FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION: PROCESS FOR THE PREPARATION OF
ANTI-BVFLAMMATORY DRUG

2. APPLICANT
(a) Name
(b) Nationality
(c) Address

Emeu re Pharmaceuticals Ltd.
India
R & D Center II, 12/2 F - n Block, M.I.D.C. Pimpri,
Pune - 411018, Maharashtra



3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL
The following specification describes the
Invention.

COMPLETE V
The following specification particularly
describes the invention and the manner in
which it is to be performed.

4. DESCRIPTION (Description starts from next page.)
5. CLAIMS (not applicable for provisional specification.)
6. DATE AND SIGNATURE (to be given at the end of the last page of specification)
7. ABSTRACT OF THE INVENTION (to be given along with complete specification
on separate page)
Note: -
*Repeat boxes in case of more than one entry
*To be signed by the applicant(s) or by the authorized registered patent agent.
*Name of the applicants should be given in full, family name in the beginning
*Complete address of the applicant should be given stating the postal index
no./code, state and country.
*Strike out the column which is/are not applicable.


PROCESS FOR THE PREPARATION OF ANTI-INFLAMMATORY DRUG
FIELD OF THE INVENTION
The present invention relates to the process, which is industrially feasible, improved and
high yielding, for the preparation of an anti-inflammatory drug.
BACKGROUND OF THE INVENTION
Page 1 of 12
2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetic acid i.e. Aceclofenac (I), belongs to
the group of non-steroidal anti-inflammatory drugs (NSAID). Aceclofenac reduces
inflammation caused by the body's own immune system and is an effective pain killer.
This drugs acts on the body by blocking the action of cyclooxygenase, which is involved
in the production of prostaglandins. Prostaglandins are produced in response to injury.
Aceclofenac is used to relieve pain and inflammation in arthritic conditions (Ref:
http://www.tiscali.co.uk/lifesWle/healmfitness/health advice/netdoctor/archive/10000423
3.html ). Aceclofenac has properties similar to Diclofenac. The gastrointestinal
tolerability of Aceclofenac is better than that of Diclofenac and other NSAIDs and it has
a faster onset of action (Drugs Vol. 52(1), 113-124 [1996]).



SCHEME 0): PROCESS FOR PREPARATION OF ACECLOFENAC AS PER US 4,548,952
US 4,548,952 discloses the preparation of Aceclofenac (I) as depicted in Scheme (I).
According to this patent, the sodium salt of 2-[(2,6-dichlorophenyl)amine] phenylacetate
(II) is reacted with benzyl bromo acetate (III) to yield benzyl aceclofenac (IV). This
intermediate is then debenzylatd over palladium charcoal to yield Acelofenac (I).
However, this process has the following disadvantages, which limits its scope on
industrial level. The time taken for each reaction completion is higher, thus increasing the
time cycle of the entire process. The reaction conditions for the debenzylation reaction
are highly stringent due to
a) hydrogenation, which is the explosive reaction,
b) hydrogenation is carried out under pressure, thus requiring the expert manpower
for such pressure reactions,
c) hydrogenation needs special assembly such as autoclave / hydrogenator, thus
increasing cost and
d) the catalyst used is Pd/C, which is costly and gets poisioned easily.
Page 2 of 12

Hence, almost care is needed.
SCHEME (II): PROCESS FOR PREPARATION OF ACECLOFENAC AS PER US 20030060657
Page 3 of 12
ES 2020146 describes the preparation of Aceclofenac by treating the esters with iodine
trimethylsilane in methyl cyanide. This is prepared from chlorotrimethylsilane and
anhydrous sodium iodide in an inert atmosphere. The major disadvantage of this process
is the high cost of the silane systems used and iodine trimethyl silanc i.e. (iodo trimethyl
silane) is explosive. It causes eye and skin burns. It is highly flammable reagent. (Ref:
http://www.coleparmer.com/catalog/Msds/42745.htm ). It is also volatile and hence
storage and handling becomes more stringent. Further, it is also very difficult to recover
these trimethyl silanes from the system thus making the process economically unfeasible.
Moreover, the solvent used is methyl cyanide, which is very dangerous to health.


US 20030060657 describes the process for the preparation of aceclofenac as described in
Scheme (II). The phenyl acetic derivative (V) reacts with the alpha halo acetic acid (VI)
in the presence of amine to yield the tertiary butyl acetoxy acetate (VII), which is
deprotected using formic acid or trifluoroacetic acid to give Acelofenac. However, this
process has certain disadvantages. For the industrial scale, the yield obtained of the
esterification is comparatively less (76%), thus decreasing the overall yield of
Aceclofenac. The product obtained needs to be purified via recrystallization useful for
human consumption. Further, the solvent used is formic acid or trifluoro acetic acid,
which have following disadvantages: (ref:
http ://ptcl. chem.ox.aauk/MSDS/FO/formic acid.html and
http://physchem.ox.ac.uk/MSDS/TR/trifluoroacetic acid.html
a) Trifluoroacetic acid reacts violently with bases,
b) It causes sever burns on skin,
c) It is harmful to the environment,
d) Formic acid is corrosive and causes sever burns and
e) It is a severe eye irritant and lacrimetric.
Hence, there is a need to develop the process using the safe solvent devoid of the above
mentioned disadvantages.
Thus, there are a number of problems with literature processes for preparing Aceclofenac.
a) The yield of esterification reaction is low.
b) The purification of the final product is required, which results in increased labor, time
cycle, cost of utilities, reactor occupancy and decrease in yield, while increasing the
solvent cost and time cycle.
c) The hazardous pressure dependent reaction conditions like hydrogenation are used
which require expert manpower, special assembly and a costly catalyst.
d) The reagents like trimethyl iodo silane, used in the prior art are unsafe.
e) The solvents used in the prior art are toxic.
In view of the above shortcomings, it was necessary to develop an alternate synthetic
route, which would give Aceclofenac i.e. compound of formula (I), by a process, which is
industrially feasible and viable.
Page 4 of 12

SUMMARY OF THE INVENTION
The present inventors have developed a synthetic route for preparation of Aceclofenac
(I), in good yields.
The present inventors have developed a process to prepare Aceclofenac, by avoiding the
highly hazardous reaction conditions like the hydrogenation.
In the present invention, inventors have developed a process to prepare Aceclofenac by
avoiding the highly expensive, explosive and volatile reagents like iodine trimethylsilane.
The present inventors have also provided the preparation of Aceclofenac with desired
purity by avoiding the purification steps.
The inventors further provide the hydrolysis using safe solvents.
The present inventors have also developed a process for the preparation of Aceclofenac
of desired purity by reducing the steps, making use of less amount of solvents and
reagents and thus making the entire process cost effective and industrially feasible.
OBJECT OF THE INVENTION
First object of the present invention is to provide an improved process for the preparation
of Aceclofenac of formula (I) by a synthetic route, which is simple, industrially feasible,
economical and safe.
Second object of the invention is to provide Aceclofenac by avoiding the highly perilous
reaction conditions like hydrogenation.
Third object of the invention is to prepare Aceclofenac by avoiding the use of expensive,
explosive and volatile reagents like iodine trimethylsilane.
Fourth object of the invention is to provide Aceclofenac hi good yields.
Page 5 of 12

Fifth object of the invention is to prepare Aceclofenac having high purity by avoiding the
stringent purification steps.
Sixth object of the invention is to provide aceclofenac using safe solvent such as acetic
acid / HC1 (HC l in acetic acid).
DETAILED DESCRIPTION OF THE INVENTION:
Aceclofenac (I) is prepared as per Scheme (HI) disclosed below:

The present embodiment describes the preparation of Aceclofenac as per the reaction
sequence disclosed in Scheme (III). Diclofenac sodium salt (II) i.e. 2-[(2,6-
dichlorophenyl)amine]phenyl acetate is reacted with the alpha-halo-acetic acid ester (VI)
in the presence of catalytic amount of dimethyl amino pyridine (DMAP) to yield the
Page 6 of 12

Aceclofenac ester (VII). The Aceclofenac ester is treated with acetic acid hi the presence
hydrogen bromide to yield Aceclofenac (I).
The current invention makes use of acylating agent in the catalytic amount. The acylating
agent used is dimethyl amino pyridine. This helps in significantly increasing the yield and
reduces the overall cost and time of the reaction step.
Secondly, the present embodiment makes use of AcOH/HBr (HBr in acetic acid) or
AcOH/HC l for the deesterification. The use of this reagent assists for providing the
Aceclofenac with high yields and high purity hi one shot, without purification step.
hi the current invention the halogen of the alpha halo acetic acid ester (VI) can be
selected from the group comprising of chlorine or bromine. The halogen group of the
alpha halo acetic acid ester is preferably chlorine.

In the present invention, the ratio (wt/wt) used for the dimethyl amino pyridine with
respect to diclofenac sodium ranges from 0.008% to 8%. In the preferred embodiment the
ratio used for the dimethyl amino pyridine ranges from 0.08% to 2%. More preferably,
the ratio of DMAP is 0.5% to 1.0%.

The solvent used for the reaction is selected from the group comprising of amides, esters,
ethers etc. The amides are selected from the group comprising of dimethyl formamide,
dimethyl acetamide etc. Page 7 of 12


The hydrolysis can be performed using the safe acid. The said acid performs the dual
function as solvent as well as the hydrolyzing agent. The said acid is for example acetic
acid/HCl or HBr.
The improved method of preparation of Aceclofenac according to the instant invention
reduces the load on utilities, reactor occupancy, manpower, time cycle etc. A further
result to this is the increase in the yield of the final product.
Thus, the current embodiment makes use of a process, which is advantageous in
following ways:
1) Use of catalytic amount of dimethyl amino pyridine, thus increasing the yield.
2) Formation of highly pure Aceclofenac by avoiding the purification step.
3) Adopting the safe reaction conditions, while avoiding the highly hazardous
reaction conditions like hydrogenation.
4) Cost effective and industrially feasible process.
5) Use of less amount of solvents
6) Use of safe solvents and
7) Reduction in the time cycle of the process.
which are provided merely for illustration and are not intended to restrict the scope of the
Page 8 of 12

invention in any manner. Any embodiments that may be apparent to a person skilled in
the art are deemed to fall within the scope of the present invention.
Page 9 of 12

Example 1: Preparation of Aceclofenac Ester
In a round bottom flask add dimethyl formamide (300 ml) and diclofenac sodium (100 g)
were added with stirring. Tertiary butyl chloroacetate (52.09 g) was added to the above
reaction mixture. Dimethyl amino pyridine (0.8 g) was added to the same mixture. The
reaction mixture was warmed to 30 to 35 °C and stirred for 12-14 hours. The reaction
mixture was quenched by adding 2.2% sodium bicarbonate solution in the interval of 60
minutes at ambient temperature. The reaction mixture was further stirred for one hour.
The solid was filtered and washed with water. The solid was further dried.
Yield: 92%
Example 2: Preparation of Aceclofenac
Acetic acid (3 lit) was charged in round bottom flask. Aceclofenac ester (1.0 kg) was
added and the reaction mixture was cooled to 10-15OC. Dry hydrochioric acid (0.89 kg)
was bubbled at 0-15°C. The reaction mixture was stirred for 30-40 minutes at 10-15°C.
The solid was filtered. The solid was washed with water and dried.
Yield: 0.85 kg
HPLC purity: 99.6%
Example 3: Preparation of Aceclofenac
In a round bottom flask dichloromethane (100 ml) was added to acetic acid in HBr
(177.35g). The reaction mixture was cooled to 0-5°C. Aceclofenac ester (122 g) was
added to the acetic acid in HBr at 0-5°C. Sodium hydroxide solution (24.37 g in 100 ml
water) was added. Cyclohexane (400 ml) was added to the reaction mixture at 0-5°C. The
reaction mixture was further stirred for 60 minutes. The solid was filtered and washed
with water.
%Yield: 89%
HPLC purity: 99.7%
Page 10 of 12

We claim:
1) A process for the preparation of Aceclofenac (I) comprising the steps of:
a) reacting the diclofenac sodium salt with alpha halo acetic acid ester in the
presence of catalyst to yield aceclofenac ester,

2) A process according to claim 1 (a), wherein the catalyst used is acylating agent.
3) A process according to claim 2, wherein the acylating agent used is N,N-dimethyl
amino pyridine.
4) A process according to claim 3, wherein the acylating agent is used in the weight
ratio of 0.008% to 8%.
5) A process according to claim 3, wherein the acylating agent is preferably used in
the weight ratio of 0.08% to 2%.
6) A process according to claim 3, wherein the acylating agent is more preferably
used in the weight ratio of 0.5% to 1 %.
7) A process according to claim 1 (a), wherein the solvent is selected from the group
comprising of amides, esters, ethers etc.
Page 11 of 12

8) A process according to claim 7, wherein the solvent is selected preferably from
the group comprising of amides.
9) A process according to claim 8, wherein the solvent is selected more preferably
from dimethyl formamide and dimethyl acetamide.
10) A process according to claim 9, wherein the solvent is dimethyl formamide.
11) A process according to claim l(a), wherein the halogen is selected from the group
comprising of chlorine, bromine and iodine.
12) A process according to claim 11, wherein the halogen preferably is chlorine.
13) A process according to Claim l(b), wherein the acid is HC1 in acetic acid or HBr
in acetic acid.
14) A process according to Claim 13, wherein the acid is HC1 in acetic acid.
15) A process for the preparation of Aceclofenac, substantially as describ<
foregoing examples.


Registered Patent Agent
For Emcure Pharmaceuticals Ltd.

Page 12 of 12