FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION
(See section 10]


Title of the invention: "A novel process for the preparation of Amtolmetin Guacil"
Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR THE PREPARATION OF AMTOLMETIN GUACIL
FIELD OF THE INVENTION
This invention relates to a novel improved process for the preparation of Amtolmetin Guacil, starting from N- benzyloxycarbonylglycine and & Sodium [l-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl] acetate,
The present invention provides a feasible and commercially viable process for the preparation of amtolmetin Guacil of Formula I

BACKGROUND OF THE INVENTION
Amtolmetin guaicil is chemically known as 2-methoxyphenyl 2-(2-(l-methyl-5- (4-methoxybenzoyl)-lH-pyrrol-2yl) acetamido) acetate and is disclosed in U.S.Patent No. 4,578,481. Amtolmetin Guacil is represented by Formula I.

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Amtolmetin guaicil of Formula I is known to have an anti-inflammatory, analgesic and antipyretic activity.
U.S.Patent No. 4,578.481 discloses a process for the preparation of amtolmetin gauical whereas tolmetin was reacted with N, N'-carbonyldiimidazole in tetrahydrofuran (THF), and amino acetic acid ethyl ester hydrochloride was added to the reaction mixture. Following a complex series of washings in order to remove the unreacted starting compounds, and crystallization from benzene/Cyclohexane, l-methyl-5-p-toluoylpyrrole-2-acetamidoacetic acid ethyl ester was obtained. This compound was subsequently transformed into the corresponding acid. The acid was reacted with N, N'-carbonyldiimidazole obtaining the corresponding imidazolide, to which a solution of guaiacol in THF was added. From the reaction mixture, following several washings, neutralization and crystallization from benzene/Cyclohexane. amtolmetin gauical was obtained. This process is commercially not viable as it involves the use of benzene that is carcinogenic and cannot be used. Another drawback this process is use of tolemtin acid in stage-1 and therefore overall yield of the process is quite low with respect to tolmetin acid.
U.S.Patent No. 6,288,241 discloses a process for the preparation of amtolmetin guaicil Whereas mixed anhydride of tolmetin was reacted with glycine to obtain l-methyl-5-p-toluoyl-pyrrol-2-acetoamidacetic acid, which was condensed with isobutylchloroformate to obtain mixed anhydride of l-methyl-5-p-toluoyl-pyrrol-2-acetoamidacetic acid. The mixed anhydride of l-methyl-5-p-toluoyl-pyrrol-2-acetoamidacetic acid was reacted with guaiacol to obtain amtolmetin gauical. This process is commercially not viable as it involves large number of steps and work up of final step at higher temperature that is not feasible at commercial scale.
In light of the above drawbacks in the prior art processes, there is a need for the development of a simple and commercially viable process for the preparation of amtolmetin guaicil.
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The title compound (I) is a Non -Steroidal Anti-inflammatory drugs. Various methods for the synthesis of the title compound and its related compounds were reported in the prior Patent No. BE 0896018 discloses the process for the preparation of Amtolmetin guaicil, which involves, the condensation of l-methyl-5- (4-methylbenzoyl) pyrrole-2-acetic acid with glycine ethyl ester by means of carbonyldiimidazole (CDI) and triethylamine in THF and gives the corresponding acetamidoacetate which is hydrolyzed with NaOH I in THF-water yielding 2-[2-[l-rnethyl-5- (4-methylbenzoyl) pyrrol-2-yl] acetamido] acetic acid. Finally this compound is esterifies with 2-methoxyphenol (guaiacol) by means of CDI In hot THF to obtain Amtolmetin guaicil.
A detailed synthesis of title compound is reported in US patent No. 4578481, claims a specific compounds endowed with valuable pharmacological activity, encompassed in the above mentioned class, precisely l-methyl-5-p-toluoylpyrrole-2-acetamido-acetic acid guaicil ester and a process for its preparation.
US Patent No. 4882349 disclose a class of N-mono-substituted and N, N-disubstituted amides of l-methyl-5-p-toluoylpyrrole -2-acetic acid (Known as Tolmetin) endowed of anti-inflammatory, analgesic antipyretic drugs, antisecretive and antitussive properties.
In publication Drugs FUT 1989 Vol.14 no 10 Page-963 discloses the condensation of 1-methyl -5-(4-methylbenzoyl) pyrrole-2- acetic acid with glycine ethyl ester by means of carbonyldiimidazole (CDI) and Triethylamine in THF gives the corresponding acetamidoacetate which on hydrolysis with NaOH in THF- water yields 2-[2-[l-methyl-5-(4-methylbenzoyl0pyrrol-2-yl] acetamido] acetic acid. Finally this compound is esterified with 2-methoxyphenol (guaiacol) by means of CDI In hot THF
Because of these limitations in prior art processes, there is a scientific and industrial need to develop a better, cheap, and safe process for the preparation of, Amtolmetin guaicil having more stable intermediates, use of safe chemicals and easy operations.
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This invention is, therefore, made with the following objects so that most of the drawbacks or limitations of the prior art processes for the preparation Amtolmetin guaicil could be eliminated.
1. The main objective of the present invention is to provide a process for the preparation of Amtolmetin guacil using in-house prepared intermediate, which is easy to handle, store and economically viable.
2. Other important object of the present invention is to provide an improved, safe and easy to operate process for the production of Amtolmetin guacil.
SYNTHETIC SCHEME:
The synthesis of Amtolmetin guacil can be presented schematically as given below:


Scheme-2:

SUMMARY OF THE INVENTION
The aspect of present invention is to provide process for the preparation of amtolmetin guacil of Formula I starting from tolmetin acid and tolmetin glycine.

The present invention provides two processes for the preparation of Amtolmetin guacil. Both methods are quite better as compare to prior arts and their processes can be depicted
as follows:
Method-1: The first aspect of present invention is production of Amtolmetin guacil by a completely novel, cost effective and environmental friendly process that is shown in scheme-1 and comprising the following steps:
A) Reacting 2-(benzyloxycarbonylamino) acetic acid with a condensing reagent in presence of a solvent and organic base to prepare an acid complex, which on
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treatment with 2-mthoxy phenol yields 2-methoxyphenyl-2-(benzyloxycarbonylamino) acetate of formula -V.

B) Treating compound of formula-V with hydrohalic acid to yield 2-methoxyphenyl-
2-amino acetate hydro halide salt by deprotection of amino group followed by crystallization of product using non-polar solvents.

C) Treating Tolmetin acid with a condensing reagent in a solvent to form an
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activated acid complex that on treatment with 2-methoxyphenyl-2-amino acetate hydro halide salt yields Amtolmetin guacil. The crude material is purified using a mixture of polar and non-polar solvent.


Method-2: The second aspect of present invention is formation of Amtolmetin guacil in pure form by reacting 2-(2-(l-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl) acetamido) acetic acid with 2-methoxy phenol in presence of condensing reagent and a base. The reaction scheme can be depicted as follows:

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides safe, environment friendly, economically viable and commercially feasible processes for the production of Amtolmetin guacil. There are two methods for the preparation of Amtolmetin guacil. The processes for the production of Amtolmetin guacil (I) comprise:
Method-1:
Step-A:- Treating 2-methoxy phenol of Formula VI with 2-(benzyloxycarbonylamino) acetic acid of Formula VII in the presence of an organic base and a condensing agent in chlorinated solvent to yield 2-methoxyphenyl-2- (benzyloxycarbonylamino) acetate of Formula V.
Step-B:- Acid addition salt of 2-methoxyphenyl -2-aminoacetate of Formula II may be prepared by treating 2-methoxyphenyl-2- (benzyloxycarbonylamino) acetate of Formula V with an acid and followed by crystallization in aprotic solvent.
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Step-C):- l-methyl-5-p-toluoylpyrrole-2-acetic acid of Formula III is reacted with a condensing agent to form-activated moiety, which is reacted with acid addition salt of 2-methoxyphenyl -2-aminoacetate of Formula II in chlorinated solvent to produce Arntolmetin guacil of formula (I).
In a preferred embodiment of present invention, condensing agent used in step-A is selected from group consisting of dicyclohexylcarbodiimide, N, N'-carbonyl diimidazole, hydroxy benzotriazole. The most preferred condensing agent is Dicyclohexyl carbodiimide for the reaction.
The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran, 1,4-dioxane, the most preferred solvent for the reaction methylene dichloride.
In another embodiment of the present invention, the reaction is performed in the presence of an organic base. The organic base is selected from the group consisting of trimethylamine, triethylamine, N-methyl morpholine, N-methylpyrrolidinone, 4-dimethyl Aminopyridine; the most preferred base is 4-dimethyl Aminopyridine.
In a preferred embodiment of present invention, the non-polar solvent used in step-B is selected from group consisting of ethers, hexanes, aromatic hydrocarbons and esters.
In another preferred embodiment of present invention, the most suitable solvents are esters.
In another preferred embodiment of present invention, condensing agent used in step-C is selected from group consisting of dicyclohexylcarbodiimide, N, N'-carbonyl diimidazole, hydroxy benzotriazole. The most preferred condensing agent is N, N'-carbonyl diimidazole for the conversion of the reaction.
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The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran, 1,4-dioxane, the most preferred solvent for the reaction methylene dichloride.
In yet another embodiment of the present invention, the reaction is performed at a temperature in the range of -20°C to 50°C. Most preferred temperature range for the reaction is (-) 10°C to 0°C.
Method-2:
Treating 2-(2-(I-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl) acetamido) acetic acid with 2-methoxy phenol in presence of condensing reagent and an organic base to obtain Amtolmetin guacil.
In a preferred embodiment of present invention, the condensing agent used is selected from group consisting of dicyclohexyicarbodiimide, hydroxy benzotriazole or a mixture thereof. The most preferred condensing agent is Dicvclohexyl carbodiimide for the aforementioned reaction.
The solvent used in present invention is selected from the group consisting of but not limited to toluene, methylene chloride, chloroform, water miscible ethers such as tetrahydrofuran. 1,4-dioxane, the most preferred solvent for the reaction is methylene dichloride.
In another embodiment of the present invention, the reaction is performed in the presence of an organic base. The organic base is selected from the group consisting of triethylamine, triethylamine, N-methyl morpholine, N-methylpyrrolidinone, 4-dimethyl Aminopyridine; the most preferred base is 4-dimethyl Aminopyridine.
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In yet another embodiment of the present invention, the reaction is performed at a temperature in the range of -20°C to 50°C. Most preferred temperature range for the reaction is (-) 10°C to 0°C.
In another embodiment of present invention, crude amtolmetin guacil is directly purified using polar and non-polar solvent or a mixture thereof. The most preferred solvents are Isopropanol and toluene.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in anyway.
Preparation of Amtolmetin guacil: Example-1;
Charged MDC (600 ml) and N-benzyloxycarbonyl glycine (100 gm) in a 2L-4NRBF under N2 atmosphere. Reaction mass was cooled down to -5°C. Added N, N'-dicyclohexylcarbodiimide solution (108.5 gm in 300 ml MDC) at-5°C to 0°C. Maintained temperature of reaction for 10 minutes at -5°C to 0°C. Added guaiacol solution (59.36 gm in 180 ml MDC) at -5°C to 0°C followed by addition of N, N-dimethyl aminopyridine (1 gm) at -5°C to 0°C. Monitored the reaction over TLC till the completion of reaction, while maintaining reaction at 0°C. Filtered the undissolved Dicyclohexyl urea and washed the solids with methylene dichloride (125 ml X 2). Collected filtrate and washing. Washed methylene dichloride with water (1000 ml X 2), lN-NaOH (500 ml X 2) and 1% HC1 solution (500 ml X 2), water (500 ml X 2) respectively. Organic methylene dichloride layer was dried over anhydrous sodium sulphate. Filtered sodium sulphate and collected methylene dichloride filtrate. Distilled out methylene dichloride under vacuum below 40°C to get oil. HPLC purity :> 90%
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Added 33% HBr in acetic acid solution (262,5 gm) into reaction vessel at 25-30°C. Monitored the reaction over TLC till the completion of reaction, while maintaining the reaction at 25-30°C. Added ethyl acetate (1200 ml) slowly at 25-30°C after completion of reaction. Stirred the resultant slurry for 2.5 hours at 25-30°C for complete crystallization. Filtered the solids and washed it with ethyl acetate (200 ml). Dried solids at 50-55°C. Dry weight: 102 gm. HPLC Purity: >98%
Example-2:
Charged MDC (1400 ml) and N, N'-carbonyl di imidazole (69.34 gm) into a 3L-4NRBF under N2 atmosphere. Cooled it down to -15°C. Charged Tolmetin acid (100 gm) slowly into reaction vessel at -10° ± 5°C. Monitored the progress of reaction of over HPLC. After completion of reaction, charged slowly 2-methoxyphenyl-2- (benzyloxy carbonylamino) acetate hydrobromide salt (112.05 gm) at -10° ± 5°C.Monitored the reaction over HPLC. After completion of reaction, washed the organic layer with water (300 ml), 1% NaOH solution (100 ml) and water (300 ml X 2) respectively at 3-8°C. Treated organic layer with activated carbon (2.5 gm) and filtered over hyflow bed. Washed hyflow bed with methylene dichlonde (100 ml X 2). Distilled out methylene dichloride below 40°C under vacuum and stripped off traces with toluene (100 ml X 2) at 50-55°C. Charged toluene (600 ml) and Isopropanol (50ml). Heated the mass to 63-68°C. Stirred the clear solution at 63-68°C for 1 hour. Cooled it down slowly to 30°C followed by further cooling to 5°C. Stirred the resultant slurry for 3 hours at 0-5°C. Filtered solids and washed with toluene (100 ml X 2). Dried solids at 55-60°C under vacuum. Dry Weight: 130 gm. HPLC Purity: >99%
Example-3:
Charged MDC (333 liter) and 2-(2-(l-methyl-5- (4-methylbenzoyl)-lH-pyrrol-2-yl) acetamido) acetic acid (55.5 Kg) in reactor under N2 atmosphere at 25-30°C. Cool down reaction mass to -15 to -12°C. Added a freshly prepared solution of N, N'-dicyclohexyl
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carbodiimide (47.39 Kg in 166.5 liter) slowly at -10° ± 5°C within 1 hour. Rinsed the addition funnel with MDC (55.5 liter) and added it to the reaction at -10° ± 5°C. Added guaiacol solution (24.14 Kg in 99.9 liter MDC) to the reaction mass at -10° ± 5°C within 1 hour. Rinsed the addition funnel with MDC (11.1 liter) and added to the reaction -10° ± 5°C. Charged N, N'-dimethyl aminopyridine (0.555 Kg) at -15°C. Maintained temperature of reaction mass at -10° ± 5°C for 3 hours. Monitored the reaction over TLC, After the completion of reaction, filtered the dicyclohexyl urea and washed the solids with MDC (55.5L X 2). Collected MDC filtrate and wash it with water (166.5 L X 2). Collected MDC layer and treated it with activated carbon (2.77 Kg) and filtered through sparkler. Washed the sparkler with MDC (111 L). Distilled out MDC below 40°C under vacuum and stripped off traces with toluene (55.5 L X 2) at 50-55°C. Charge toluene (333L) and Isopropanol (27.75 L). Heated reaction mass to 63-68°C to get a clear solution. Stirred the clear solution at 63-68°C for 1 hour. Cooled it down slowly to 30°C followed by further cooling to 20oC. Stirred the resultant slurry for 2 hours at 17-20°C. Filtered the solids and washed with toluene (55.5 L X 3). Dried the solids at 55-60°C under vacuum. Dry Weight: 48 Kg. HPLC Purity:>99%

Dated this 24th day of July 2008

Signature:
Name: Dr. Rajendra Agarwal

To
The Controller of Patents The patent Office. At Mumbai

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