Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTInN
PROCESS FOR THE SYNTHESIS OF 3,5-BIS(TRIFLUOROMETHYL)-
BROMOBENZENE
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of 3,5-
bis(trifluoromethyl)bromobenzene (CAS 328-70-1) which is useful as an
intermediate
in the preparation of certain therapeutic agents. In particular, the present
invention
provides a process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene
which
is an intermediate in the synthesis of pharmaceutical compounds which are
substance
P (neurokinin-1) receptor antagonists.
The preparation of 3,5-bis(trifluoromethyl)bromobenzene by
bromination of 1,3-bis(trifluoromethyl)benzene has been described various
references.
See for example: (a) Porwisiak, J; Schlosser, M. Chen2. Ber., 129(2), 233
(1996); (b)
Kunshenko, B. V.; Omarov, V. O.; Muratov, N. N.; Mikhailevskii, S. M.;
Yagupol'skii, L. M. Zh. Org. Klzina., 27(I), 125 (1991); (c) Larionova, Y. A.;
Ponomarev, A. L; Klebanskii, A. L.; Zaitsev, N. B.; Kol'tsov, A. L; Motsarev,
G. V.;
Rozenberg, V. R. Z12. Prikl. Khim." 46(9), 2012 (1973); (d) Furumata, T.
(Central
Glass Company, Ltd.) JP 9067297-A2 [J09067297] 97.03.11; Filing Date 08/28/95;
(e) Suzuki, H. (Nissan Chemical Industries, Ltd., Japan) JP 9169673-A2
[J09169673]
97.06.30 Heisei; Filing Date 12/22/95. These references describe the
preparation of
3,5-bis(trifluoromethyl)bromobenzene by brominating 1,3-bis(trifluoromethyl)-
benzene utilizing either N-bromosuccinimide (NBS) or 1,3-dibromo-5,5-dimethyl-
hydantoin (DBH) in sulfuric acid or trifluoroacetic acid. The yields are
quoted in the
90% range with isomeric and bis-brominated byproducts amounting to 5-10%.
Efforts to repeat the procedures using methods with sulfuric acid as disclosed
therein
led to inconsistent yields of the desired product.
The general processes disclosed in the art for the preparation of 3,5-
bis(trifluoromethyl)bromobenzene result in relatively low and inconsistent
yields of
the desired product. In contrast to the previously known processes, the
present
invention provides effective methodology for the preparation of 3,5-
bis(trifluoro-
methyl)bromobenzene in relatively higher yield.
In accordance with the present invention, the use of acetic acid andlor
a faster rate of stirring for the bromination of 1,3-
bis(trifluoromethyl)benzene in
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sulfuric acid results in a more selective bromination of the starting material
with
higher yields of the product and lower amounts of bis-brominated byproducts.
It will be appreciated that 3,5-bis(trifluoromethyl)bromobenzene is an
important intermediate for a particularly useful class of therapeutic agents.
As such,
there is a need for the development of a process for the preparation of 3,5-
bis-
(trifluoromethyl)bromobenzene which is readily amenable to scale-up, uses cost-
effective and readily available reagents and which is therefore capable of
practical
application to large scale manufacture.
Accordingly, the subject invention provides a process for the
IO preparation of 3,5-bis(trifluoromethyl)bromobenzene via a very simple,
short and
highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of 3,5-
bis(trifluoromethyl)bromobenzene. In particular, the present invention is
concerned
with novel processes for the preparation of a compound of the formula:
CF3 ~ Br
CF3
This compound is an intermediate in the synthesis of compounds
which possess pharmacological activity. In particular, such compounds are
substance
P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment
of
inflammatory diseases, psychiatric disorders, and emesis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of
3,5-bis(trifluoromethyl)bromobenzene of the formula:
CF3 ~ Br
CF3
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The general process for the preparation of 3,5-bis(trifluoromethyl)-
bromobenzene is as follows:
CF
CF Sulfuric Acid
Acetic Acid / ~ Br
CF NBS or DBH CF3
3
In a highly preferred embodiment, the present invention is directed to
the preparation of 3,5-bis(trifluoromethyl)bromobenzene by the reaction of 1,3-
bis-
(trifluoromethyl)benzene with 1,3-dibromo-5,5-dimethylhydantoin in a mixture
comprising glacial acetic acid and 96 ~o sulfuric acid.
In accordance with the present invention, the use of acetic acid and/or a
high rate of mixing in this reaction system increases solubilization of the
starting
material and results in less sensitivity to stirring parameters, as well as
increased
regioselectivity with respect to the position of bromination.
An embodiment of the present invention concerns a process for the
preparation of 3,5-bis(trifluoromethyl)bromobenzene of the formula:
CF3
~ Br
CF3
which comprises:
treating a reaction mixture which comprises sulfuric acid, acetic acid,
and 1,3-bis(trifluoromethyl)benzene of the formula:
C F3
CF3
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with a brominating agent to give 3,5-bis(trifluoromethyl)bromo-
benzene.
A preferred embodiment within the present invention concerns a
process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene of the
formula:
CF3
~ Br
CF3
which comprises:
treating a reaction mixture which comprises concentrated sulfuric acid,
glacial acetic acid, and 1,3-bis(trifluoromethyl)benzene of the formula:
CF3
CF3
with a brominating agent selected from: N-bromosuccinimide and 1,3
dibromo-5,5-dimethylhydantoin, to give 3,5-bis(trifluoromethyl)bromobenzene.
Although numerous brominating agents may be employed in this
process, N-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin (DBH)
are preferred, and 1,3-dibromo-5,5-dimethylhydantoin is more preferred.
This process is carried out in a solvent which comprises sulfuric acid
and acetic acid, and which may additionally comprise water. The preferred
solvent
system is a mixture of sulfuric acid and acetic acid, and a more preferred
solvent
system is a mixture of concentrated sulfuric acid and glacial acetic acid. In
the
present invention it is preferred that the ratio of sulfuric acid:acetic acid
is
approximately 5:1 to 7:1 (v:v), and it is more preferred that the ratio of
sulfuric
acid:acetic acid is approximately 6:1 (v:v). In the present invention it is
preferred that
the sulfuric acid is added to the acetic acid at a controlled rate with
cooling and
rapidly mixing (such as with mechanical stirring).
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In the present invention it is preferred that the ratio of the sulfuric
acid/acetic acid to the 1,3-bis(trifluoromethyl)benzene substrate is
approximately 2:1
to 1:2 (v:v). In the present invention it is more preferred that the ratio of
the sulfuric
acid/acetic acid to the 1,3-bis(trifluoromethyl)benzene substrate is
approximately
1.5:1 (v:v). In the present invention it is preferred that the 1,3-
bis(trifluoromethyl)-
benzene is added to the sulfuric acid:acetic acid at a controlled rate with
cooling and
rapidly mixing (such as with mechanical stirnng).
In the present invention it is preferred that the reaction mixture is
rapidly mixed (such as with mechanical stirnng) and cooled upon treatment with
the
brominating agent. In the present invention it is preferred that the
brominatina agent
is added to rapidly mixed reaction mixture which comprises sulfuric acid,
acetic acid,
and 1,3-bis(trifluoromethyl)benzene. In the present invention it is also
preferred that
the brominating agent is added to the reaction mixture in a controlled manner
as
individual portions.
The preferred temperature range following addition of the brominating
agent is between about 10 and 70°C, a more prefered reaction
temperature range is
between about 40 and 50°C, and the most preferred temperature is about
45°C.
In a preferred embodiment, 1,3-bis(trifluoromethyl)benzene is
brominated with N,N'-dibromo-5,5-dimethylhydantoin in sulfuric acid/acetic
acid at
45 °C. The reaction mixture is then diluted into cold water, and the
phases are
separated, washed with aqueous sodium hydroxide (preferably SN sodium
hydroxide)
and allowed to separate to produce 3,5-bis(trifluoromethyl)bromobenzene.
The product may contain approximately 2.6% isomeric impurities
(which typically include 1,2-dibromo-3,5-bis(trifluoromethyl)benzene, 1,4-
dibromo-
3,5-bis(trifluoromethyl)bromobenzene, as well as small amounts of 2,4-
bis(trifluoro-
methyl)bromobenzene, 2,6-bis(trifluoromethyl)bromobenzene, and 3,5-
bis(trifluoromethyl)biphenyl.
The 3,5-bis(trifluoromethyl)bromobenzene obtained in accordance
with the present invention may be used directly without distillation as
starting
material in further reactions.
None of the references cited above discuss problems associated with
low rates of mixing, nor do they mention brominations in a mixture of acetic
acid and
sulfuric acid. Surprisingly, in accordance with the present invention it was
discovered
that if the reaction is not stirred at an appropriate speed, the rate of
bromination
decreases, the yield of 3,5-bis(trifluoromethyl)bromobenzene drops, and
production of
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isomeric, bis-brominated and tris-brominated byproducts increases to upwards
of
30%. This indicates that more than one mechanism for the bromination reaction
is
operative in this system. Two reactions were performed on the same scale with
N-
bromosuccinimide (NBS) (1.05 eq) but at different stirrer speeds. The
reactions were
run in identical jacketed round bottom flasks, with identical stir bars and
magnetic
stirrers. The reaction rates differed as would be expected from a two-phase
reaction,
but the selectivity of the reactions were also different. The slower stirnng
reaction
produced less product and more bis-brominated byproducts. Bromination of 1,3-
bis(trifluoromethyl)benzene with N,N'-dibromo-5,5-dimethylhydantoin (DBH) is
similarly facilitated by the use of acetic acid and/or a higher rate of
mixing. Low
stirring of the reaction mixture leads to slower, less selective brominations,
and this
effect is ameliorated by the use of acetic acid.
The effect of excess amounts of DBH on the bromination in sulfuric
acid alone relative to the bromination in a combination of sulfuric
acid/acetic acid
was examined. Using a 5 mol % excess of DBH (10 mol % excess Br+) at a
slightly
lower ratio of solvent: 1,3-bis(trifluoromethyl)benzene (3.2:1 v:v), the
brominations
were rapid. In sulfuric acid alone, however, bis-bromination of 3,5-
bis(trifluoro-
methyl)bromobenzene continued after the starting material was completely
consumed,
whereas in sulfuric/acetic acid there was little or no loss to bis-bromination
when 1,3-
bis(trifluoromethyl)benzene was completely consumed. Accordingly, the use of
sulfuric acid/acetic acid avoids consumption of the product 3,5-bis(trifluoro-
methyl)bromobenzene when excess brominating reagent is present.
Many of the starting materials are either commercially available or
known in the literature and others can be prepared following literature
methods
described for analogous compounds. The skills required in carrying out the
reaction
and purification of the resulting reaction products are known to those in the
art.
Purification procedures include e.g., distillation, crystallization, normal
phase or
reverse phase chromatography.
The following examples are provided for the purpose of further
illustration only and are not intended to be limitations on the disclosed
invention.
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EXAMPLE 1
3 5-Bis(trifluoromethyl)bromobenzene
CF3 Sulfuric Acid CFs
Acetic Acid ~ ~ Br
DBH
CF3 CF3
Materials MW Densit Amount Mmol E uiv.
1,3-Bis(trifluoro- 214.1 1.38 107 g 500 1.0
meth 1)benzene
96% H,SO 142 mL
Glacial HOAc 22 mL
1,3-Dibromo-5,5- 285.93 77.25 270 1.08
dimeth 1h dantoin g (Br')
SN A NaOH 75 mL
To glacial acetic acid (22.0 mL), cooled to 15 °C in a 1 L 3-n RB
flask
(equipped with mechanical stirrer, thermocouple, and addition funnel), was
added
concentrated (96%) sulfuric acid (142 mL) in one portion. An exothermic heat
of
solution raised the temperature to 35 °C. After cooling to 25
°C, 1,3-bis(trifluoro-
methyl)benzene (107 g, 500 mmol) was added. With the acid mixture rapidly
stirnng,
1,3-dibromo-5,5-dimethylhydantoin (77.25 g; 270 mmol) was added over 2 min to
give a multiple phase mixture (solid and two liquid). An exothermic reaction
occured
that raised the internal temperature to ~40 °C (jacket cooling at 15
°C). After the
reaction temperature began to drop (after 5 min) the reaction mixture was
maintained
at 45 °C for 4.5 hr.
The rate and selectivity of the bromination is highly dependent on the
agitation of the two phase reaction. Slower stirring increases the amount of
bis-
bromination and slows the overall rate of reaction. The reaction mixture
remains
heterogeneous throughout the reaction and the organic phase separates when
agitation
is interrupted. At the end of the reaction, the phases separate slowly
(bromide density
= 1.699). The rate of bromination is also dependent on the ratio of acetic to
sulfuric
acid.
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Progress of the reaction is monitored by GC analysis, as follows.
Sample: ~50 ~ul of mixed phase, dilute with cyclohexane (1.5 mL), wash with
water (1
mL), then 2N NaOH (1 mL), separate and inject.
Resteck RTX-1701 [60 meter x 0.320 mm]: 100 °C; ramp: 5 °C/min
to 200 °C; 200
°C for 10 min; Flow 1.15 mL/min
R~:1,3-bis(trifluoromethyl)benzene: 7.0 min
3,5-bis(trifluoromethyl)bromobenzene: 9.4 min
Biaryl: 19.2 min
The mixture was cooled to 2 °C and poured slowly into cold water
(250 mL). The mixture was stirred vigorously for 10 min, allowed to settle,
and the
lower organic layer was separated and washed with SN NaOH (75. mL) to give
145.1 g
of a clear, colorless organic layer.
The assay yield of 1,3-bis(trifluoromethyl)bromobenzene was 93.7%
(137.3 g, 469 mmol), which contained 0.6°10 1,3-
bis(trifluoromethyl)benzene, 1.0°0
1,2-dibromo-3,5-bis(trifluoromethyl)benzene, and 0.3% 1,4-dibromo-3,5-bis
(trifluoromethyl)benzene. Total isomer byproducts measured by GC were 2.0 mol
%.
While the invention has been described and illustrated with reference
to certain particular embodiments thereof, those skilled in the art will
appreciate that
various adaptations, changes, modifications, substitutions, deletions, or
additions of
procedures and protocols may be made without departing from the spirit and
scope of
the invention. For example, reaction conditions other than the particular
conditions as
set forth herein above may be applicable as a consequence of variations in the
reagents or methodology to prepare the compounds from the processes of the
invention indicated above. Likewise, the specific reactivity of starting
materials may
vary according to and depending upon the particular substituents present or
the
conditions of manufacture, and such expected variations or differences in the
results
are contemplated in accordance with the objects and practices of the present
invention. It is intended, therefore, that the invention be defined by the
scope of the
claims which follow and that such claims be interpreted as broadly as is
reasonable.
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