Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-12-08
2002-06-25
Siegel, Alan (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
Reexamination Certificate
active
06410796
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for the preparation of acetophenones that are substituted by two or more fluoroalkyl groups on the aromatic ring. Such compounds are useful intermediates for the preparation of active ingredients for the treatment of inflammation, migraines, vomiting, and pain. In particular, the present invention relates to a process for the preparation of bis-3,5-(trifluoromethyl) acetophenone.
It is known that bis-3,5-(trifluoromethyl)acetophenone can be prepared from bis-3,5-(trifluoromethyl)benzoyl chloride by reaction with organic copper compounds (
Tetrahedron Letters
, No. 53, 4647-50 (1970)). A disadvantage of this process is the required preparation and use of lithium dialkylcopper compounds at −78° C. and with the absolute exclusion of water. Such methods can be used in the laboratory, but not on an industrial scale.
As a process for the preparation of bis-3,5-(trifluoromethyl)acetophenone, it is known to prepare the corresponding diazonium salt mixture from fluoroalkylaniline and sodium nitrite in the presence of sulfuric acid, then to add the mixture, at −5 to ±0° C., to an initial charge that comprises water, acetaldoxime, a copper(II) salt, possibly a reducing agent (sodium thiosulfate), and in every case a large amount of sodium acetate buffer. For work-up, hydrochloric acid is added, the mixture is refluxed, steam distillation or phase separation is carried out, and the mixture is distilled under reduced pressure. This gives bis-3,5-(trifluoromethyl)acetophenone in a yield of 51% of theory. See EP-A1 949,243, Example 6-3.
A disadvantage of this process is the use of a large amount of auxiliaries, e.g., buffer salts that hinder work-up, lead to a considerable salt content in the wastewater and, following their removal, give rise to high costs for an environmentally-friendly disposal.
Also known is a process for the preparation of mono(fluoroalkyl)-acetophenones in which the process of EP-A1 949,243 is modified inasmuch as the process is carried out in the presence of halide ions, e.g., in the presence of hydrochloric acid, and without the addition of buffer salts (DE 197 19 054 A1). The above-mentioned disadvantages then do not arise. However, the transference of this process to the preparation of poly(fluoroalkyl)acetophenones has not been obvious because the poly-(fluoroalkyl) anilines that would then be required as starting materials are weaker bases than mono(fluoroalkyl)anilines and therefore tend to form triazenes. A reworking of the process according to DE 197 19 054 A1 using bis-3,5-(trifluoromethyl)aniline as starting material gave bis-3,5-(trifluoromethyl) acetophenone in a yield of only 33% (see Example 3). An increase in the amount of hydrochloric acid did not lead to an improvement in the yield.
There is therefore still a need for a simple and cost-effective process for the preparation of acetophenones which are di- or poly-substituted by fluoroalkyl groups on the aromatic ring that can be carried out on an industrial scale.
A process has now been found for preparing acetophenones that are di- or polysubstituted by fluoroalkyl groups on the aromatic ring from corresponding fluoroalkylanilines and acetaldoxime.
SUMMARY OF THE INVENTION
The present invention accordingly relates to a process for the preparation of acetophenones that are di- or polysubstituted by fluoroalkyl groups on the aromatic ring comprising
(a) preparing a diazonium salt mixture from the corresponding fluoroalkylaniline,
(b) reacting the diazonium salt mixture with acetaldoxime at 5 to 50° C. in the presence of halide ions, at least one strong acid that is not a hydrohalic acid, and at least one copper and/or palladium compound and in the absence of buffer salts and reducing agents, and
(c) heating the mixture from step (b) to a temperature in the range 70 to 160° C.
DETAILED DESCRIPTION OF THE INVENTION
In the process according to the invention it is possible, for example, to use fluoroalkylanilines of the formula (I)
wherein
m is an integer from 1 to 4,
n is zero or an integer from 1 to 2 m,
o is an integer from 1 to 2 m+1, and
p is an integer from 2 to 4,
with the proviso that n+o=2 m+1.
In formula (I) the C
m
H
n
F
o
radicals present can be identical or different but are preferably identical.
In the formula (I) m is preferably 1 or 2 (particularly preferably 1), n is preferably zero, o is preferably 2 m+1, and p is preferably 2.
If, in the formula (I), p is 2, then both C
m
H
n
F
o
groups are preferably arranged in the meta position relative to the NH
2
group. If, in the formula (I), p is 3 or 4, then two of the C
m
H
n
F
o
groups are preferably arranged in the meta position relative to the NH
2
group.
Particular preference is given to using bis-3,5-(trifluoromethyl)-aniline as compound of the formula (I).
It is an essential feature of the present invention that the reaction with acetaldoxime is carried out in the presence of halide ions and at least one strong acid that is not a hydrohalic acid. Examples of such suitable strong acids are sulfuric acid, perchloric acid, alkyl- and arylsulfonic acids, and strong carboxylic acids. Alkylsulfonic acids can contain, for example, 1 to 6 carbon atoms and can be optionally substituted by halogen atoms. Arylsulfonic acids can contain, for example, 6 to 10 carbon atoms and can be optionally substituted by halogen atoms. The strong carboxylic acids may, for example, be alkanecarboxylic acids containing 2 to 6 carbon atoms substituted by halogen atoms. Individual examples of sulfonic acids and strong carboxylic acids are methanesulfonic acid, trifluoromethane-sulfonic acid, trichloroacetic acid, and trifluoroacetic acid. Preference is given to using sulfuric acid or mixtures of sulfuric acid and one or more other strong acids different from hydrohalic acids. Particular preference is given to using sulfuric acid.
The procedure may involve, for example, carrying out the reaction of the fluoroalkylaniline with sodium nitrite in the presence of a hydrohalic acid and at least one strong acid that is not a hydrohalic acid. The acids are preferably used as concentrated aqueous solutions, for example, hydrochloric acid having a concentration in the range 25 to 40% by weight, hydrobromic acid having a concentration in the range 25 to 70% by weight, and sulfuric acid having a concentration in the range 35 to 100% by weight. Instead of hydrochloric acid or hydrobromic acid, it is also possible to introduce hydrogen chloride gas or hydrogen bromide gas into the reaction mixture.
Preference is given to using a mixture of hydrohalic acid, particularly hydrochloric acid, and sulfuric acid. The molar ratio of such hydrohalic/sulfuric acid mixtures can, for example, be in the range 1:2 to 4:1.
Based on 1 mol of fluoroalkylaniline, it is possible, for example, to use 5 to 9 equivalents of protons in the form of hydrohalic acid and at least one strong acid that is not a hydrohalic acid. This amount is preferably 5.5 to 6 equivalents.
The water content of the reaction mixture for the preparation of the diazonium salt mixture can, for example, be 45 to 80% by weight.
The diazonium salt mixture can be prepared by initially introducing the acids and water, adding the fluoroalkylaniline, then slowly adding an aqueous sodium nitrite solution at, for example, −20 to 0° C., and allowing the mixture to react fully.
It is a further essential feature of the present invention that no buffer salts (e.g., no sodium acetate) are added to the prepared diazonium salt mixture.
For the reaction with acetaldoxime it is possible, based on 1 mol of fluoroalkylaniline, to use, for example, 1 to 4 mol of acetaldoxime (preferably 1.2 to 3.2 mol).
Examples of suitable copper compounds are salts and complex compounds of copper in which copper is present in the +1 or +2 oxidation states.
Examples of copper salts are copper halides, copper sulfates, copper nitrates, copper tetrafluoroborates, and copper salts of organic acids, such as alkyl- and arylcarb
Höpfner Thomas
Kühnle Wulf
Henderson Richard E. L.
Siegel Alan
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