FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR PREPARATION OF
MORNIFLUMATE"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a novel, cost-effective process for the preparation of the morpholinoethyl ester of niflumic acid also known as Morniflumate. The invention specifically relates to the preparation of Morniflumate conforming to regulatory specifications by esterification of 2-[3-(trifluoromethyl)phenyIamino]nicotinic acid (niflumic acid) with 4-(2-hydroxyethylmorpholine) of formula (III) in presence of a condensing agent or with 4-(2- mesyl ethylmorpholine) of formula (Ilia) in absence of a condensing agent.
BACKGROUND OF THE INVENTION
Morniflumate (I), chemically known as 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid 2-(4-morpholinyl)ethyl ester is a non-steroidal anti-inflammatory drug used in respiratory track disorders such as laryngitis, tracheitis and also in symptoms related to arthritis and bone defects. Morniflumate is marketed under various brand names such as Flomax, Flumarin, Morniflu etc.

US 3,708,481 first disclosed morniflumate and described two different routes for its synthesis involving esterification of 2-[3-(trifluoromethyl)phenylamino]nicotinic acid. The first route involved coupling of m-trifluoromethylanilino nicotinic acid with 2-chloroethylmorpholine in anhydrous isopropyl alcohol, wherein the desired product is obtained with a modest yield of 42%. The other route involved reaction of morpholinoethanol with m-[(trifluoromethyl)phenylamino]nicotinic acid chloride, which, in turn, was prepared by reaction of the substituted nicotinic acid with thionyl chloride.

While both these routes employ conventional methodologies for the synthesis of Morniflumate, however, they required hazardous reagents such as thionyl chloride and stringent anhydrous conditions. These factors coupled with low yields adversely affected the commercialization of these routes on industrial scale.
EP 0349902 describes two different approaches for synthesis of Morniflumate. The first approach involves reaction of 2-chloro-nicotinic acid chloride with 2-morpholinoethanol in presence of triethylamine to give 2-morpholinoethanol ester of 2-chloro-nicotinic acid. The resulting ester, when treated with 3-trifluoromethylaniline in presence of zinc oxide and catalytic iodine, gave Morniflumate with only 35% yield after an abnormally long reaction time of about 50 hours. The second approach comprises reaction of 2-chloro-nicotinic acid chloride with methanol followed by coupling reaction of the resulting product with 3-trifluoromethylanilme. Methyl ester of 2-[3-(trifluoromethylanilino)]nicotinic acid is further treated with 2-morpholinoethanol in presence of sodium metal to give Morniflumate. The starting material, 2-Chloro nicotinic acid chloride utilized in both the routes is obtained by the reaction of thionyl chloride with the corresponding acid. Further, the utilization of extremely hazardous reagents like sodium metal and chemicals such as zinc oxide which required special recycling arrangements, abnormally long reaction times clubbed with modest yields, hampered the industrial feasibility of both these processes.
International Journal of Chem Tech Research, (2010), 2(2), 780-786 discloses synthesis of morpholinoalkyl ester of niflumic acid using dicyclohexylcarbodiimide and dimethylaminopyridine. The method also requires long reaction time at 0-5 C and the desired product Morniflumate is obtained in 47% yield after chromatographic purification. The requirement of maintaining low temperatures for a long time is a highly energy intensive industrial operation. Also, due to the use of dicyclohexylcarbodiimide, a solid by product, dicyclohexylurea is formed during the reaction, which needs to be separated. The separation of this by product from the desired product requires special techniques, which is tedious and time consuming. Further, low yields and the need for chromatographic separation to obtain the finished product render the process unviable for industrial application.

Thus, there is a need for a high-yielding, convenient chemical process for the synthesis of Morniflumate on industrial scale, which overcomes the shortcomings in the prior art.
OBJECT OF THE INVENTION
An objective of the present invention is to provide a safe, industrially applicable process for synthesis of Morniflumate which avoids use of toxic and environmentally hazardous reagents such as sodium metal, thionyl chloride, iodine etc.
Another object of the invention is to provide a high yielding, energy efficient esteriflcation methodology for the synthesis of Morniflumate comprising esteriflcation of 2-[3-(trifluoromethyl)phenylamino]nicotinic acid with 4-(2-hydroxyethyl)morpholine in presence of a condensing agent or its mesyl derivative in absence of any condensing agent.
Yet another object of the invention is to provide economical and scalable synthetic procedures to provide Morniflumate (I) having purity conforming to regulatory specifications.
SUMMARY OF THE INVENTION
The present invention relates to a novel process for the preparation of Morniflumate (I) having purity conforming to regulatory specifications.
An aspect of the invention relates to an improved and energy efficient process for the preparation of 2- [ [3 -(trifluoromethyl)phenyl] amino] -3 -pyridinecarboxylic-acid-2-(4-morpholinyl)ethyl ester (I), comprising reaction of 2-[3-(trifluoromethyl)phenylamino]-pyridine-3-carboxylic acid of formula (II) with 4-(2-hydroxyethylmorpholine) of formula (III) or 4-(2- mesyl ethylmorpholine) of formula (Ilia) in an organic solvent and isolating Morniflumate (I) of desired purity.
An aspect of the invention relates to an improved and energy efficient process for the preparation of 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic-acid-2-(4-morpholinyl)ethyl ester (I), comprising reaction of 2-[3-(trifluoromethyl)phenylamino]-

pyridine-3-carboxylic acid of formula (II) with 4-(2-hydroxyethylmorpholine) of formula (III)) in an organic solvent and in presence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) hydrochloride and l-hydroxy-l,2,3-benzotriazole (HOBT) and isolating Morniflumate (I) of desired purity.
These objectives of the present invention will be apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors, while carrying out experimentation for process optimization of Morniflumate, have found out a convenient method for esteriflcation of niflumic acid. It was observed that reaction of 2-[3-(trifluorornethyl)phenyl amino]-pyridine-3-carboxylic-acid (niflumic acid) with 4-(2-hydroxyethyl) morpholine could be easily carried out in high yield by treatment of the acid either with 4-(2-hydroxyethylmorpholine) in presence of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) hydrochloride and 1-hydroxy-1,2,3 benzotriazole (HOBT) or with 4-(2-mesylethyl)morpholine. In both the cases, Morniflumate (I) was obtained in good yield and possessed desired purity, thus eliminating the need of any additional purification step.

Scheme 1: Method embodied in the present invention for preparation of Morniflumate (I)
In an embodiment, reaction of 2-[3-(trifluoromethyl)phenyl amino]-pyridine-3-carboxylic acid of formula (II) with 4-(2-hydroxyethyl) morpholine of formula (III) was carried out in presence of 1 -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide hydrochloride and 1 -

hydroxy-1,2,3 benzotriazole in an organic solvent. The reaction was performed at 30-50 C, followed by isolation of the desired product.
The organic solvent was selected from the group of halogenated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, preferably dichloromethane.
The reactants were mixed at ambient temperature and then stirred at 40-50°C till completion of reaction as monitored by TLC. The reaction mixture was cooled to ambient temperature and quenched with water. The organic layer was separated and concentrated. The residue was triturated with a second organic solvent, which was selected from the group comprising of methanol, ethanol, n-butanol, isobutanol, n-propanol and isopropanol, but preferably isopropanol.
Morniflumate of formula (I), which separated out was filtered and dried to give the product having the desired purity and conforming to regulatory specifications.
It was also found that when N-(2-mesylethyl)morpholine (Ilia) was employed instead of compound (III), the reaction took place in absence of l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxy-1,2,3-benzotriazole. The solvent for the reaction was selected from the group comprising of methanol, ethanol, n-butanol, isobutanol, n-propanol and isopropanol, but preferably isopropanol.
The reaction was carried out in the temperature range of 80 to 90°C. After completion of the reaction, the reaction mass was cooled, filtered and resulting morniflumate mesylate was hydrolyzed using 30% aqueous solution of sodium carbonate. After the hydrolysis reaction, pure Morniflumate was isolated by addition of a second organic solvent to the residue. The second organic solvent was selected from the group comprising methanol, ethanol, n-butanol, isobutanol, n-propanol and isopropanol, preferably isopropanol.
Starting material for the above mentioned scheme, 3-trifluoromethylanilino nicotinic acid of formula (II) was prepared by conventional method comprising reaction of 2-chloronicotinic acid and 3-trifluoromethyl aniline in water at reflux temperature.

The compound of formula (Ilia), N-(2-mesylethyl) morpholine was prepared by the
reaction of 2-hydroxyethyl morpholine with methylsulfonyl chloride in dichloromethane as
solvent and in presence of triethylamine.
The following examples are meant to be illustrative of the present invention. These
examples exemplify the invention and are not to be construed as limiting the scope of the
invention.
EXAMPLES
Example 1: Synthesis of Momiflumate (I)
2-[3-(trifluoromethyl)phenyl amino]-pyridine-3-carboxylic acid (compound II), (100 g)
was added to 4-(2-hydroxyethyl) morpholine (III; 139 g) and the resulting mass was mixed
with 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (101.6gms), 1 -
hydroxy-l,2,3-benzotriazole (71.6gms) and methylene dichloride (500 ml) at 20-30°C . The
mixture was heated to 40-50°C and stirred at the same temperature till completion of the
reaction as monitored by TLC. The reaction mixture was cooled, quenched with water; the
organic layer was separated and concentrated. Isopropanol was added to the obtained
residue and the product separating out was cooled to 0-5°C and filtered, dried to give
Momiflumate having desired purity.
Yield: 100 g
Purity: 99.82%
Example 2: Synthesis of Momiflumate (I)
A mixture of 2-[3-(trifluoromethyl)phenyl amino]-pyridine-3-carboxylic acid (180 gms), 4-(2-mesylethyl) morpholine (240 gms) and isopropanol (900 ml) were stirred at 80-90°C till the completion of reaction as monitored by TLC. The reaction mixture was cooled and filtered to give momiflumate mesylate, which was then dissolved in dichloromethane (500 ml) and treated with aqueous solution (30%) of sodium carbonate (250ml). The reaction mixture was stirred at room temperature till completion of reaction as monitored by TLC. The organic layer was separated and concentrated. Isopropanol (100 ml) was added to the residue with stirring and the product separating out was cooled to 0-5°C, filtered and dried to give Momiflumate (I). Yield: 120 g (60%) Purity: 99.80%.

Example 3: Synthesis of 2-[3-(trifluoromethyl)phenyl amino] -pyridine-3-carboxylic acid (II)
2-Chloro-pyridine-3-carboxylic acid (100 g) was mixed with 3-trifluoromethyl aniline
(133.3 g) and water (1500 ml), and the mixture was heated at reflux temperature till
completion of the reaction, as monitored by TLC.
When the reaction was complete, the resultant mass was cooled to 15 to 20°C, filtered and
dried to give 2-[3-(trifluoromethyl)phenyl amino]-pyridine-3-carboxylic acid (niflumic
acid)
Yield: 165.5 g (92%)
Purity: 99.70%.

We claim,
1) An improved process for the preparation of 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic-acid-2-(4-morpholinyl)ethyl ester (I), comprising reaction of 2-[3-(trifluoromethyl)phenylamino]-pyridine-3-carboxylic acid of formula (II) with 4-(2-hydroxyethylmorpholine) of formula (III) or 4-(2-mesylethylmorpholine) of formula (Ilia) in an organic solvent and isolating Moraiflumate (I) of desired purity.
2) A process as claimed in claim 1, wherein l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) hydrochloride and l-hydroxy-l,2s3-benzotriazole (HOBT) are employed if 4-(2-hydroxyethyimorpholine) of formula (III) is utilized for the preparation of Morniflumate (I).
3) A process as claimed in claim 1 & 2, wherein the organic solvent is selected from the group comprising of chloroform, dichloromethane and ethylene dichloride, but preferably dichloromethane.
4) A process as claimed in claim 1 & 2, wherein the reaction is carried out at 40-50°C.
5) A process as claimed in claim 1 & 2, wherein Morniflumate of formula (I) is isolated by quenching the cooled reaction mixture with water, separating and concentrating the organic layer and adding a second organic solvent to the residue.
6) A process as claimed in claim 1, 2 & 5, wherein the second organic solvent is selected from the group comprising of methanol, ethanol, n-butanol, isobutanol, n-propanol and isopropanol, but preferably isopropanol.
7) A process as claimed in claim 1, wherein the reaction between 2-[3-(trifluoromethyl)phenylamino]-pyridine-3-carboxylic acid of formula (II) and 4-(2-mesylethylmorpholine) of formula (Ilia) is carried out in absence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) hydrochloride and l-hydroxy-1,2,3-benzotriazole (HOBT)

8) A process as claimed in claim 1 and 7, wherein the organic solvent is selected from the group comprising of methanol, ethanol, n-butanol, isobutanol, n-propanol and isopropanol, but preferably isopropanol.
9) A process as claimed in claim 1 and 7, wherein Morniflumate of formula (I) is isolated by cooling the reaction mixture, filtering morniflumate mesylate and dissolving in dichloromethane followed by treatment with an aqueous solution of sodium carbonate, concentrating the organic layer and adding isopropanol to the residue for obtaining the product of desired purity.