DESC:FIELD OF THE INVENTION:-
The present invention relates to process for the preparation of 2-amino-3-benzoyl-phenylacetyl derivatives having general Formula 1. More particularly, the invention relates to a non-hazardous and economical process for preparation of 2-amino-3-benzoyl-phenylacetyl derivatives having general Formula 1 and the intermediates thereof.

Formula 1
Wherein
X= -OH, -ONa, -OK, -NH2, NHR2; -OR1
Y= H, Br, Cl, F, I, -OH, -NO2, -NH2, and wherein, R1 is selected from C1 to C4 alkyl; R2 is selected from C1 to C3 alkyl, aryl or substituted aryl group.

BACKGROUND OF THE INVENTION:-
2-amino-3-benzoyl-phenylacetyl derivatives having general Formula 1 are belonging to a class of nonsteroidal anti-inflammatory drugs (NSAID) approved for ophthalmic use. 2-amino-3-benzoyl-phenylacetyl derivatives of general Formula 1according to the present invention encompass Nepafenac, Amfenac and Bromfenac and various intermediates thereof.

Nepafenac is chemically designated as 2-(2-Amino-3-benzoylphenyl) acetamide or 2-Amino-3- benzoylbenzeneacetamide, and is structurally represented as below.

Formula 1
Amfenac is chemically designated as 2-amino-3-benzoylphenylacetic acid and is structurally represented as below. Amfenac is active metabolite of Nepafenac.

Formula 5

Bromfenac is chemically designated as 2-(2-Amino-3-(4-bromobenzoyl) phenyl)acetic acid and is structurally represented as below.

Formula 6

There are processes for preparation of nepafenac, bromfenac and intermediates thereof disclosed in various articles and patents. However, there is scant literature about the methods for preparation of amfenac.

US 4,313,949 discloses process for preparation of nepafenac by treating 2-aminobenzophenone with 2-(methylthio) acetamide in the presence of t-butylhypochlorite as a chlorinating agent, triethylamine as a base and a mixture of methylene chloride, methylthioacetamide and tetrahydrofuran to form 2-amino-3-benzoylphenyl-a-(methylthio) acetamide, which is further reduced in presence of Raney nickel and tetrahydrofuran to form 2-amino-3-benzoyl-N-methylphenylacetamide i.e. nepafenac. The process involves the use of chlorinating agent during the preparation of intermediate 2-amino-3-benzoylphenyl-a-(methylthio) acetamide resulting in the formation of chlorinated impurities thereby reducing the yield of the final product. This reaction is shown in scheme I below.

Scheme-I

US8,278,484 discloses a process for the preparation of nepafenac, wherein 2-aminobenzophenone is treated with 2-(methylthio)acetamide under inert atmosphere, a mixture N-chlorosuccinimide dicholoromethane as a chlorinating agent ,triethylamine as a base to form 2-amino-3-benzoylphenyl-a-(methylthio)acetamide, which on desulfurization in the presence of Raney nickel and Tetrahydrofuran affords 2-amino-3-benzoyl-N-methylphenylacetamide i.e. nepafenac. The process involves the use of chlorinating agent during the preparation of intermediate 2-amino-3-benzoylphenyl-a-(methylthio)acetamide resulting in the formation of chlorinated impurities that necessitates purification of the intermediate before subjecting to desulfurization. This reaction is shown in scheme II below.
Scheme II

Journal of hetrocyclic chemistry (17), 1663 (1980) discloses a process for preparation of 2-amino-3-benzoylphenyl)acetate, wherein 7-benzoylindole is chlorinated with N-chlorosuccinimide in a N2 atmosphere forming 3-chloro-7-benzoylindole which, on hydrolysis using phosphoric acid and 2-methoxyethanol forms 7-Benzyloxindole followed by reaction with NaOH in presence of toluene and ethanol giving Sodium (2-amino-3-benzoylphenyl)acetate. This reaction is shown in scheme III below.

Scheme III

Letters in Organic Chemistry 9, 461-464, 2012 has described the use of chlorinating agent N-chlorophthalimide and 1,3-dichloro-5,5-dimethylhydantoin in Gassman-type ortho substitution used in the preparation of Nepafenac ,the reaction is represented by the scheme IV below :-

Scheme IV

Journal of Medicinal Chemistry, 1979, Vol. 22, No. 9, the article discloses a process for preparation of Ethyl (2-Amino-3-benzoylpheny1) acetate by reacting Sodium (2-Amino-3-benzoylpheny1) acetate Monohydrate with DMF and ethyliodide.
US4,182,774 discloses a process for preparation of methyl 2-amino-3-benzoylphenylacetate by reacting 2-Amino-3-benzoyl-phenylaceticacid in presence of DMF and methyl iodide whereas, CA1156655 discloses the process of preparation of 2-Amino-3-benzoyl-N-methylphenylacetamide, by reacting 2-amino-3-benzoyl-a-(methylthio)-N-methylphenylacetamide in presence of Tetrahydrofuran and Raney Ni. However the desulfurization process as described above is cumbersome and does not lead to a consistent final product.

The above said processes all have certain drawbacks which reduce the yield and efficiency of the final product and also leads to the formation of impurities; making the overall process less feasible to be adapted on a larger scale. Moreover, the entire prior art process comprises a step of desulfurization thereby produces hazardous sulfur containing waste. Therefore, there remains a need in the art to provide an efficient and robust process that gives Nepafenac with good yields and high purity, which becomes the objective of the present invention.

Journal of The American Chemical Society.1974.95: 5508- 5517 reported the preparation of bromfenac that comprises Friedel-crafts acylation reaction of ethyl 2-amino-4-bromo benzophenone and 2-methylthio compound as raw materials in presence of aluminum chloride catalyst, followed by reduction with Raney nickel or tin and hydrolysis and further conversion into bromfenac sodium. The synthetic route is shown in scheme V.
Scheme V:

EP0221753A2 discloses preparation of bromfenac sodium sesquihydrate in example 74, wherein 7-(4-bromobenzoyl)-1,3-dihydro-2H-indol-2-one is reacted with Sodium hydroxide under reflux.

Another method for the preparation of bromfenac sodium in Journal of medicinal chemistry.1984 11 (27): 1379 – 1388 (China Pharmaceutical University , 2003,34 (5): 405 – 406) which discloses Friedel-crafts acylation reaction of 4-bromocyano benzene and indoline as starting material, trichloroacetic boron and aluminum trichloride as catalyst followed by oxidization with manganese dioxide, reaction with NBS or NCS, reduction with and hydrolysis with sodium hydroxide. The synthesis route is depicted in scheme VI below.

Scheme VI

CN104177272A discloses preparation of bromfenac sodium which comprises (a) reacting a compound represented by a formula (V) with an electrophilic reagent in the presence of N,N-dimethylformamide or dimethyl sulfoxide to obtain a compound represented by a formula (IV); (b) hydrolysis of formula IV in 2-methoxyethanol in presence of phosphoric acid adding the compound represented by the formula (IV); (c) hydrolyzing the compound represented by the formula (III) with sodium hydroxide to obtain a compound represented by a formula (II) and (d) reacting the formula (II) with sodium hydroxide solution to form bromfenac sodium, The synthetic route is depicted in scheme VII.

Scheme VII

As is evident above, the synthesis of bromfenac of the prior art process also either involves desulfurization or involves costly starting materials. Also, these processes result in lower yields and purities and thus not feasible for industrial scale. Further, none of the prior art provides simple and industrially scalable process for the preparation of 2-amino-3-benzoyl-phenylacetyl derivatives having general Formula 1 in general and nepafenac, amfenac and bromfenac in particular.

SUMMARY OF THE INVENTION:-
In line with the above, the present invention provides process of preparation of 2-amino-3-benzoyl-phenylacetyl derivatives of general Formula 1 which comprises the steps of;

Formula 1
Wherein
X= -OH, -ONa, -OK, -NH2, NHR2; -OR1,
Y= H, Br, Cl, F, I, -OH, -NO2, -NH2, and wherein, R1 is selected from C1 to C4 alkyl; R2 is selected from C1 to C3 alkyl, aryl or substituted aryl group.

a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid followed by treating with an acid to obtain compound of Formula 5, wherein X=OH and Y=H;

Formula 5

d) brominating the compound of formula 5 with suitable brominating agent to obtain compound of formula 6, wherein, X=OH and Y=Br;

Formula 6
e) reacting the sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5 in presence of a mixture of an acid and alcohol having C1 to C4 linear chain C atoms to obtain the corresponding ester of Formula 7;

Formula 7
Wherein R1 is an alkyl group with C1 to C4 Carbon atoms;

f) Reacting the ester compound of formula 7 with an amine selected alkyl amine, aryl amine or substituted arylamine to yield respective N-benzyl acetamide of formula 8,

Formula 8
Wherein R2 is C1 to C3 alkyl, aryl group or substituted aryl group; and
g) Reacting the Compound of Formula 8 with a catalyst to give compound of formula 1, wherein X= NH2 and Y= H.

Formula 1
The present process uses non-hazardous and environment friendly reagents which are safe and easy to handle and also obviates the formation of hazardous waste. Thus the process of the present invention encompasses preparation of various compounds of Formula 1, viz.,

Formula 1
Wherein
X= -OH, -ONa, -OK, -NH2, -NHR2; -OR1,
Y= H, Br, Cl, F, I, -OH, -NO2, -NH2, and wherein, R1 is selected from C1 to C4 alkyl and R2 is selected from C1 to C3 alkyl, aryl or substituted aryl group,

Formula 5: wherein, X=OH and Y=H; or X=ONa and Y=H or X=OK and Y=H;
Formula 6: wherein, X=OH and Y= Br;
Formula 7: wherein, X=OR1 and Y=H;
Formula 8: wherein, X=-NHR2 and Y=H; and
Formula 1: wherein, X= NH2 and Y= H

While compound of formula 5, compound of formula 6 and compound of formula 1 pertains to 2-amino-3-benzoyl-phenylacetyl derivatives belonging to a class of nonsteroidal anti-inflammatory drugs (NSAID); the compound 8 is novel intermediate compound for preparing the compound of formula 1.

The present process shows a better yield, consistency and is a commercially conducive method as compared to the prior art processes that are pre-dominantly based on desulfurization using pyrophoric catalyst such as Raney Nickel, expensive starting materials and catalysts for production of 2-amino-3-benzoyl-phenylacetyl derivatives having general Formula 1.

DETAILED DESCRIPTION:-
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

According to the main embodiment, the present invention provides novel and nonhazardous process for preparation of 2-amino-3-benzoyl-phenylacetyl derivatives having general Formula 1 that encompasses amfenac of formula 5, bromfenac of formula 6 and Nepafenac of Formula 1.

Accordingly, the process for preparation of 2-amino-3-benzoyl-phenylacetyl derivatives of general Formula 1, which comprises the steps of;

Formula 1
Wherein
X= -OH, -ONa, -OK, -NH2, -OR1, -NHR2;
Y= H, Br, Cl, F, I, -OH, -NO2, -NH2 and wherein, R1 is selected from C1 to C4 alkyl and R2 is selected from C1 to C3 alkyl, aryl or substituted aryl group.

a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid followed by treating with an acid to obtain compound of Formula 5;

Formula 5
d) brominating the compound of formula 5 with suitable brominating agent to obtain compound of formula 6;

Formula 6
e) reacting the sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5 in presence of a mixture of an acid and alcohol having C1 to C4 linear chain C atoms to obtain the corresponding ester of Formula 7;

Formula 7
Wherein R1 is an alkyl group with C1 to C4 Carbon atoms;

f) Reacting the ester compound of formula 7 with a an alkyl amine or aryl or substituted aryl amine to yield respective N-substituted acetamide of formula 8,

Formula 8
Wherein R2 is C1 to C3 alkyl, arylgroup or substituted arylgroup; and

g) Reacting the Compound of Formula 8 with a catalyst to give compound of Formula 1.

Formula 1
The process of the present invention efficiently provides the synthesis of 2-amino-3-benzoyl-phenylacetyl derivatives of general Formula 1 that encompasses particularly amfenac of formula 5, bromfenac of formula 6 and nepafenac of formula 1,

The process for the preparation of 2-amino-3-benzoyl-phenylacetyl derivatives of general Formula 1 according to the invention is represented by the scheme VIII below:-

Scheme VIII

Wherein R1 consisting of alkyl group with C1 to C4 Carbon atoms and R2 consisting of C1 to C3 alkyl, aryl or substituted aryl group.

The further embodiment of the invention specifically describes, the use of nonhazardous reagents thereby circumventing the formation of dangerous waste, as described in the prior art processes.

Further, the process of the present invention aims at avoiding the step of desulfurization and alternatively uses other methods and reagents thereby preventing the production of hazardous sulfur containing waste during the production of 2-amino-3-benzoyl-phenylacetyl derivatives of general Formula 1.

Another embodiment of the present invention involves use of N-bromosuccinamide or liquid bromine as a brominating agent of 7-benzoylindole in the preparation of (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3.

The brominating agent used in the bromination of compound of Formula 5 may also be selected from liquid bromine or NBS.

The acid used in the preparation of Formula 7 is selected from sulfuric acid or tosic acid, preferably sulfuric acid.

The alcohol used in the preparation of Formula 7 is selected from C1 to C4 linear chain alcohols.

Yet another embodiment of the invention provides process for preparation of Nepafenac of formula 1 comprising simpler steps of esterification of the compound of formula 5 and and amidation of the compound of formula 7.

The alkylamine used in the amidation of the compound of formula 7 is selected from methylamine or ethylamine and the aryl amine preferably benzyl amine.

A further embodiment of the invention, specifically aims at making use of catalyst, viz., Pd/C during the deprotection of alkyl or aryl group in the compound of formula 8 for preparation of Nepafenac of formula 1. The use of Pd/C does not require specific temperature and handling conditions making it more feasible and economically viable to carry out the process on industrial scale.

The present invention further encompasses a novel intermediate compound of Formula 8 having following structural formula,

Wherein, R2 is C1 to C3 alkyl, aryl group or substituted aryl group

In one preferred embodiment, R2 is C1 to C3 alkyl group.
In another preferred embodiment, R2 is benzyl group or substituted benzyl group.

The novel intermediate compound of formula 8 efficiently facilitates the production of Nepafenac, compound of Formula 1, with high yields.

Accordingly, in another embodiment, the invention provides a process for preparation of compound of formula 8, which comprises the steps of;
a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3
b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5;

Formula 5

d) reacting the sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5 in presence of a mixture of an acid and alcohol having C1 to C4 linear chain C atoms to obtain its corresponding ester of Formula 7;


Formula 7
Wherein R1 is an alkyl group with C1 to C4 Carbon atoms;

e) Reacting the ester compound of formula 7 with a benzylamine or substituted benzylamine to yield respective N-benzyl acetamide of formula 8,

Formula 8
Wherein R2 is a benzyl group or substituted benzyl group;
Accordingly, in one embodiment, the invention provides process for preparation of amfenac encompassed by the general Formula 1, wherein, X=OH; Y= H, the said process comprises;
a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid followed by treating with an acid to obtain Amfenac, compound of Formula 5.

Formula 5

The brominating agent in step a) is selected from N-bromosuccinamide or liquid bromine. In a preferred embodiment, the brominating agent is liquid bromine. The bromination of 7-benzoylindole of formula 2 can be conveniently carried out at low temperature, for example, at a temperature range of 5 to 15°C for 3 to 5 hrs.

The oxidation reaction of compound of formula 3 can be carried out at elevated temperature of 80 to 110°C.

The hydrolysis of compound of formula 4 with aqueous alkali can be conducted at reflux temperature of the solvents used. The solvents for the hydrolysis of formula 4 are selected from methanol or ethanol. The acid employed for neutralization of sodium or potassium salt of compound of formula 5 may be selected from any mineral acid such as dil. HCl, HNO3 or H2 SO4 or organic acid such as acetic acid. In one preferred embodiment, the acid is acetic acid, to precipitates the amfenac compound of formula 5.

The detailed process for preparation of Amfenac is shown in below scheme IX.

Scheme IX
According to another embodiment, the invention provides process for preparation of bromfenac encompassed by the general Formula 1, wherein, X=OH; Y= Br, the process comprises;
a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid followed by treating with an acid to obtain compound of Formula 5; and

Formula 5
d) brominating the compound of formula 5 with suitable brominating agent to obtain Bromfenac, compound of formula 6;

Formula 6
The brominating agent in step a) and step d) for the preparation of Bromfenac is selected from N-bromo succinamide or liquid bromine.

In a preferred embodiment, the brominating agent is liquid bromine. The bromination of 7-benzoylindole of formula 2 can be conveniently carried out at low temperature, for example, at a temperature range of 5 to 15°C for 3 to 5 hrs.

The oxidation reaction of compound of formula 3 can be carried out at elevated temperature of 80 to 110°C.

The hydrolysis of compound of formula 4 with aqueous alkali can be conducted at reflux temperature of the solvents used. The solvents for the hydrolysis of formula 4 are selected from methanol or ethanol. The acid employed for neutralization of sodium or potassium salt of compound of formula 5 may be selected from any mineral acid such as dil. HCl, HNO3 or H2 SO4 or organic acid such as acetic acid. In one preferred embodiment, the acid is acetic acid.

According to yet another embodiment, the present invention provides a novel, economical and nonhazardous process for preparation of Nepafenac encompassed by compound of general Formula 1 wherein Y= H, X=-NH2, the said process comprises steps of;
a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5;

Formula 5

d) reacting the sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5 in presence of a mixture of an acid and alcohol having C1 to C4 linear chain C atoms to obtain its corresponding ester of Formula 7;


Formula 7
Wherein R1 is an alkyl group with C1 to C4 Carbon atoms;

e) Reacting the ester compound of formula 7 with an amine selected from alky amine, arylamine or substituted aryl amine to yield respective N-substituted acetamide compounds of formula 8,

Formula 8
Wherein R2 is a benzyl group or substituted benzyl group; and
f) Reacting the Compound of Formula 8 with a catalyst to give Nepafenac, compound of Formula 1.

Formula 1

The brominating agent used in step-a) and step d) is selected from N-bromosuccinamide or liquid bromine. In one preferred embodiment, the brominating agent is liquid bromine.

In a preferred embodiment, the brominating agent is liquid bromine. The bromination of 7-benzoylindole of formula 2 can be conveniently carried out at low temperature, for example, at a temperature range of 5 to 15°C for 3 to 5 hrs.

The oxidation reaction of compound of formula 3 can be carried out at elevated temperature of 80 to 110°C.

The hydrolysis of compound of formula 4 with aqueous alkali can be conducted at reflux temperature of the solvents used. The solvents for the hydrolysis of formula 4 are selected from methanol or ethanol. The acid employed for neutralization of sodium or potassium salt of compound of formula 5 may be selected from any mineral acid such as dil. HCl, HNO3 or H2 SO4 or organic acid such as acetic acid. In one preferred embodiment, the acid is acetic acid.

The alcohol used in step-e) comprises of C1 to C4 linear chain C atoms. The reaction of step e) is conducted at reflux temperature of the alcoholic solvent employed.

The alkylamine in step-f) consists of alkyl amine selected from methylamine and ethylamine or aryl amine like benzyl amine. In a preferred embodiment, the amine is benzyl amine. The amidation recation in step f) can be conducted at a temperature of 50-80°C for 8 hours.

Reaction of compound of 8 with Pd/C at hydrogen at pressure of 1.0 to 2.0 Kg/cm3 results in Nepafenac.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

EXAMPLES:

Example 1:
Preparation of 3-bromo-1H-indole-7-yl-phenyl methanone-
7-benzoyl indole (70g, 0.32moles) was treated with liquid bromine (0.34 moles, 54.8 g) in dichloromethane (350ml) at 5-10°C for 3 hours. The completion of reaction was monitored by TLC. After completion of reaction, MDC was distilled off and residue was treated with 1% sodium bisulphite solution. Solid product was filtered, dried to get 3-bromo-1H-indole-7-yl-phenyl methanone, Wt. 92g [ Yield: 95.83%molar] Mass: [M+1] : 301, 303.

Preparation of 7-benzoylindolin-2-one
3-bromo-1H-indole-7-yl-phenyl methanone (50g, 0.0.166 moles) was suspended in 2-methoxy ethanol 400 ml and heated to 80-90°C and phosphoric acid (150ml) was added over 30 minutes and reaction mixture was stirred at 80-90°C for about 8 hours. Reaction was monitored by TLC. After completion of reaction, water (500ml) was added dropwise and reaction mass was cooled to 5-10°C and filtered the product, washed with water and dried to get 7-benzoylindolin-2-one, Wt 26.8g [Yield : 68.48% molar ] Mass : [M+1] : 238

Preparation of sodium salt of 2-(2-amino-3-benzoylphenyl) acetic acid (Sodium salt of amfenac)
7-benzoylindolin-2-one (26g, 0.11 mole) was dissolved in mixture of Toluene and ethanol (156ml) and 50% aqueous sodium hydroxide(17.6ml) solution was added to it; heated to reflux for 10 hours. The reaction was monitored by TLC. After completion of reaction, reaction mass was cooled and filtered to get sodium salt of 2-(2-amino-3-benzoylphenyl) acetic acid. Wt. 17.07g [ Yield: 58.68% molar] Mass: [M-1] 253.98.

Preparation of 2-(2-amino-3-benzoylphenyl) acetic acid (amfenac, compound of formula 5)
Amfenac Sodium (5.0 g, 0.018 moles) is dissolved in water at room temperature, Acetic Acid (10.5g, 0.175 moles) drop wise added in solution. Product precipitates out. Solid product is filtered, dried to get (Amfenac, Wt. 4.19 g [Yield: 91 .0% molar] Mass: [M+1] : 256.18

Preparation of [2-Amino-3-(4-bromobenzoyl)phenyl]acetic acid (Bromfenac, compound of formula 6)
Sodium salt of 2-(2-amino-3-benzoylphenyl) acetic acid (17.0g, 0.06mole) was treated with liquid bromine (0.06mol) in dichloromethane (170ml) at 5-10°C for 3 hours. The completion of reaction was monitored by TLC. After completion of reaction, MDC was distilled off and residue was treated with 1% sodium bisulphite solution. Solid product was filtered, dried to get [2-Amino-3-(4-bromobenzoyl)phenyl]acetic acid.

Preparation of methyl-2-(2-amino-3-benzoylphenyl)acetate (compound of formula 7)
Sodium salt of 2-(2-amino-3-benzoylphenyl) acetic acid (17.0g, 0.06mole) was dissolved in methanol (85ml) and concentrated sulphuric acid(0.85ml) was added and reaction mixture was heated to reflux for 8-10 hours until completion of reaction monitored by TLC. Methanol was distilled off and product was precipitated with the addition of water. Product was filtered and washed with water, dried in vacuum to get methyl-2-(2-amino-3-benzoylphenyl)acetate Wt. 16.5g ( 88.23% molar) Mass : [M+1] 270.

Preparation of 2-(2-amino-3-benzoylphenyl)benzeneacetamide (compound of formula 8)
Methyl-2-(2-amino-3-benzoylphenyl)acetate (16.0g, 0.06mole) was treated with benzylamine (48ml) in toluene(30ml) solvent at 50-60°C for 8 hours, until completion of reaction monitored by TLC. Benzyl amine was distilled off and stripped out with methanol (50ml), to obtain 2-(2-amino-3-benzoylphenyl)benzeneacetamide.

Preparation of Nepafenac 2-amino-3-benzoylbenzeneacetamide (Compound of formula 1)
The residue containing 2-(2-amino-3-benzoylphenyl)-N-benzylacetamide was taken in situ for debenzylation using 5%Pd/C catalyst(1g) and Hydrogen gas at 1.0Kg/cm3 pressure. Reaction was monitored by TLC and after completion, catalyst was filtered off. Filtrate was concentrated to get crude product 2-amino-3-benzoylbenzeneacetamide. Crude product was purified in Isopropyl alcohol, filtered, dried under vacuum to form 2-(2-amino-3-benzoylphenyl)benzeneacetamide Wt. 8.0g (52.98% molar) Mass: [M+1] 255.19.
,CLAIMS:1. A process of preparation of compounds of general formula1comprising the steps of;

Formula 1
Wherein
X= -OH, -ONa, -OK, -NH2, -OR1, -NHR2;
Y= H, Br, Cl, F, I, -OH, -NO2, -NH2 and wherein, R1 is selected from C1 to C4 alkyl and R2 is selected from C1 to C3 alkyl, aryl or substituted aryl group.

a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of an aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid followed by treating with an acid to obtain compound of Formula 5;

Formula 5

d) brominating the compound of formula 5 with suitable brominating agent to obtain compound of formula 6;

Formula 6

e) reacting the sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5 in presence of a mixture of an acid and alcohol having C1 to C4 linear chain C atoms to obtain the corresponding ester of Formula 7;


Formula 7
Wherein R1 is an alkyl group with C1 to C4 Carbon atoms;

f) Reacting the ester compound of formula 7 with a benzylamine or substituted benzylamine to yield respective N-benzyl acetamide of formula 8,

Formula 8
Wherein R2 is selected from C1 to C3 alkyl, aryl or substituted aryl group; and

g) Reacting the Compound of Formula 8 with a catalyst to give compound of formula 1.

Formula 1

2. The process of preparation of compound of formula 5 (amfenac) as claimed in claim 1, wherein, X=OH; Y= H, the said process comprises;
a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3
b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4

c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid followed by treating with an acid to obtain compound of Formula 5.

Formula 5

3. The process of preparation of compound of formula 5 as claimed in claim 2, wherein, the brominating agent in step a) is selected from N-bromo succinamide or liquid bromine and the acid used in step c) is selected from a diluted mineral acid or acetic acid.

4. The process of preparation of compound of formula 6 as claimed in claim 1, wherein, X=OH; Y= Br, the process comprises;

a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4

c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid followed by treating with an acid to obtain compound of Formula 5; and

Formula 5
d) brominating the compound of formula 5 with suitable brominating agent to obtain compound of formula 6;

Formula 6

5. The process of preparation of compound of formula 5 as claimed in claim 4, wherein, the brominating agent in step a) and step d) is selected from NBS or liquid bromine and the acid used in step c) is selected from a diluted mineral acid or acetic acid.

6. The process of preparation of compounds of formula 1 as claimed in claim 1, wherein Y= H, X=-NH2, the said process comprises steps of;

a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4
c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5;

Formula 5

d) reacting the sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5 in presence of a mixture of an acid and alcohol having C1 to C4 linear chain C atoms to obtain its corresponding ester of Formula 7;


Formula 7
Wherein R1 is an alkyl group with C1 to C4 Carbon atoms;

e) Reacting the ester compound of formula 7 with a benzylamine or substituted benzylamine to yield respective N-benzyl acetamide of formula 8,

Formula 8
Wherein R2 is a benzyl group or substituted benzyl group; and

f) Reacting the Compound of Formula 8 with a catalyst to give compound of formula 1.

Formula 1

7. The process for preparation of compound of formula 1as claimed in claim 1 or claim 6, wherein, the brominating agent used in step-a) is selected from N-bromosuccinamide or liquid bromine.

8. The process for preparation of compound of formula 1as claimed in claim 1 wherein, the acid used in step-c) comprises of sulfuric acid or tosic acid.

9. The process for preparation of compound of formula1 as claimed in claim 1 or claim 6, wherein, the alcohol used in step-e) comprises of C1 to C4 linear chain C atoms.

10. The process for preparation of compound of formula1 as claimed in claim 1 or claim 6, wherein, the alkylamine in step-f) consists of methylamine or ethylamine.

11. The process for compound of formula1 as claimed in claim 1 or claim 6, wherein, the arylamine in step-f) consists of benzylamine.

12. The process for compound of formula 1 as claimed in claim 1or claim 6 wherein, the catalyst used in step-f) consists of palladium/ carbon.

13. A compound of formula 8 having following structural formula,

Wherein R2 is a benzyl group or substituted benzyl group.

14. A process for preparation of compound of formula 8, as claimed in claim 13, comprising the steps of ;
a) Brominating 7-benzoylindole of formula 2 with a brominating agent to get (3-bromo-1H-indol-7-yl) phenyl methanone of Formula 3;

Formula 2 Formula 3

b) oxidizing the compound of Formula 3 with an oxidizing agent, phosphoric acid, to give 7-benzoyl indolin-2-one of Formula 4;

Formula 4

c) Hydrolyzing the 7-benzoyl indolin-2-one of Formula 4 in presence of aqueous sodium hydroxide or potassium hydroxide to obtain sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5;

Formula 5

d) reacting the sodium or potassium salt of 2-(2-amino-3-benzoylphenyl) acetic acid of Formula 5 in presence of a mixture of an acid and alcohol having C1 to C4 linear chain C atoms to obtain its corresponding ester of Formula 7;


Formula 7
Wherein R1 is an alkyl group with C1 to C4 Carbon atoms;

e) Reacting the ester compound of formula 7 with a benzylamine or substituted benzylamine to yield respective N-benzyl acetamide of formula 8,

Formula 8
Wherein R2 is a benzyl group or substituted benzyl group.