2001-10-04
2003-06-10
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonate esters
C558S054000, C558S070000, C560S129000, C560S130000, C564S218000
Reexamination Certificate
active
06576782
ABSTRACT:
Synthetic process comprising a halogenation in the meta position of an aromatic acid derivative, intermediate compounds and use of the latter.
The present invention relates to a technique for the protection of phenols for the purpose of rendering selective a functionalization of the latter or at least of their backbone. A more particular subject matter of the invention is the protection of ortho- and para-substituted phenols so as to functionalize in the meta position, advantageously in the 5 position, of the phenyl backbone.
In the field of aromatic organic synthesis, one of the most acute problems is the selectivity of the functionalization of an aromatic nucleus and more specifically the regioselectivity of the functionalization of aromatic nuclei.
This problem becomes more acute when the functionalization takes place at an advanced stage in the synthesis. The more expensive the starting material in this functionalization stage, the more important it is to obtain selective reactions with a high yield.
This is in particular the case with trifunctionalized benzene nuclei which are to be functionalized a fourth time (that is to say, that it already comprises 3 substituents).
The problem is often complicated by the directing effect of some functional groups, in particular when these functional groups have a very marked directing effect, as is the case with phenol functional groups and their derivatives and aniline functional groups and their derivatives.
Thus, in Japanese Patent JPA 4356438, which relates to a general synthesis comprising a stage of halogenation of similar products to those which have just been mentioned above, the halogenation is carried out on the methyl ether of the phenol and a most indifferent yield is obtained since an isolated yield of less than 30% is obtained, which implies a doubtless very low selectivity (CY).
In addition, mention should be made, among the functionalizations which are the most difficult to carry out, of halogenations, which can be nonselective in several respects, first, with regard to the regio-selectivity and, secondly, with regard to the number of halogenations which the nucleus has to be subjected to.
This is why one of the aims of the present invention is to provide a process for the selective halogenation in the meta position of an aromatic derivative exhibiting an aniline functional group or a phenol functional group.
Another aim of the present invention is to provide a process of the above type in which the aromatic nucleus exhibits electron-withdrawing functional groups in the ortho position (in the 2 position) and in the para position (in the 4 position) (these electron-withdrawing functional groups advantageously being electron-withdrawing by an inductive effect; it is preferable for said electron-withdrawing functional groups to be electron-withdrawing by an inductive effect and advantageously electron donating by a mesomeric effect), whether these electron-withdrawing functional groups are alike or different.
Another aim of the present invention is to provide a protective system which promotes the above selectivity of halogenations.
Another aim of the present invention is to provide the use of molecule thus protected for the purpose of a selective halogenation.
Another aim of the present invention is to provide a process for the halogenation of the molecule thus protected for the purpose of a selective halogenation in the 5 position when the latter is distinct from the 3 position.
Another aim of the present invention is to provide a process of the above type which exhibits a selectivity (CY, that is to say conversion yield, namely the ratio of the amount of the desired product obtained to the amount of the starting substrate which has disappeared, everything being expressed in moles) at least to 80%, advantageously to 85%, preferably to 90%.
Another aim of the present invention is to provide a process of the above types which makes it possible to obtain a reaction yield (RY, that is to say the ratio of the amount of product obtained to the amount of starting substrate introduced) at least equal to 60%, advantageously to 70%, preferably to 80%.
Another aim of the present invention is to provide synthetic intermediate compounds.
These aims and others which will become apparent subsequently are achieved by means of an organic synthesis process comprising at least a stage of halogenation of the aromatic derivative of a moderate or advantageously strong acid in which the aromatic residue is a phenyl substituted in the ortho position and para position by functional groups which are electron-withdrawing by an inductive effect.
Thus, according to the present invention, it has been shown that the protection, by means of a strong acid and by means of a phenol or an aniline, played a role of induction in the meta and in particular in the 5 position of the derivatives of the above type.
This regioselectivity is particularly marked in the case of phenyl esters.
At least one (in particular that ortho to the protected phenol functional group), advantageously both electron-withdrawing functional groups, exhibit(s) an electron-donating property by mesomeric effect.
The most advantageous effects are obtained in the case where said electron-withdrawing functional groups, in any event at least one, preferably both, are halogen atoms.
In order to avoid side reactions, it is preferable for at least one if not both electron-withdrawing functional groups to be light halogens, that is to say chlorine or fluorine atoms.
The selectivity becomes increasingly advantageous in proportion as the starting materials become difficult to obtain. Thus, starting materials or the electron-withdrawing functional groups are respectively a chlorine and a fluorine are particularly well suited to the process of the present invention.
Mention may in particular be made of the compounds which exhibit a chlorine in the ortho position and a fluorine in the para position.
As regards said strong or moderate acids, it is preferable for said strong or moderate acid to be chosen from oxygen-comprising acids.
It is also desirable for said strong or moderate acid to exhibit a pK
a
of less than or equal to 4, advantageously of less than or equal to 2, preferably of less than or equal to 0.
The easiest acids to use are those which can be chosen from the following list: acids or acid esters of phosphoric (ortho-, pyro- or poly-) or phosphonic acids, indeed even phosphinic, sulfonic and alpha-polyhalocarboxylic acids.
A specific mention must be made of sulphonic acids, which are particularly well suited to the present invention. Thus, use may be made either of arylsulfonic acids, the outstanding examples of which are benzenesulfonic and para-toluenesulfonic acids; use may also be made of alkylsulfonic acids, the outstanding example of which is methanesulfonic acid, more often known as mesylic acid. The latter acid exhibits a not insignificant hydrophilicity, which can sometimes be an advantage and sometimes a disadvantage. When more lipophilic acids are desired, it is advisable to turn toward acids either comprising more than 5 carbon atoms or fluorinated acids, as will be seen below. If more hydrophilic acids are desired, it is possible to turn toward polyacids, such as phosphoric or phosphonic acids; polyhalocarboxylic acids are to be ranked among compounds with a lipophilic tendency (this lipophilicity means good solubility in the organic phases).
A specific mention must be made of sulfonic acids fluorinated on the alpha position and, if appropriate, beta position. Mention may thus be made of trifluoromethylsulfonic acid or trifluoric acid. However, it should be emphasized that perfluorosulfonic acids are particularly fat-soluble acids, which makes possible good solubility in water-imiscible organic phases.
This solubility in organic phases can constitute an advantage or else a disadvantage, depending upon the situation and according to whether it is or is not desired to separate the final product by recovering it in an organic phase.
The halogenation is advantageously carri
Desmurs Jean-Roger
Padilla Genevieve
Spindler Jean-Francis
Kumar Shailendra
Rhodia Chimie
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