FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF NEPAFENAC."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, PlotNo.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF NEPAFENAC
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of compound of structural formula VI comprising reacting compound of structural formula II with a compound of structural formula V in the presence of N-halophthalimide to get a compound of structural formula VI and converting compound of structural formula VI into substantially pure nepafenac compound of structural formula I.

wherein R is a linear or branched C1-C12 alkyl group, or a cyclic C3-C12-alkyl group, wherein the linear or branched C1-C12 alkyl group is optionally substituted or interrupted with a substituent selected from the group consisting of a cyclic C3-C6 alkyl group, a cyclic C3-C6-alkylene group, a phenyl group, and a phenylene group, and wherein the cyclic C3-C6-alkyl group, the cyclic C3-C6-alkylene group, the phenyl group, or the phenylene group is optionally further substituted by 0, 1, 2, or 3 methyl groups.
BACKGROUND OF THE INVENTION:
Nepafenac is chemically 2-amino-3-benzoylbenzeneacetamide and is known from US Patent No. 4,313,949 and is represented by compound of structural formula I.


Formula I Nepafenac is a non-steroidal anti-inflammatory drug (NSAID) and sold in USA market under the proprietary name NEVANAC used to treat pain and inflammation associated with cataract surgery.
U.S. patent no. 4,313,949 describes a process for the preparation of nepafenac compound of structural formula I in which 2-amino benzophenone compound of structural formula II is reacted with 2-(methylthio)acetamide compound of structural formula III in dichloromethane solvent in presence of t-butylhypochlorite to get 2-(2-amino-3-benzoylphenyl)-2-(methylthio) acetamide compound of structural formula IV , which is being reduced by raney nickel in into nepafenac compound of structural formula I as described below in scheme no. 1

U.S. patent publication no. 2009/0312575 describes a process for the preparation of nepafenac compound of structural formula I in which 2-amino benzophenone compound of structural formula II was reacted with 2-(methylthio)acetamide

compound of structural formula III in anhydrous dichloromethane solvent in the presence of N-chlorosuccinimide to get a 2-(2-amino-3-benzoylphenyl)-2-(methylthio) acetamide compound of structural formula IV, which is being reduced by raney nickel in into nepafenac compound of structural formula I as described below in scheme no. 2.

The above mentioned prior-art processes for preparing nepafenac compound of structural formula I resulted an impure nepafenac compound along with impurities of structural formula II, IV, VII, VIII and IX, which are being removed by employing crystallization or column chromatographic technique, which resulted into decrease in yield of final nepafenac compound of structural formula I hence these processes are not economic at commercial scales.


SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a commercial viable process for the preparation of substantially pure nepafenac compound of structural formula I.
A second aspect of the present invention is to provide an improved process for the preparation of substantially pure compound of structural formula VI comprising reacting compound of structural formula II with a compound of structural formula V in the presence of N-halophthalimide.

Formula II Formula V Formula VI
Wherein R is a linear or branched C1-C12 alkyl group, or a cyclic C3-C12-alkyl group, wherein the linear or branched C1-C12 alkyl group is optionally substituted or interrupted with a substituent selected from the group consisting of a cyclic C3-C6-alkyl group, a cyclic C3-C6-alkylene group, a phenyl group, and a phenylene group, and wherein the cyclic C3-C6-alkyl group, the cyclic C3-C6-alkylene group, the phenyl group, or the phenylene group is optionally further substituted by 0, 1, 2, or 3 methyl groups.
A third aspect of the present invention is to provide a process for the preparation of substantially pure nepafenac compound of structural formula I comprising the steps of:
a. reacting 2-amino benzophenone compound of structural formula II with a
compound of structural formula V in the presence of N-halophthalimide to get
a compound of structural formula VI and


Formula II Formula V Formula VI
b. converting compound of structural formula VI into substantially pure nepafenac compound of structural formula I.

Wherein R is as described above
A fourth aspect of the present invention is to provide a process for preparation of substantially pure 2-(2-amino-3-benzoylphenyl)-2-(methylthio) acetamide compound of structural formula IV comprising reacting compound of structural formula II with a compound of structural formula III in the presence of N-halophthalimide.

DETAIL DESCRIPTION OF THE INVENTION:
The reaction of 2-amino benzophenone compound of structural formula II with a compound of structural formula V may be carried out in presence of N-halophthalimide in halogenated aliphatic hydrocarbon solvent at a temperature in the range of -50°C to 0°C for a period of 30 minutes to 3 hours.

The examples of N-halophthalimide may be selected from the group comprising of N-chlorophthalimide, N-bromophthalimlde or N-iodophthalimide.
The examples of halogenated aliphatic hydrocarbon solvents may include but not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The reaction of 2-amino benzophenone compound of structural formula II with a compound of structural formula V may be carried out in presence of N-halophthalimide and organic base.
The examples of organic base may include but not limited to triethyl amine, diisopropyl amine, dibutyl amine, methyl isopropyl amine, 1, 8-diazabiicyclo [5.4.0] undec-7-ene, N-methyl morpholine.
The compound of structural formula VI may be isolated by filtering the reaction mixture at a temperature in the range of 25-30°C and then the filtrate may be further treated with an aqueous solution of inorganic base and then organic layer may be separated.
The examples of inorganic base may include alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali earth metal hydroxide such as calcium hydroxide, magnesium hydroxide, alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, alkali earth metal carbonate such as calcium carbonate, magnesium carbonate, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate.
The organic layer containing compound of structural formula VI may be concentrated under reduced pressure to get a residue, which may be dissolved in an alkyl acetate solvent.

The examples of alkyl acetate solvents may include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixture(s) thereof.
The compound of structural formula VI may be dissolved in an alkyl acetate solvent at a temperature in the range of 60°C to 90°C and then the resulting solution may be first stirred at 60°C to 90°C for a period of 1 hour to 6 hours and then at 0° to 5°C for a period of 1 hour to 3 hours and then the resulting solids may be isolated by the steps of filtration, washing, drying and the combination thereof.
The compound of structural formula VI may be washed with an alkyl acetate solvent.
The compound of structural formula VI may be dried at a temperature in the range of 40°C to 60°C for period of 2 hours to 4 hours under reduced pressure.
The compound of structural formula VI obtained from the reaction of compound of structural formula II with a compound of structural formula V in the presence of N-halophthalimide is free from following impurities of structural formula II and VII.

The compound of structural formula VI may be converted into crude nepafenac compound of structural formula I by reacting compound of structural formula VI with raney nickel in an ether solvent at a temperature in the range of 20°C to 30°C for a period of 30 minutes to 4 hours.


Wherein R is as described above
The examples of ether solvent may include but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, methyl tertiary butyl ether, diethyl ether, diisobutyl ether, di-n-butyl ether, di-n-propyl ether, di-isopropyl ether, dimethoxyethane or mixture(s) thereof.
The isolation of nepafenac compound of structural formula I may be carried out by filtering the reaction mixture, followed by the concentrating the filtrate under reduced pressure to get residue.
The substantially pure nepafenac compound of structural formula I may be isolated by crystallizing crude nepafenac in an alcohol solvent at a temperature in the range of 10°C to 85°C for a period of 10 minutes to 3 hours.
The examples of alcohol solvents may include but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, sec-butyl alcohol, tert-butyi alcohol or mixture(s) thereof.
The substantially pure nepafenac compound of structural formula I may be further crystallized in above mentioned alcohol solvent.
The substantially pure nepafenac compound of structural formula I may be isolated by the steps of centrifugation. filtration, washing, drying and the combination thereof.

The substantially pure nepafenac compound of structural formula I may be dried at a temperature in the range of 40°C to 60°C for period of 2 hours to 6 hours under reduced pressure.
The substantially pure nepafenac compound of structural formula I may contain less than 0.1% weight / weight of following compounds of structural formula II, IV, VII, VIII and IX.

The limit of detection (LOD) and limit of quantitation (LOQ) of compound of structural formula II, IV and VII is 0.001 and 0.01 respectively.
The limit of detection (LOD) and limit of quantitation (LOQ) of compound of structural formula VIII and IX is 0.001 and 0.002 respectively.


EXAMPLE:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of substantially pure nepafenac.
Step-1: Preparation of 2-{2-amino-3-benzoylphenyl)-2-(methylthio) acetamide compound of structural formula IV.
The solution of 2-(methylthio) acetamide compound of structural formula III (80gm) in dichloromethane (1000ml) was added dropwise a solution of N-chlorophthalimide (101.3gm) in dichloromethane (1000ml) at -45°C to -50°C for a period of 1 hour. The resulting reaction was agitated for a period of 30 minutes at -45°C to -50°C and then the solution of 2-amino benzophenone compound of structural formula II (100gm) in dichloromethane (1000ml) was added slowly at -45°C to -50°C for a period of 40 minutes. The resulting reaction mixture was stirred 30 minutes at -45°C to -50°C and then it was heated up to 0°C. The triethyl amine (77gm) was added to the reaction mixture at 0-5°C and then it was stirred 30 minutes at 20° to 30°C. The resulting reaction mixture was filtered and then the filtrate was treated with 2% aqueous sodium hydroxide solution (100ml) [sodium hydroxide (20gm) dissolved in water (1000ml)] and then organic layer was separated. The organic layer was washed with water (2x1000ml) and then it was concentrated under reduced pressure to get residue. The residue was dissolved in ethyl acetate (1500ml) at 80°C to 85°C and then it was stirred at 0-5°C for 2 hours and then resulting solids were filtered, washed with ethyl acetate (100ml) and dried at 50-55°C for 8 hours to get title compound. Yield: 142 gm Purity: 99.88% (By HPLC)

Step-2: Preparation of substantially pure nepafenac compound of structural formula I.
The solution of 2-(2-amino-3-benzoylphenyl)-2-(methylthio) acetamide compound of structural formula IV (90gm) obtained from step 1, in tetrahydrofuran (1800ml) was added raney nickel (900gm) at 25°C and then the resulting reaction mixture was agitated for 15 minutes. The reaction mixture was filtered on hyflow bed and filtrate was concentrated under reduced pressure to get a residue. The residue was dissolved in isopropanol (3780ml) at 80°C and then it was stirred at 10-15°C for 2 hours. The resulting solids were filtered, washed with isopropanol (45ml) and dried under at 50-55°C under reduced pressure to get title compound. Yield: 70.4gm Purity: 99.96% (By HPLC)

WE CLAIM:
1. An improved process for the preparation of substantially pure compound of structural formula VI comprising reacting compound of structural formula II with a compound of structural formula V in the presence of N-halophthalimide.

wherein R is a linear or branched C1-C12 alkyl group, or a cyclic C3-C12-alkyl group, wherein the linear or branched C1-C12 alkyl group is optionally substituted or interrupted with a substituent selected from the group consisting of a cyclic C3-C6-alkyl group, a cyclic C3-C6-alkylene group, a phenyl group, and a phenylene group, and wherein the cyclic C3-C6-alkyl group, the cyclic C3-C6-alkylene group, the phenyl group, or the phenylene group is optionally further substituted by 0, 1, 2, or 3 methyl groups.
2. A process for the preparation of substantially pure nepafenac compound of structural formula I comprising the steps of:
a. reacting 2-amino benzophenone compound of structural formula II with a
compound of structural formula V in the presence of N-halophthalimide to get
a compound of structural formula VI and

b. converting compound of structural formula VI into substantially pure nepafenac compound of structural formula I.


wherein R is a linear or branched C1-C12 alkyl group, or a cyclic C3-C12-alkyl group, wherein the linear or branched C1-C12 alkyl group is optionally substituted or interrupted with a substituent selected from the group consisting of a cyclic C3-C6-alkyl group, a cyclic C3-C6-alkylene group, a phenyl group, and a phenylene group, and wherein the cyclic C3-C6-alkyl group, the cyclic C3-C6-alkylene group, the phenyl group, or the phenylene group is optionally further substituted by 0, 1, 2, or 3 methyl groups.
3. A process for preparation of substantially pure 2-(2-amino-3-benzoylphenyl)-2-(methylthio) acetamide compound of structural formula IV comprising reacting compound of structural formula II with a compound of structural formula III in the presence of N-halophthalimide.

4. The process according to claim no. 2, wherein reaction of 2-amino benzophenone compound of structural formula II with a compound of structural formula V is carried out in presence of N-halophthalimide in halogenated aliphatic hydrocarbon solvent at a temperature in the range of-50°C to 0°C for a period of 30 minutes to 3 hours.

5. The process according to claim no. 4, wherein the examples of N-halophthalimide is selected from the group comprising of N-chlorophthalimide, N-bromophthalimide or N-iodophthalimide.
6. The process according to claim no. 4, wherein examples of halogenated aliphatic hydrocarbon solvents is selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
7. The process according to claim no. 2, wherein reaction of 2-amino benzophenone compound of structural formula II with a compound of structural formula V is carried out in presence of organic base such as triethyl amine, diisopropyl amine, dibutyl amine, methyl isopropyl amine, 1, 8-diazabiicyclo [5.4.0] undec-7-ene or N-methyl morpholine.
8. The process according to claim no. 2 wherein compound of structural formula VI is converted into crude nepafenac compound of structural formula I by reacting compound of structural formula VI with raney nickel in an ether solvent such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 4-dioxane, methyl tertiary butyl ether, diethyl ether, diisobutyl ether, di-n-butyl ether, di-n-propyl ether, di-isopropyl ether, dimethoxyethane or mixture(s) thereof at a temperature in the range of 20°C to 30°C for a period of 30 minutes to 4 hours.

wherein R is a linear or branched C1-C12 alkyl group, or a cyclic C3-C12-alkyl group, wherein the linear or branched C1-C12 alkyl group is optionally substituted or interrupted with a substituent selected from the group consisting of a cyclic C3-C6-alkyl group, a cyclic C3-C6-alkylene group, a phenyl group, and a phenylene group, and wherein the cyclic C3-C6-alkyl group, the cyclicC3-C6-alkylene group, the phenyl

group, or the phenylene group is optionally further substituted by 0, 1, 2, or 3 methyl groups.
9. The process according to claim no. 8, wherein substantially pure nepafenac compound of structural formula I is formed by crystallizing crude nepafenac in an alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, sec-butyl alcohol, tert-butyl alcohol or mixture(s) thereof at a temperature in the range of 10°C to 85°C for a period of 10 minutes to 3 hours.
10. The process according to claim no. 2 and 9 wherein substantially pure nepafenac compound of structural formula I contain less than 0.1% weight / weight of following compounds of structural formula II, IV, VII, VIII and IX.