FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"PROCESS FOR THE MANUFACTURE OF HIGHLY PURE NEPAFENAC"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-amino-3-benzoylbenzeneacetamide structurally represented by Formula-(I) and commonly known as Nepafenac.

The process provides Nepafenac in higher purity and minimizes formation of Nepafenac related impurities compared to the processes known in the prior art.
The invention also relates to crystalline Form A obtained by process of the present invention, the said Form A being substantially pure, stable and characterized by X-ray powder diffraction pattern comprising 29 peaks selected from 5.85, 11.72, 17.37 and 24.99 ± 0.2.
BACKGROUND OF THE INVENTION
Nepafenac is a nonsteroidal anti-inflammatory drug (NSAID). It is approved for ophthalmic use in the form of prescription eye drops marketed under the brand names Nevanac (0.1% solution) or Ilevro (0.3% solution) in the US by Novartis.
U.S. Patent No. 4,313,949 discloses Nepafenac and a process for its synthesis by treating 2-aminobenzophenone (II) with 2-(methylthio)acetamide (III) in the presence of t-butyl hypochlorite in DCM solvent to give 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), which is further reduced in the presence of Raney nickel to obtain Nepafenac of formula (I). This process is depicted below in Scheme I.


There are a number of drawbacks related to the process as described in US '949. The process as disclosed in the instant patent produced several chlorination by-products of compound II and IV in considerable amounts, giving low reproducibility rates. Further, synthesis of compound IV as described in '949 patent requires very low temperatures, e.g., about -65 °C, which is difficult to achieve at industrial scale and would involve the use of special apparatus. Also, the chlorinating agent tert-butyl hypochlorite poses a handling hazard as it is unstable, light-sensitive, and decomposes explosively and must be stored at low temperatures (10 °C).
U.S. Patent No. 8,278,484 discloses a process for the preparation of Nepafenac wherein 2-aminobenzophenone (II) is treated with 2-(methylthio)acetamide (III) in the presence of N-chlorosuccinimide to obtain 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), which is further reduced in the presence of Raney nickel to give Nepafenac. This process is represented below in Scheme II.


The process as disclosed in the '484 patent requires low temperature conditions (-45 to -40 °C). The N-chlorosuccinimide used, decomposes rapidly and must be stored at low temperatures.
Indian application No. 2823/CHE/2013 (Mylan US 9630909) treating 2-aminobenzophenone (II) with 2-(methylthio)acetamide (III) in the presence of sulfuryl chloride and a base at temperatures ranging from (-40 to 0 °C) to afford 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), and removing the thiomethyl moiety from the 2-(2-amino-3-benzoylphenyl)-2 (methylthio)acetamide (IV) to afford Nepafenac.
The process for the preparation of Nepafenac as disclosed in Indian application '823 requires low temperature conditions i.e. from -40 to 0 °C. The sulfuryl chloride used in the reaction is known to be toxic, corrosive, and forms a fuming mixture with water, dimethyl formamide, and dimethyl sulfoxide.
Indian Patent No. 298253 discloses a process for the preparation of Nepafenac in which 2-aminobenzophenone (II) is treated with 2-(methylthio)acetamide (III) in the presence of N-chloro phthalimide at temperature range of -50 to -40 °C to give 2-(2-amino-3-benzoylphenyl)-2-(methylthio)acetamide (IV), which is consequently reduced in the presence of Raney nickel under hydrogen pressure to obtain Nepafenac.
The process as described in '253 patent requires low temperature range for the reaction. Also, N-chlorothalimide is corrosive in nature.
The prior art processes listed above all require low temperatures for the reaction of compound of formula III and formula II to proceed; which is difficult to achieve at industrial scale and poses scalability problems. All of the processes require the use of Raney Nickel for the reduction of compound of formula IV to Nepafenac. Raney Nickel is a highly pyrophoric reagent requiring handling at inert temperatures. The present invention avoids the use of Raney Nickel for the manufacture of Nepafenac.
Also, listed prior-arts all go through Thiomethyl intermediates which have a distinctive putrid smell. The present invention does not go through any thiomethyl intermediates.

The processes of the prior art references involve tedious workup to isolate the required product and thus results in longer time cycle, which in turn renders the process more costly and less ecofriendly while making the process unamenable for commercial scale up.
Subsequently, there is a persistent need for developing new and improved processes for the preparation of Nepafenac, in addition to methods for reducing or eliminating the impurities formed during the preparation of Nepafenac.
The present invention has focussed the research work towards preparation of Nepafenac which is of high purity and also without all the disadvantages as reflected in the prior art processes.
The process for the preparation of Nepafenac as per the present invention is cost effective and avoids the drawback of the prior art processes.
SUMMARY OF THE INVENTION
One aspect of the present invention provides a process for preparation of Nepafenac of Formula (I) by reacting Amfenac sodium of formula (A) with dicyclohexylcarbodiimide and hydroxybenzotriazole in presence of a suitable solvent and a base and is further reacted with ammonium chloride to obtain Nepafenac of formula (I);

An object of the present invention provides a process for the preparation of Nepafenac which is substantially free from impurity and also industrially viable.
Another object of the present invention is to provide an improved process for preparation of highly purified Nepafenac while avoiding the use of hazardous reagents and use of thiomethyl intermediates.

It has been surprisingly found that the process according to the present invention provides Nepafenac having Nepafenac related impurities less than 0.1%
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 is an example of XRPD pattern of crystalline Form A.
Fig 2 is an example of Differential Scanning Calorimetry (DSC) of Form A. Fig 3 is an example of TGA of Form A.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the term "suitable solvent" refers to, but is not limited to Dimethyl formamide (DMF), Dimethoxyethane (DME), Dimethyl sulfoxide (DMSO) and the like; water or mixtures thereof.
As used throughout the specification, the term "base" refers amines such as triethylamine, N,N-diisopropylethylamine (DIPEA), tertiary butyl amine (TBA), methylamine, n-methyl morpholine (NMM), ethylamine, n-propyl amine, and the like. The term alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and the like.
In one embodiment, the present invention provides a process for preparation of Nepafenac of Formula (I), comprising

Reacting Amfenac sodium of formula (A) with a coupling reagent and an additive in the presence of a base and an organic solvent and further reacting it with Ammonium chloride at 25-30 °C to give Nepafenac.


In one embodiment the examples of coupling reagent may be selected from the group consisting of dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), diisopropylcarbodiimide (DIC), N-Cyclohexyl-N'-(2-morpholinoethyl)carbodiimide (CMCT).
The examples of additive to coupling reaction may be selected from the group consisting of 1-hydroxy-lH-benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), Hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine (HOOBt), 4-(N,N-Dimethylamino)pyridine (DMAP).
In one embodiment, reaction between Amfenac sodium and HOBt/DCC may be performed in the presence of a suitable base and a suitable solvent.
In one embodiment, an organic base used, includes, but is not limited to, primary, secondary or tertiary amines such as methylamine, n-methyl morpholine (NMM), ethylamine, n-propyl amine, isopropyl amine, triethylamine, N,N-diisopropylethylamine and the like.
In one embodiment, the suitable solvent used, includes, but is not limited to polar aprotic solvents like dimethyl sulfoxide; dimethylformamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water; or mixtures thereof. Preferably the solvent selected is dimethylformamide.
In one embodiment, after completion of the reaction, suitable work up may be performed, as known to a skilled artisan, to isolate crude Nepafenac before purification. The reaction mixture may be washed with Petroleum ether: Ethyl acetate mixture at a temperature in the range of 50-55 °C, filtered and dried to obtain crude Nepafenac.
In one embodiment, the crude Nepafenac may be purified by refluxing with suitable alcohol solvent and activated charcoal at a temperature range of 80- 82 °C and further filtered through Hyflo bed.

The examples of alcohol solvents may include but not limited to methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, n-pentanol, isopentanol, sec-butyl alcohol, tert-butyl alcohol or mixture(s) thereof, preferably Isopropyl alcohol.
The substantially pure Nepafenac compound of structural formula I may be dried at a temperature in the range of 80 °C to 85 °C after a period of 7 to 8 h.
In another embodiment of the present invention provides crystalline Form A of Nepafenac which is characterized by-
1) 5.85, 11.72, 17.37, 24.99 ±0.2 20°
2) DSC isothermal peak ranging 183.5 °C
3) TGA
EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not proposed to limit the scope of the present invention in any way.
Example 1: Preparation of Nepafenac:
To 325 ml of dimethylformamide, 25 g amfenac sodium was added at 25-30 °C and the reaction mixture was stirred until clear. Further, hydroxybenzotriazole (14.58 g), N-Methylmorpholine (178.5 ml) and Ammonium chloride (86.91 g) was added to the reaction mixture and continued to stir at 25-30 °C. A solution of (22.28 g) N,N'-dicyclohexylcarbodiimide in 50 ml of dimethyl¬formamide was prepared and added to the reaction mixture at 30-45 min. The mixture was maintained for 12-15 h at 25-30 °C. After filtering, the wet cake was washed with 50 ml dimethylformamide, stirred for 50-60 min at 10-15 °C, and further washed with 200 ml purified water at 25-30 °C. The wet cake was then refluxed in 375 ml petroleum ether: ethyl acetate (1:1) at 60-65 °C and further washed with hot petroleum ether:ethyl acetate (1:1) (250 ml) at 50-55 °C. Crude nepafenac was filtered and dried after 7-8 h at 80-85 °C.

Example 2: Purification of Nepafenac:
Crude Nepafenac was refluxed in 910 ml Isopropyl alcohol and activated charcoal was added to it at 80-82 °C. The solution was filtered hot through Hyflo bed at 80-82 °C. The Hyflo bed was then washed with hot (455 ml) Isopropyl alcohol at 65-70 °C. The wet mass was further dried to obtain pure nepafenac. Yield: 7.5 g; Purity: 99.9%

We Claim:
1) A process for the preparation of Nepafenac of formula (I) comprising:

reacting Amfenac sodium of formula (A) with a coupling reagent and an additive in the presence of an organic base and a suitable solvent and further reacting it with a source of ammonia at 25-30 °C to give Nepafenac.

2) A process according to claim 1, wherein the coupling reagent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide-l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), diisopropyl carbodiimide (DIC) preferably DCC.
3) A process according to claim 1, wherein the additive to coupling reagent is selected from 1-hydroxy-1H-benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), Hydroxy-3,4-dihydro-4-oxo-l,2,3-benzotriazine (HOOBt), 4-(N,N-Dimethylamino) pyridine (DMAP), preferably HoBt.
4) A process according to claim 1, wherein the solvent is selected from Dimethyl formamide (DMF), Dimethoxyethane (DME), and Dimethyl sulfoxide (DMSO) preferably DMF.
5) A process according to claim 1, wherein the organic base is N-Methylmorpholine (NMM).
6) A process for the preparation of Nepafenac of formula (I) comprising:


reacting Amfenac sodium of formula (A) with a DCC/HOBt in the presence of N-Methylmorpholine and DMF and further reacting it with Ammonium chloride at 25-30 °C to give Nepafenac.

7) A process for the preparation of polymorph of Form A of Nepafenac of formula (I) characterized by X-ray powder diffraction angle peak at 5.85, 11.72, 17.37, 24.99 ± 0.2 20° comprising the steps of

a. providing a solution of nepafenac in an alcohol,
b. stirring the reaction mass a temperature ranging between 65-80 °C,
c. recovering the crystalline Nepafenac.
8) A process for the preparation of crystalline Form A of nepafenac according to claim 7 wherein Step c of recovering the pure crystalline material comprises the steps of:
a. optionally adding activated carbon to the solution, stirring the solution followed by
filtering and concentrating the reaction mass,
b. isolating the crystalline material,
c. drying under reduced pressure conditions to recover the crystalline Form A of nepafenac.

9) A process for the preparation of crystalline Form A according to claim 7 wherein the alcohol is selected from ethanol, methanol and isopropyl alcohol, preferably isopropyl alcohol.