Field of the invention
The present invention provides a process for the preparation of halogenated benzene derivatives.
Background of the invention
Halogenated benzene derivatives are important as intermediates for synthesis of agricultural
chemicals and medicines.
The Organic letters, 14(14), 3644-3647, 2012 provides palladium catalyzed reaction of 1, 2, 3-
trifluoro-5-bromobenzene with cyano acetic acid ethyl ester and sodium carbonate in N, Ndimethylformamide
for the preparation of ethyl cyano (3,4,5-trifluorophenyl) acetate.
The EP Patent No. 0,394,644 provides a process for preparation of halogenated benzene
derivatives by reacting poly halogen benzene with alkyl cyano acetate in solvent in the presence
of a 1.0 to 1.5 moles of base per mole of poly halogen benzene.
Such synthesis, with respect to what is known in the prior art, is apparently advantageous in that
it requires few steps and reagents. However, present inventors, while performing due
experimentation, have found out that halogenated benzene derivatives prepared by reacting poly
halogen benzene with alkyl cyano acetate in the presence of a 1.0 to 1.5 moles of base per mole
of poly halogen benzene as in EP Patent No. 0,394,644 is not reproducible.
Such non-reproducible results and yield is unsatisfactory in terms of industrial application, and it
is essentially due to these reasons, there still arises the need for providing an efficient as well as
economic reagents and purification methods that can be used at industrial scale for the synthesis
of halogenated benzene derivatives.
Summarv of the Invention
In an aspect, the present invention provides a process for preparation of halogenated benzene
derivatives of Formula I comprising,
Formula I
in which
R' represents hydrogen or Cl to C4 alkyl and
m and n independently of one another represent 0, 1, 2 and 3, wherein m+n is at least 1 and not
more than 5.
a) contacting compound of Formula I1 with compound of Formula 111,
Formula I1
R~
iCOOR'
Formula I11
in which
R2 represents halogen,
Halogen represents fluoro, chloro, bromo or iodo,
R~ is CN or COOR', and
R' represents hydrogen or CI to C4 alkyl
b) isolating compound of Formula I, wherein step a) is carried out in the presence of at least
2.2 mole equivalent of base per mole equivalent of compound of Formula 11.
Detailed Description of the Invention
In an embodiment, the present invention provides a process for preparation of halogenated
benzene derivatives of Formula I comprising,
Formula I
in which
R' represents hydrogen or C1 to C4 alkyl and
m and n independently of one another represent 0, 1, 2 and 3, wherein m+n is at least 1 and not
more than 5.
a) contacting compound of Formula TI with compound of Formula 111,
Formula I1
in which
R%epresents halogen,
Halogen represents fluoro, chloro, bromo or iodo,
R3 is CN or COOR' , and
R' represents hydrogen or CI to Cq alkyl
R~
i ~ O ~ ~ '
Formula I11
b) isolating compound of Formula I, wherein step a) is carried out in the presence of at least
2.2 mole equivalent of base per mole equivalent of compound of Formula 11.
The compound of Formula I1 and compound of Formula I11 may be prepared by any method
known in the art. The contacting of compound of Formula I1 and compound of Formula I11 may
take place in the presence of solvent.
The solvent may be selected from ether solvent and amide solvent or mixture thereof. The ether
solvent may be selected from dioxane, tetrahydrofuran, glyme and diethylne glycol dimethyl
ether or mixture thereof. The amide solvent may be selected from dimethylformamide,
dimethylacetamide, N-methylpyrrolidine and N-methylcaprolactam or mixture thereof. The
solvent may be a mixture of ether solvent and amide solvent.
The base is selected from ammonia, alkali metals, alkaline earth metals, alkali metal hydrides,
alkali metal carbonates, alkaline metal carbonates, alkali metal bicarbonates, alkaline metal
bicarbonates and organic base or mixture thereof. The alkali metal may be selected from sodium
and potassium. The alkaline metal may be selected from magnesium and calcium. The alkali
metal hydride may be selected from lithium hydride, sodium hydride and potassium hydride. The
alkaline metal hydride may be calcium hydride. The alkali metal carbonate may be selected from
lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate and cesium
carbonate. The alkaline metal carbonate may be selected from magnesium carbonate, calcium
carbonate and barium carbonate. The alkali metal bicarbonate may be selected from lithium
bicarbonate, sodium bicarbonate, potassium bicarbonate, rubidium bicarbonate and cesium
bicarbonate. The alkaline metal bicarbonate may be selected from magnesium bicarbonate,
calcium bicarbonate and barium bicarbonate. The organic base may be selected from
organolithiums, grignard reagents, amines, N-heterocyclic compounds, tetraalkylarnrnonium and
phosphonium hydroxides, metal alkoxides and amides and metal silanoates.
The base is about 2.2 mole equivalent to about 4.0 mole equivalent per mole equivalent
compound of Formula 11.
The step a) may be carried out at a temperature of about 15OC to about 150°C, for example, at
about 25OC to about 125°C. The step a) may be aided by stirring the contents. The step a) may
take place for about 5 minutes to about 24 hours, for example, 10 minutes to about 10 hours.
The "about" refers to k 10% of the value referred therein.
The process for preparation of compound of Formula I may be carried in a continuous mode.
The compound of Formula I is isolated from step a) reaction mixture. The compound of Formula
I may be isolated by filtration, layer separation, decantation, evaporation, concentration,
crystallization and distillation or mixture thereof.
While the present invention has been described in terms of its specific embodiments, certain
modifications and equivalents will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
Examples
1. Preparation of Ethyl Cyano-(2,4,5-Trifluoropheny1)Acetate
la) Sodium hydride (6.0 g, 0.25 moles) and N,N-dimethylformamide (100 mL) were
taken in a reaction vessel. The cyano acetic acid ethyl ester (14 g, 0.124 moles) was
added to the vessel and the temperature of the mixture was raised to 120°C. The 1, 2, 4,
5-tetrafluorobenzene (15 g, 0.10 moles) was added to the reaction mixture and the
mixture was stirred for 8 hours at 120°C. The reaction mixture was concentrated, cooled
and acidified with dilute sulhric acid to obtain a title compound.
Yield: 22.5 g
Ib) Sodium metal (1.7 g, 0.074 moles) and N-methyl-2-pyrrolidine (35 g) were taken in a
reaction vessel. The cyano acetic acid ethyl ester (4.3 g, 0.038 moles) was added to the
vessel and the temperature of the mixture was raised to 120°C. The 1, 2, 4, 5-
tetrafluorobenzene (5 g, 0.033 moles) was added to the reaction mixture and the mixture
was stirred for 8 hours at 120°C. The reaction mixture was concentrated, cooled and
acidified with dilute sulfuric acid to obtain a title compound.
Yield: 6.9 g
Comparative Example
Preparation of Ethyl Cyano-(2,4,5-Trifluorouhen~l~Acetate
Sodium hydride (1.34 g, 0.056 moles) and N,N-dimethyl formamide (40 mL) were taken
together in a reaction vessel. Cyanoacetic acid ethyl ester (5.5 g, 0.048 moles) was added to
the reaction vessel and the temperature of the reaction mixture was raised to 120°C. Then
1,2,4,5-tetrafluorobenzene( 7 g, 0.046 moles) was added to the reaction mixture and the
mixture was stirred for 8 hours. The mixture was acidified to obtain title compound.
Yield: 5.5 g
Conversion - 53%
We claim:
1. A process for preparation of halogenated benzene derivatives of Formula I comprising,
Formula I
in which
R' represents hydrogen or C1 to C4 alkyl and
m and n independently of one another represent 0, 1, 2 and 3, wherein m+n is at least 1 and not
more than 5.
a) contacting compound of Formula I1 with compound of Formula 111,
Formula I1
in which
R~ represents halogen,
Halogen represents fluoro, chloro, bromo or iodo,
R3 is CN or COOR'. and
R1 represents hydrogen or CI to C4 alkyl
Formula I11
b) isolating compound of Formula I, wherein step a) is carried out in the presence of at
least 2.2 mole equivalent of base per mole equivalent of compound of Formula 11.
2. The process of claim 1, wherein base is selected from sodium, potassium, magnesium,
calcium, lithium hydride, sodium hydride, potassium hydride, calcium hydride, lithium
carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium
carbonate, magnesium carbonate, calcium carbonate, barium carbonate, lithium
bicarbonate, sodium bicarbonate, potassium bicarbonate, rubidium bicarbonate, cesium
bicarbonate, magnesium bicarbonate, calcium bicarbonate, barium bicarbonate,
organolithiums, grignard reagents, amines, N-heterocyclic compounds,
tetraalkylammonium and phosphonium hydroxides, metal alkoxides, amides and metal
silanoates.
3. The process of claim 1, wherein the base is 2.2 mole equivalent to 4.0 mole equivalent
per mole equivalent compound of Formula 11.
4. The process of claim 1, wherein step a) is carried out at a temperature range of 15°C to
150°C.
5. The process of claim 4, wherein step a) is carried out at a temperature range of 25°C to
125°C.
6. The process of claim 1, wherein the process is carried in a continuous mode.
7. The process of claim 1, wherein the compound of Formula I is isolated by filtration, layer
separation, decantation, evaporation, concentration, crystallization and distillation or
mixture thereof.
Dated this 26th day of July, 2013
(Ramesh C. Dhawan)
of La11 Lahiri & Salhotra
Agents for the Applicant