Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-11-01
2001-02-06
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S335000
Reexamination Certificate
active
06184417
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for preparing acetophenones which are substituted on the aromatic ring by fluoroalkyl. Such compounds are useful intermediates for preparing antibacterial agents (see DE-A 26 04 207).
A known process for preparing trifluoromethylacetophenone on an industrial scale involves the preparation, from trifluoromethylaniline and sodium nitrite in the presence of hydrochloric acid, of the corresponding diazonium salt solution, which is then buffered with sodium acetate and added, at from 5 to 15° C., to an initial charge comprising water, acetaldoxime, a copper(II) salt, a reducing agent (sodium thiosulphate) and a large amount of sodium acetate buffer. For work-up, hydrochloric acid is added and the mixture is heated to reflux, subjected to steam distillation and extracted, and the distillate is dried, the extracting agent is stripped off and the residue is distilled under reduced pressure. Based on the fluoromethylaniline employed, this gives trifluoromethylacetophenone in a yield of 33% of theory (see DE-A 26 04 207, Preparation Example 1.4).
In addition to the low yield, this process has the disadvantage that large amounts of auxiliaries, for example buffer salts, reducing agents and hydrochloric acid, are used which render work-up more difficult, result in a considerable salt load of the waste water and, after they have been separated off, cause great costs for an environmentally safe disposal.
Other known processes for preparing trifluoromethylacetophenone (see, for example, Liebigs Ann. Chem. 717, 80-90 (1968), J.Am. Chem. Soc. 68, 736 (1946), J. Organomet. Chem. 489, (1-2), 137-143 (1995)) are not suitable to be employed on an industrial scale because they require apparatus and reagents which are expensive and difficult to handle.
DESCRIPTION OF THE INVENTION
We have now found a process for preparing acetophenones which are substituted on the aromatic ring by fluoroalkyl from fluoroalkylanilines and acetaldoxime, in which from a fluoroalkylaniline a corresponding diazonium salt solution is prepared which is reacted with acetaldoxime in the presence of at least one copper compound, characterized in that no buffer salts and no reducing agents are added, the reaction is carried out at from 20 to 50° C. and in the presence of halide ions and the mixture is subsequently heated to a temperature in the range from 70 to 110° C.
For the process according to the invention, it is possible to employ, for example, fluoroalkylanilines of the formula (I)
in which
m represents 1, 2 or 3,
n represents (2m+1)−o and
o represents (2m+1)−n.
In the formula (I), n preferably represents zero and o preferably represents (2m+1). The C
m
H
n
F
o
group is preferably in the 3-position to the amino group. Particular preference is given to using 3-trifluoromethylaniline.
The preparation of the diazonium salt solution can be carried out in a customary manner, for example by reaction with sodium nitrite in the presence of a strong inorganic acid at from 0 to −15° C. It is an essential feature of the present invention that the finished diazonium salt solution is not admixed with any buffer salts, for example sodium acetate.
Based on 1 mole of fluoroalkylaniline employed, it is possible to use, for example, from 1 to 2 mol, preferably from 1.2 to 1.6, of acetaldoxime.
Suitable copper compounds are, for example, salts and complex compounds in which the copper is present in the oxidation state +1 or +2. Examples of salts are halides and sulphates, examples of complex compounds are those with hydroxylamine or acetaldoxime ligands. The copper compounds may contain water. Specific examples are CuSO
4
, CuSO
4
×5H
2
O, CuCl, CuBr, CuCl
2
, CuBr
2
, Cu(O—N═CH—CH
3
) and Cu(O—N═CH—CH
3
)
2
. Based on 1 mole of fluoroalkylaniline employed, it is possible to use, for example, from 0.04 to 0.2 mol, preferably from 0.045 to 0.1 mol, of one or more copper compounds.
The process according to the invention can be carried out in different ways. For example, a mixture of acetaldoxime, copper compound(s) and a little water is initially charged and the diazonium salt solution is metered in. It is also possible to prepare, for example, initially the diazonium salt solution, which is then metered into an aqueous solution of one or more copper compounds which had been charged initially, and the resulting mixture is metered into acetaldoxime which had been charged initially.
It is an essential feature of the present invention that prior to or during the reaction of the diazonium salt solution with acetaldoxime no buffer salts (such as sodium acetate) and no reducing agents (such as sodium thiosulphate) are added.
The reaction according to the invention is preferably carried out at from 25 to 45° C.
The presence of halide ions during the reaction, which is required according to the invention, can be achieved in the most simple case by using as strong inorganic acid for the preparation of the diazonium salt solution a hydrohalic acid, for example from 25 to 40% by weight strength aqueous hydrochloric acid or from 25% by weight strength aqueous hydrobromic acid. If it is intended to use another strong inorganic acid in the preparation of the diazonium salt solution, this is possible, but in this case halide ions have to be added in another manner, for example in the form of metal halide, such as in the form of NaCl or KBr. Based on 1 mole of copper compounds, for example, at least 1 mole, preferably at least 10 mol, of halide ions are present in the reaction mixture.
During the metered addition of the diazonium salt solution to the acetaldoxime, it is advantageous to ensure that the reaction mixture is mixed intensively, for example by means of a vibration or a dispersion apparatus of the Ultra-Turrax® type.
When preparing the components to be reacted with one another, and during the reaction, it is furthermore advantageous to substantially exclude the presence of oxygen. To this end, it is possible, for example, to work in a nitrogen atmosphere, to introduce nitrogen into the reaction mixtures and/or components to be handled or to apply a slight vacuum for degassing.
After the diazonium salt solution and the acetaldoxime component have been admixed completely, the reaction mixture may be allowed, if appropriate, to react for some more time, for example for from 15 minutes to 1 hour, at temperatures in the range of from 20 to 50° C.
It is not necessary to admix (more) hydrochloric acid before work-up.
If the fully reacted reaction mixture is worked up by steam distillation, no particular attention should be paid to the subsequent heating to from 70 to 110° C., preferably from 80 to 105° C., since the mixture has to be heated to temperatures in this range in any case. If work-up is to be carried out in a different way, for example by extraction, heating to from 70 to 110° C. has to be carried out beforehand separately, for example for from 5 to 30 minutes.
The crude acetophenones which are substituted at the aromatic ring by fluoroalkyl and which are present after work-up, for example by steam distillation or extraction, can be purified further by fractional distillation, for example over a column.
Thus, it is possible to obtain the desired products in purities of more than 98% and in yields of from 48 to more than 55% of theory.
If a fluoroalkylaniline of the formula (I) has been employed, the corresponding product of the formula
in which the symbols used have the meaning given under formula (I) is obtained.
Even though the process according to the invention, in contrast to the prior art, does not require the addition of buffer salts and reducing agents and can be carried out with lower amounts of strong inorganic acids and copper compounds, its yield of target products is generally increased by at least 50% (relative). This is particularly surprising and renders the process according to the invention considerably more efficient than the known processes. The amounts of waste water and their salt
Kühnle Wulf
Marhold Albrecht
Steffan Guido
Bayer Aktiengesellschaft
Eyl Diderico van
Gil Joseph C.
Padmanabhan Sreeni
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