FORM 2
THE PATENTS ACT 1970
39 of 1970
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(See sections 10 & rule 13)
1. TITLE OF THE INVENTION
AN IMPROVED PROCESS FOR THE SYNTHESIS OF FIPRONIL
2. APPLICANTS
NAME NATIONALITY ADDRESS
ATUL LIMITED
IN
P.O. - Atul,
District - Valsad,
Gujarat - 396020, INDIA
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to
be performed
2
AN IMPROVED PROCESS FOR THE SYNTHESIS OF FIPRONIL
FIELD OF THE INVENTION
[0001] The present invention relates to a new, improved and efficient
process for preparing 5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-
trifluoro methyl sulphinyl-3-carbonitrile pyrazole, also known as Fipronil, by
oxidation of Fipronil sulfide using a medium comprising at least one resin(s), at
least one oxidizing agent(s) and at least one solvent(s).
BACKGROUND OF THE INVENTION
[0002] Fipronil, chemically “5-Amino-1-(2,6-dichloro-4-
trifluoromethylphenyl)-4-trifluoro methyl sulphinyl-3-carbonitrile pyrazole” is a
broad spectrum insecticide that disrupts insect’s central nervous system by
blocking the passage of chloride ions through GABA receptor and glutamategated
chloride (Glu-Cl) channels, components of the central nervous system. This
causes hyper excitation of contaminated insects' nerves and muscles, resulting in
death.
[0003] Fipronil was discovered and developed by Rhone-Poulenc between
1985 and 1987 and placed on the market in 1993. It was first introduced in the
U.S. in 1996 for commercial turf and indoor pest control protected under the US
Patent No. US 5,232,940 B2.
[0004] Fipronil is mostly used to control ants, beetles, cockroaches, fleas,
ticks, termites, mole crickets, thrips, rootworms, weevils, and other insects.
Fipronil is used in a wide variety of pesticide products, including granular
products for grass, gel baits, spot-on pet care products, liquid termite control
products, and products for agriculture.
[0005] There are various routes to synthesize Fipronil by oxidation of
Fipronil sulfide with different oxidizing agents in a number of suitable solvents.
3
Oxidation of such sulfides is a very useful route for preparation of Fipronil.
Literature is replete with conversion of sulfides to sulfoxides and/or sulfones.
However, most of the existing methods use expensive, toxic or rare oxidizing
reagents, which are difficult to prepare, are very expensive and cannot be used on
commercial scale. Many of these processes suffer from poor selectivity.
[0006] US Patent US 5,232,940 B2 discloses preparation of Fipronil by
oxidation of 5-amino-l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-
trifluoromethyl-thiopyrazole with meta-chloroperbenzoic acid. A problem
encountered in the preparation is the co-formation of the corresponding sulfone
compound 5-amino- l-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoro
methylsulfonyl pyrazole, which is difficult to remove from the sulfoxide. The
process as described in US 5,232,940 has, however, some disadvantages. The
oxidizing agent m-chloroperbenzoic acid is a highly explosive and expensive
reagent, and is, therefore, not a preferred reagent for use in commercial scale
production. Additionally, the process is disadvantageous in that it is lengthy;
Fipronil is purified by means of a silica gel column chromatography; and Fipronil
is obtained in a relatively low yield of 58%, which makes this process unattractive
for industrial implementation.
[0007] PCT Publication WO 2012/004692 describes another process for
preparing Fipronil by oxidizing the Fipronil sulfide in a medium comprising
dichloroacetic acid and oxidizing agents such as benzoyl peroxide, sodium
peroxide, tert-Bu peroxide, and hydrogen peroxide. Additionally use of acid
catalyst such as sulfuric acid, methanesulfonic acid, hydrochloric acid, nitric acid,
and their mixtures is disclosed. However, the acid catalysts comprising mineral
acids are not useful as a medium for oxidation due to instability of Fipronil
towards strong mineral acids.
[0008] Chinese Patent CN101168529 teaches oxidation of Fipronil sulfide
with trichloroisocyanuric acid as oxidant in a solvent mixture of ionic liquid and
4
acetonitrile and also in the presence of catalyst Ruthenium trichloride, which is
however not economically viable at industrial level.
[0009] PCT Publication WO 2012/007938 describes yet another process
for preparing Fipronil by oxidizing the Fipronil sulfide in a medium comprising
dichloroacetic acid and hydrogen peroxide in the presence of a strong acid
(H2SO4, MSA, PTSA or combination). However, use of such strong acid is not
recommended as it adversely impacts the raw material as well as the final
compound.
[00010] Chinese Patent CN 101544607 discloses a process for the synthesis
of Fipronil by oxidation of Fipronil sulfide in presence of oxidant sodium
percarbonate and catalyst Sodium 2-methylnaphthalene sulfonate or aliphatic
alcohol polyethenoxy ether.
[00011] Chinese Patent CN 101628895 discloses a process for the synthesis
of Fipronil by oxidation of Fipronil sulfide in presence of oxidant selected from
hydrogen peroxide, m-chloroperoxybenzoic acid or sodium perborate and catalyst
vanadium pentoxide. Use of vanadium pentoxide as catalyst can not be recovered
and not economically viable.
[00012] PCT Publication WO 2013/037291 describes yet another process
for preparing Fipronil by oxidizing the Fipronil sulfide in a medium comprising
quinone, peroxide, hypohalite or alkali metal hydroxide as oxidant and Sodium
tungstate / HCl as catalyst, which is also not suitable at industrial scale.
[00013] PCT Publication WO 2012/164571 describes another process for
preparing Fipronil by oxidizing the Fipronil sulfide in a medium comprising
sulfuric acid, H2O2 in solvent (EDC, MDC, CCl4, CHCl3, dibromomethane,
bromobenzene, chlorobenzene or ODCB). Use of strong sulfuric acid is not
recommended as it adversely impacts the raw material and final compound.
5
PCT Publication WO 2011051284 discloses a process for the synthesis of Fipronil
by oxidation of Fipronil sulfide in presence of an oxidising agent selected from
trifluoroperacetic acid and trichloroperacetic acid in the presence of a corrosion
inhibitor and a catalyst selected from hydroxides, oxides, sulfates, acetates or
trifluoroacetates of lithium, magnesium, calcium, strontium, barium, titanium
(IV), zinc (II) and manganese (II). Use of trifluoroperacetic acid and
trichloroperacetic acid is costly at commercial scale.
[00014] PCT Publication WO 2007/122440 describes yet another process
for preparing Fipronil by oxidizing Fipronil sulfide in a medium comprising
hydrogen peroxide and trichloroacetic acid which forms trichloroperacetic acid in
situ as the reactive species. Since trichloroacetic acid is a solid under the
conditions of oxidation, at least one melting point depressant, such as methylene
dichloride, is required. Furthermore, it is also mentioned by the inventors that
mineral acids (that is, inorganic acids) are generally not useful as a medium for
oxidation due to the instability of Fipronil & Fipronil sulfide towards strong
mineral acids. Use of chlorinated hydrocarbon, such as methylene chloride,
chloroform, carbon tetrachloride and ethylene dichloride, is not particularly
desirable for industrial implementation due to the hazards associated with such
solvents.
[00015] Chinese Patent CN101250158 discloses a process for the synthesis
of Fipronil by oxidation of Fipronil sulfide in presence of a phase transfer catalyst
selected from the group consisting of tetrabutyl ammonium chloride, tetrabutyl
ammonium bromide, 4-N, N-dimethyl pyridine, triethylbenzylammonium
chloride, sodium dodecyl sulphonate and trimethyl dodecyl ammonium chloride,
in a solvent and sulphuric acid medium. However, the process disclosed is
expensive process as it utilizes phase transfer catalyst. Further, the process
disclosed in CN101250158 involves dissolution of the oxidant in sulphuric acid
6
which causes degradation of oxidant and leads to incomplete oxidation. The
process therefore shows inconsistency in the yield and the quality.
[00016] Based on the disadvantages of the above processes known in the
prior art, it would be highly desirable to have an improved process for the
production of Fipronil which is suitable for industrial use, simple, low-cost,
highly efficient and environmentally friendly, thereby overcoming the deficiencies
of the prior art. The present invention provides a process having one or more of
the foregoing advantages.
[00017] Furthermore, the present inventors have intensively studied based
on above mentioned findings and tried to complete the present invention more
closely to green chemistry.
OBJECTS OF THE INVENTION
[00018] The main object of the invention is to provide a process for
preparing Fipronil from Fipronil sulfide using a medium comprising at least one
resin(s), at least one oxidizing agent(s) and solvent(s).
[00019] Another object of the present invention is to provide a process for
preparing Fipronil which is simple, safe, time saving, having convenient
operational steps at commercial scale and environment friendly.
[00020] A further object of the present invention is to provide a process for
preparing Fipronil that abides green chemistry synthesis.
[00021] A further object of the present invention is to provide a process for
preparing Fipronil that prevents degradation of oxidant by avoiding a step of
dissolution of oxidant in concentrated sulfuric acid.
7
[00022] A further object of the present invention is to provide a process for
preparing Fipronil which involves effective degree of required oxidation resulting
in competitive high yield of the Fipronil with optimum purity at commercial
scale.
[00023] Yet, another object of the present invention is to provide a process
for preparing Fipronil in mild reaction condition without any adverse effect on
yield, purity & stability of final compound.
[00024] Yet another object of the present invention is to provide a process
for preparing Fipronil which do not corrode the equipments used.
[00025] Other objects and advantages of the present invention will be more
apparent from the following description, which is not intended to limit the scope
of the present disclosure.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of 5-amino-3-cyano-l-
(2, 6-dichloro-4- trifluoromethylphenyl)-4-trifluoromethylsulphinyl-pyrazole, also
known as Fipronil, represented by Formula (I), comprising oxidation of 5-amino-
3-cyano-l- (2, 6-dichloro-4- trifluoromethylphenyl)-4-trifluoromethyl
thiopyrazole, also known as Fipronil sulfide, represented by Formula (II), in a
medium comprising at least one solvent, at least one resin and at least one
oxidizing agent.
CF3
NC
H2N
CF3
CF3
NC
H2N
CF3
8
Formula (1) Formula (II)
(Fipronil) (Fipronil Sulfide)
[00026] In one aspect of the present invention, the solvent used is selected
from the group consisting of dichloroacetic acid, trichloroacetic acid,
monochloroacetic acid and mixture(s) thereof.
[00027] In another aspect of the present invention, the resin used is selected
from the group comprising ion exchange resins such as cation exchange resin
containing sulfonic acid groups, polymeric catalytic cation exchange resin and
corresponding salts thereof.
[00028] In a yet another aspect of the present invention, the oxidizing agent
is preferably a peroxide.
DETAILED DESCRIPTION OF THE INVENTION
[00029] The present invention is directed to a process for preparing 5-
amino-3-cyano-l- (2, 6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethyl
sulphinyl-pyrazole of Formula (I) from 5-amino-3-cyano-l- (2, 6-dichloro-4-
trifluoromethylphenyl)-4-trifluoromethylthiopyrazole of Formula (II) using a
medium comprising at least one resin(s), at least one oxidizing agent(s) and at
least one solvent(s).
CF3
NC
H2N
CF3
CF3
NC
H2N
CF3
Formula (1) Formula (II)
(Fipronil) (Fipronil Sulfide)
9
[00030] The term “green chemistry” as used herein refers to a utilization of
a set of principles that reduces or eliminates use or generation of hazardous
substance in the design, manufacture and application of chemical products" with
12 principles: 1) prevention, 2) atom economy, 3) less hazardous chemical
syntheses, 4) safer chemicals, 5) safer solvents and auxiliaries, 6) energy
efficiency, 7) use of renewable feed stocks, 8) derivatives reduction, 9) catalysis,
10) design for degradation, 11) real-time analysis for pollution prevention, and
12) inherently safer chemistry for accident prevention.
[00031] The term "peroxide" as used herein refers to any organic and
inorganic compound whose structure includes peroxy-group, -O-O-. The
characteristic properties of peroxide compounds are liberation of oxygen as a
result of thermal decomposition and the decomposition into oxygen and water.
Inorganic peroxides (such as alkali or alkaline earth metals) first decompose into a
metal hydroxide and hydrogen peroxide, prior to the decomposition of hydrogen
peroxide into oxygen and water.
[00032] The term "ion exchange resin" is used conventionally herein and
refers generally to weak and strong acid cation exchange resins of either the gel or
macroporous type. Ion exchange resins (IER) are insoluble polymers that contain
acidic or basic functional groups and have the ability to exchange counter-ions
within aqueous solutions surrounding them. Based on the nature of the
exchangeable ion of the resin as a cation or anion, it is classified as cationic or
anionic exchange resins, respectively. The efficacy of ion exchange resins mainly
depends upon their physical properties such as degree of cross-linking, porosity,
acid base strength, stability, purity and particle size.
[00033] In one embodiment of the present invention, there is provided an
improved process for the synthesis of compound of formula (I) by oxidation of
compound of formula (II) comprising the following steps:
10
a) adding a compound of formula (II) in a solvent for dissolution;
b) adding a resin to form a mixture and cooling the mixture to an optimum
temperature;
c) adding an oxidizing agent to the mixture to form a reaction mass;
d) stirring the reaction mass and monitoring completion of reaction;
e) adding a suitable second solvent after completion of reaction and raising
temperature of the reaction mass;
f) removing the resin by filtration and distilling the second solvent out from
filtrate completely to leave a residue,
g) adding water to the residue for crystallization to obtain the compound of
formula (I).
[00034] In one embodiment of the present invention, the solvent used in
step (a) is selected from the group consisting of dichloroacetic acid,
trichloroacetic acid, monochloroacetic acid and mixture(s) thereof.
[00035] In another embodiment of the present invention, the oxidizing
agent used in step (c) is a peroxide. Preferably, the peroxide is hydrogen peroxide.
[00036] Oxidation of compounds of the type of formula (II) entails several
difficulties, such as the molecule has to be stable under the conditions of
oxidation, the oxidation should proceed to the desired level without leaving
significant starting materials unreacted and the oxidation should not produce an
excessive level of sulfonyl derivative. Accordingly, the reaction conditions should
be selected to address these issues.
[00037] In an embodiment of the present invention, the resin used in step
(b) is selected from the group comprising ion exchange resins such as cation
exchange resin containing sulfonic acid groups, polymeric catalytic cation
exchange resin and corresponding salts thereof.
11
[00038] In an embodiment of the present invention, the corresponding salts
of resin are selected from the group comprising polysulfonated salts of
polymerized styrene, including but not limited to, for example, Kayexalate,
Kionex, Resonium A, Calcium Resonium, Sorbisterit, and Resikali or
combinations thereof.
[00039] A typical cation-exchange resin is prepared by co-polymerization
of styrene and divinylbenzene. During the polymerization, polystyrene is formed
as linear chains and these become covalently bonded to each other by
divinylbenzene cross links to form a co-polymer. If sulfuric acid is then allowed
to react with this copolymer, sulfonic acid groups are introduced into most of the
benzene rings of the styrene-divinylbenzene polymer, and the final substance
formed is known as cation-exchange resin.
[00040] Cation exchange resins contain covalently bound negatively
charged functional groups and exchanges positively charged ions. Cation
exchange resins are prepared by copolymerization of styrene and divinyl benzene
and have sulfonic acid groups (-SO3H) introduced into most of the benzene
rings. The mechanism of cation exchange process can be represented by the
following reaction in equation (1):
R- -ex+ +C+ → R- -C+ +ex+ …………………………..(1)
where, R is a resin polymer with SO3-sites available for bonding with
exchangeable cation (ex+), and C+ indicates a cation in the surrounding solution
getting exchanged.
[00041] In an embodiment of the present invention, addition of resin in the
process prevents degradation of oxidizing agent by avoiding the steps of
dissolution of oxidizing agent in concentrated acids, thereby reduces use of
12
hazardous chemicals in the preparation of Fipronil. Furthermore, according to the
present invention, use of resin reduces the impurity profile in the final product as
resin restricts formation of sulfonyl derivatives during the process
[00042] In one embodiment of the present invention, the resin is acidic
cation exchange resin. Preferably, the resin is a strongly acidic cation exchange
resin, such as strongly acidic cation exchange resins containing sulfonic acid
groups, or corresponding salts thereof.
[00043] In a further embodiment of the present invention, the resin is
strongly acidic polymeric cation exchange resin containing sulfonic acid groups
and corresponding salts thereof. Preferably, the polymeric cation exchange resins
have cation exchangers on polystyrene.
[00044] As used herein, “strongly acidic cation exchange resin” refers to
any resin whose active group is sulfonic acid group (RSO₃H) having a
pKa generally below a value of about 3.5.[(R. Kunin, Ion Exchange Resins, 2nd
Edition, Robert F. Krieger Publishing Company, Inc., Malabar, FL (1985)].
[00045] According to another embodiment of the present invention, pH of a
reaction mixture using acidic cation exchange resin is in the range of 0-7.
[00046] In another embodiment of the present invention, particle size of the
acidic cation exchange resin is in the range of 0.2 – 1.5 mm; more preferably 0.4
– 1.2 mm.
[00047] In another embodiment of the present invention, the temperature
after cooling in step (b) is in the range of -5 °C to +20 °C.
13
[00048] In another embodiment of the present invention, molar ratio of
oxidizing agent to the compound of formula (II) ranges from 0.1: 10 to 10: 0.1.
[00049] In another embodiment of the present invention, the solvent used
in step (e) is selected from the group comprising methylene dichloride, ethylene
dichloride, carbon tetrachloride, chloroform, o-dichlorobenzene, chlorobenzene,
bromobenzene, dibromomethane or mixture(s) thereof.
[00050] In another embodiment, the temperature at step (e) is in the range
of 10°C to 60°C.
[00051] In one embodiment, distillation at step (f) is carried out optionally
under pressure and temperature is in the range of 1°C to 50°C.
[00052] In another embodiment, the solvent used for crystallization in step
(g) is water.
[00053] In another embodiment of the present invention, sequence of
adding the compound of formula (II), the solvent, the resin and the oxidising
agent as mentioned in steps (a) to (e) can be interchanged according to the
suitability of the reaction conditions.
[00054] In accordance with the present invention, Fipronil can be obtained
in a yield of over 90%, more preferably over 95%, with respect to the starting
amount of the compound.
[00055] Fipronil produced in accordance with the process disclosed herein
has a purity of greater than about 95%, more preferably a purity of greater than
about 96%. Purity can be determined by HPLC, for example, or other methods
known in the art.
14
[00056] In one embodiment of the present invention, the strong acidic
cation exchange resins are selected from the commercially available brands
selected from the group comprising DOWEX, INDION, AMBERLYST, DIAION,
AMBERLITE, PUROLITE and the like. AMBERJET, AMBERLITE,
AMBERLYST, and DUOLITE are registered trademarks of Rohm and Haas Co.;
DOWEX, MARATHON, AND RETARDION are registered trademarks of Dow
Chemical Co.; INDION is the registered trademark of Ion Exchange (India) Ltd.
Suitable strongly acidic cation exchange resins for the present invention can
include, but not limited to, for example, INDION 140, INDION 130, INDION
190, INDION 770, DOWEX MONOSPHERE M-31, DOWEX M-31, DOWEX
88, DUOLITE C-26, AMBERLITE 15, AMBERLYST 15 DRY, AMBERLYST 15
WET, AMBERLYST 36 WET, DOWEX DR-2030, DOWEX 50WX2-100,
DOWEX 50WX4-100, DOWEX 50WX8-100, DOWEX MARATHON C,
AMBERLITE IRP 69 and the like.
[00057] Above examples of commercially available strongly acidic cation
exchange resin are merely illustrative of the invention and should not be
construed as limiting. Other similar class of resins with similar effect also falls
within the scope of this invention. The main advantage of using this class of
resins as reaction medium is that these can be recycled, easily handled, efficient
and environment friendly.
15
ADVANTAGES OF THE INVENTION
1. The present invention provides a process for preparing Fipronil from
Fipronil sulfide using a medium comprising at least one resin(s), at least
one oxidizing agent(s) and at least one solvent(s).
2. The present invention provides a process for preparing Fipronil which
utilizes easily available and effective solvents as a substitute for corrosive
and expensive solvents.
3. The present invention provides a process for preparing Fipronil which
involves effective degree of required oxidation resulting in competitive
high yield of the Fipronil with optimum purity at commercial scale.
4. The present invention provides a process for preparing Fipronil which
provides lower impurity profile in Fipronil, as mild reaction condition
restricts the formation of undesired sulfonyl derivative.
5. The present invention provides a process for preparing Fipronil which is
simple, safe, time saving, having convenient operational steps at
commercial scale.
6. The present invention provides a process for preparing Fipronil, wherein
the process uses resin that supports Green Chemistry.
7. The present invention provides a process for preparing Fipronil using
resin, wherein the resin is recyclable, efficient & environment friendly.
8. The present invention provides a process for preparing Fipronil that
obviates the use of a phase transfer catalyst.
9. The present invention provides a process for preparing Fipronil wherein
solvent recovery is possible from mother liquor.
10. The present invention provides a process for preparing Fipronil that
prevents degradation of oxidant by avoiding a step of dissolution of
oxidant in concentrated Sulfuric acid.
16
11. The present invention provides a process for preparing Fipronil that saves
utility at commercial scale, has simple work-up & crystallization
procedure.
17
EXAMPLES
[00058] The present invention is further explained in the form of following
examples. However it is to be understood that the foregoing examples are merely
illustrative and are not to be taken as limitations upon the scope of the invention.
Various changes and modifications to the disclosed embodiments will be apparent
to those skilled in the art. Such changes and modifications may be made without
departing from the scope of the invention.
EXAMPLE 1
Preparation of Fipronil
[00059] In a glass reactor, 5-amino-l-(2,6-dichloro-4-trifluoro
methylphenyl)-3-cyano-4-trifluoromethyl-thiopyrazole (42.1gm, 0.1mol) and
dichloro acetic acid (230gm) were mixed at room temperature to get a clear
solution. To this solution 40gm Indion-190 cation exchange resin was added and
cooled to 10-15°C, followed by the addition of 50% w/w H2O2 (10.2gm, 0.15mol)
slowly. The reaction was monitored on HPLC. After the completion of reaction,
methylene dichloride (60ml) was added and the temperature was raised up to
35°C in order to dissolve the product completely. The resin was filtered out and
washed with methylene dichloride followed by drying for re-use in subsequent
reactions. The filtrate was distilled out under vacuum at 35-40°C to get the
residue. To this residue 400 ml water was added. Solid thus obtained is filtered,
washed with water and dried to get 42 gm of the final product, Fipronil. Fipronil
was obtained in 96%yield having a purity of 95%.
EXAMPLE 2
Preparation of Fipronil
[00060] In a glass reactor trichloro acetic acid (79 gm) and Methylene
dichloride (25ml) were stirred at room temperature to get a clear solution. To this
solution Indion-190 cation exchange resin (20gm) was added and cooled to 15-
20°C, followed by the addition of 50% w/w H2O2 (8gm, 0.117mol) slowly. To this
18
slurry, 5-amino-l-(2,6-dichloro-4-trifluoro methylphenyl)-3-cyano-4-trifluoro
methyl-thiopyrazole (28gm, 0.066 mol) was added lot wise over a period of 1.0
hour. The reaction was monitored on HPLC. After the completion of reaction,
Methylene dichloride (40 ml) was added to the reaction mass and temperature was
raised up to 35°C in order to dissolve product completely. The resin was filtered
out and washed with methylene dichloride followed by drying for re-use in
subsequent reaction. The filtrate was distilled under vacuum at 35-40°C to get
residue. To this residue, 200ml water was added. The mixture was heated up to
40-50°C. Solid thus obtained was filtered, washed with water and 2% sodium
bicarbonate solution to obtain a wet cake. The wet cake was again washed with
water and dried to get 25 gm of the final product, Fipronil. Fipronil was obtained
in 96% yield having a purity of 95%.
[00061] The numerical values of various parameters given in the
specification are at approximations and slightly higher or slightly lower values of
these parameters fall within the ambit and the scope of the invention.
[00062] While considerable emphasis has been placed herein on the
specific steps of the preferred process, it will be highly appreciated that many
steps can be made and that many changes can be made in the preferred steps
without departing from the principles of the invention. These and other changes in
the preferred steps of the invention will be apparent to those skilled in the art from
the disclosures herein, whereby it is to be distinctly understood that the foregoing
descriptive matter is to be interpreted merely as illustrative of the invention and
not as a limitation.
For ATUL LIMITED
Tarun Khurana
Regd. Patent Agent [INPA-1325]
Dated: 2nd June 2014
19
We Claim:
1. An improved process for the synthesis of a compound of formula (I)
CF3
NC
H2N
CF3
CF3
NC
H2N
CF3
Formula (I) Formula (II)
comprising oxidation of a compound of formula (II) in a medium comprising at
least one solvent, at least one resin and at least one oxidizing agent.
2. The process as claimed in claim 1, wherein said at least one solvent is selected
from the group consisting of dichloroacetic acid, trichloroacetic acid,
monochloroacetic acid or mixture(s) thereof and said at least one resin is selected
from the group consisting of cation exchange resin containing sulfonic acid
groups, polymeric catalytic cation exchange resin or corresponding salts thereof.
3. The process as claimed in claim 3, wherein particle size of said at least one
resin is in the range of 0.1 – 1.5 mm.
4. The process as claimed in claim 1, wherein said at least one oxidizing agent is
hydrogen peroxide and a molar ratio of said oxidizing agent to the compound of
formula (II) ranges from 0.1: 10 to 10: 0.1.
5. An improved process for the synthesis of a compound of Formula (I) by
oxidation of a compound of Formula (II) comprising the steps of:
20
CF3
NC
H2N
CF3
CF3
NC
H2N
CF3
Formula (I) Formula (II)
a. adding the compound of formula (II) in a solvent;
b. adding a resin to form a mixture;
c. cooling the mixture to an optimum temperature;
d. adding an oxidizing agent to the mixture to form a reaction mass;
e. stirring the reaction mass and monitoring reaction;
f. adding a second solvent after completion of the reaction;
g. raising temperature and removing the resin by filtration;
h. distilling out the second solvent completely to leave residue; and
i. adding water to the residue to obtain the compound of formula (I).
6. The process as claimed in claim 5, wherein pH of the reaction mixture in step
(b) ranges from 0-7 and the temperature after cooling in step (c) ranges from -5
°C to +25 °C.
7. The process as claimed in claim 5, wherein said second solvent used in step (f)
is selected from the group comprising methylene dichloride, ethylene dichloride,
carbon tetrachloride, chloroform, o-dichlorobenzene, chlorobenzene,
bromobenzene, dibromomethane or mixtures thereof.
8. The process as claimed in claim 5, wherein said temperature in step (g) ranges
from 10°C to 60°C and said distillation in step (h) is carried out optionally under
pressure.
9. The process as claimed in claim 6, wherein a sequence of adding the compound
of formula (II), the solvent, the resin and the oxidising agent in steps (a) to (f) are
interchanged according to suitability of reaction conditions.
10. The process as claimed in claims 1 and 4, wherein yield of the compound of
formula (I) is more than 90% with respect to the compound of formula (II) and
HPCL purity of the compound of Formula (I) is ≥ 96%.