Note: Descriptions are shown in the official language in which they were submitted.
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HOECHST AKTIENGESELLSCHAFT HOE 95/F 276 Dr. Mu/pp
Description
5 A process for preparing 1-bromo-3,5-difluorobenzene
The present invention relates to a process for preparing 1-bromo-3,5-
difluorobenzene.
10 1-Bromo-3,5-difluorobenzene is an intermediate for preparing
pharmaceutics and liquid crystals.
According to the prior art,1-bromo-3,5-difluorobenzene can be prepared
by the following processes:
1. by bromination of 2,4-difluoroaniline, subsequent diazotization with
NaNO2 and deamination using hypophosphorous acid in acid
solution.
Employing this process, A. Roe and W.F. Little, J. Org. Chem. 20
(1955) 1577/1590 obtained 1-bromo-3,5-difluorobenzene in a yield
of 60%.
L. l. Kruse et al., J. Org. Med., 29 (1986) 887/889 and J. Org. Med.,
30 (1987) 486/494 obtained a total yield of 1-bromo-3,5-difluoro-
enzene of 57%.
In US 5 157 169, a yield of 1-bromo-3,5-difluorobenzene of 70% is
described.
The yields obtained when employing this process are low, especially
in the deamination step, expensive starting materials are wasted.
The process comprises many steps.
2. by photochemical bromination of m-difluorobenzene
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R. Bolton and E.S.E. Owen, J. Fluor. Chem. 46 (1990) 393/406
state that according to this process 19% of 1 -bromo-3,5-
difluorobenzene are formed in addition to 10% of other
bromodifluorobenzene isomers and 43% of more highly brominated
difluorobenzenes. In this process, the formation of 1-bromo-3,5-
difluorobenzene is of poor selectivity.
1-Bromo-3,5-difluorobenzene cannot be obtained by direct
bromination of m-difluorobenzene. It selectively produces 1-bromo-
2,4-difluorobenzene.
- 3. by isomerization of 1-bromo-2,4-difluorobenzene
In EP 63066, the isomerization of 1-bromo-2,4-difluorobenzene is
carried out in the presence of alkali metal bases, preferably alkali
metal amides, and macrocyclic compounds such as polyethers.
This process has a number of disadvantages. The macrocyclic
compounds are of a complex structure and therefore very
expensive. They are not recovered after the reaction. To work up
the product, the basic reaction mixture has to be neutralized,
resulting in the formation of salts. Because of the low yields of 1-
bromo-3,5-difluorobenzene (about 63%) and the high costs of
material, this process is of little economic value.
JP 04 182 440 (CA 117: 170951n) describes the isomerization of 1-
bromo-2,4-difluorobenzene in the presence of alkali metall t-
butoxides or aluminum halides. This process likewise requires an
additional, salt-forming neutralization step. The yield of 1-bromo-3,5-
difluorobenzene is only 41.4%.
EP 648 724 describes the isomerization of 1-bromo-2,4-
2 1 9 1 652
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difluorobenzene using acidic zeolites as catalysts. Disadvantages of
this process are, on the one hand, the large amounts which have to
be recycled because of the limited conversion and, on the other, the
cost of continuous apparatus.
No other starting materials for the preparation of 1-bromo-3,5-
difluorobenzene are described in the literature.
Therefore, there was a need for a process avoiding the disadvantages
10 described and providing an easy industrial route to 1-bromo-3,5-difluoro-
benzene in high yields and with high selectivity.
-
This object is achieved by a process for preparing 1-bromo-3,5-difluoro-
benzene, which comprises converting 3,5-difluoroaniline into its diazonium
15 salt and then converting the diazonium salt in the presence of CuBr and
HBr into 1-bromo-3,5-difluorobenzene.
3,5-Difluoroaniline is a known compound. An advantageous way for
preparing 3,5-difluoroaniline is described for example in EP 562 435.
The preparation of halogenated aromatic compounds from the
- -corresponding anilines is known and comprehensively described in the
literature (Sandmeyer reaction). For instance, there are synthetic
procedures for the diazotization of anilines and the Sandmeyer reaction of
25 the diazonium salts to the corresponding halogenated aromatic
compounds, for example in Organikum, 4th edition (1964), 491/492 and
497/499, Org. Synth., Coll. Vol. 3,185-187, Houben-Weyl, Halogen
compounds, Volume V/4 (1960), 438/446. According to these procedures,
halogenated aromatic compounds can be prepared in high yields between
30 80 and 95% from the respective anilines.
It is all the more surprising, then, that the technical literature does not
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mention the conversion of 3,5-difluoroaniiine into 1-bromo-3,5-difluoro-
benzene.
On the other hand, several papers describe the preparation of 1-bromo-
3,5-difluorobenzene starting from 2,4-difluoroaniline, an isomer of 3,5-
difluoroaniline. 2,4-Difluoroaniline is first converted by bromination into
2-bromo-4,6-difluoroaniline, followed by diazotization with NaNO2 and
deamination using hypophosphorous acid in acid solution to give 1-bromo-
3,5-difluorobenzene. This pathway involves one more step than the
process according to the invention. In addition, yields of the deamination
using hypophosphorous acid are substantially lower than the yields for the
- Sandmeyer reaction described in the literature.
Since the direct conversion of 3,5-difluoroaniline into 1-bromo-3,5-
15 difluorobenzene has not been described, it is reasonable to assume that
this reaction can only be carried out with difficulties and that the indirect
route via 2,4-difluoroaniline, bromination, diazotization and deamination is
more favorable.
20 By contract, it was now been found that, surprisingly, 1-bromo-3,5-
difluorobenzene can be prepared in high yield directly from 3,5-
difluoroaniline by diazotization and subsequent Sandmeyer reaction.
For the diazotization of 3,5-difluoroaniline with an equimolar amount of
25 NaNO2, a 2.5- to 3-fold excess of HBr is sufficient. It proved useful to add
the acid in 48% strength and to carry out the reaction at low temperatures,
most favorably at temperatures c1 0C.
NaNO2 is added as about 50% strength solution. By checking the color
30 reaction with starch-iodide paper, it is ensured that no excess nitrite is
present. If necess~ry, some urea is added.
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The diazonium salt formed is kept at about 10C until further processing.
Either, the entire diazonium salt is added at 0C to the CuBr/HBr, and only
then heated to the boil. Or, alternatively, the initially charged CuBr/HBr
mixture is heated to the boil and the cooled diazonium salt is added a little
at a time, so that the whole mixture is kept at the boil.
The 1-bromo-3,5-difluorobenzene formed is distilled off together with
steam. Heating is continued until no further gas is evolved. Then, to
recover all the reaction products, the remaining organic product is distilled
using steam.
The organic phase is separated off from the aqueous phase, neutralized
with dilute alkali metal hydroxide solution, washed, dried and then
redistilled to purity.
The following example illustrates the process according to the invention.
Example 1:
Diazotization:
A 500 ml four-neck flask fitted with stirrer, thermometer and dropping
funnel is initially charged with 64.5 g (0.5 mol) of 3,5-difluoroaniline and
210 ml of 48% strength HBr (1.25 mol of HBr), and at <10C 34.5 g
(0.5 mol) of NaNO2 in 60 ml of water are added with stirring. NaNO2 is
added until free HNO2 is just detectable by color reaction with starch-iodide
paper.
Sandmeyer reaction:
The reaction mixture kept at 10C is added a little at a time with stirring to aboiling mixture of 35.4 g (0.25 mol) of CuBr in 46 ml of 48% strength HBr
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(0.27 mol of HBr) in a 1 I four-neck flask fitted with a distillation apparatus,steam-inlet tube, dropping funnel and thermometer. Heating is continued to
keep the mixture at the boil. Organic product and water begin to distill over
during the addition of diazonium salt. On completion of the addition, steam
5 distillation is continued until no more organic product is collected in the
receiving flask.
The phases in the receiving flask are separated, the organic phase is
washed first with water, then neutralized with 5% strength NaOH and
10 subsequently washed neutral. After drying over Na2SO4 and redistillation
to purity, 80 9 (0.41 mol) of 1-bromo-3,5-difluorobenzene are obtained,
equivalent to a yield of 83% of theory.
