Title of Invention

INTAKE APPARATUS FOR VEHICLE

Abstract The present invention relates to a process for the preparation of nimesulide which involves a reduced number of stages, resulting in high yields of the desired product and is suitable for industrial scale production.
Full Text

PROCESS FOR THE PREPARATION OF NIMESULIDE
INTRODUCTION TO THE INVENTION
The present invention relates to a process for the preparation of Nimesulide. The process of the present invention involves reduced number of stages, resulting in high yields of the desired product and is suitable for industrial scale production.
Nimesulide is described chemically as N-(4-nitro-2-phenoxy-phenyl)-methanesulfonamide (hereinafter referred to by the adopted name "Nimesulide") and is structurally represented by Formula I.

Nimesulide is a sulphonanilide analogue widely used as a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It was proved to be safe and effective in the treatment of a wide range of inflammatory and painful conditions, including osteoarthritis, extra-articular disorders such as tendinitis and bursitis, post-operative pain, and primary dysmenorrhoea.
Nimesulide is commercially available in the market in products sold under the trademark NIMEDEX as tablets, suppositories, and in some countries also as oral drops and oral suspension. Now it is also being marketed as topical gel.
U.S. Patent No. 3,840,597 discloses nimesulide generically and specifically, and its pharmaceutical^ acceptable salts, pharmaceutical compositions and their use in controlling inflammation. It also discloses a process for the preparation of nimesulide, which can be depicted by the following Scheme 1.


Processes for preparation of nimesulide and its salts have also been described in European Patent Nos. 937709, 869117, 1604976, and International Application Publication No. WO 97/46520 A1.
The aforementioned processes involve isolation of intermediates in all the stages, which leads to loss of product and operational difficulty. They also suffer from the disadvantage of poor yields.
A process with reduced number of stages, which does not involve isolation of intermediates, would be helpful. Also a process which is easily scalable and is industrially feasible would be helpful.
A desirable goal met by the present invention has been to devise a method which avoids expensive reagents and which cleanly produces nimesulide in high yields.
The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield based on the starting materials employed.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of nimesulide which involves a reduced number of stages, resulting in high yields of the desired product and is suitable for industrial scale production.
In an embodiment, the process for the synthesis of nimesulide of Formula I comprises the steps of:



Suitably, one or more sequential steps a) to d) are carried out in situ. In one embodiment of the invention, steps a) to c) are carried out in situ followed by isolation of the compound of Formula V.
In another embodiment, the invention includes usage of the intermediates prepared by this process for the preparation of nimesulide.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention relates to an improved process for the preparation of nimesulide. The process of the present invention involves reduced number of stages, resulting in high yields of the desired product and is suitable for industrial scale production.
This process is advantageous over the prior processes in that, it allows the final product to be made in high yields on a large scale and in pure form by using a simple and industrially feasible one-pot procedure, thus avoiding the need for time consuming and costly isolation of intermediates. The new process also involves usage of simple and commercially viable reagents and solvents.
In an embodiment, the process for the preparation of nimesulide comprises the steps of:
a) condensation of phenol with 1-chloro-2-nitrobenzene of Formula II in the
presence of a strong base in a suitable solvent to give 2-
phenoxynitrobenzene of Formula III;

b) reduction of 2-phenoxynitrobenzene of Formula III in presence of a suitable
reducing agent in a suitable solvent to give 2-phenoxyaniline of Formula IV;


c) condensation of 2-phenoxyaniline of Formula IV with methanesulfonyl
chloride in the presence of a base in a suitable solvent to give N-(2-
phenoxy-phenyl)-methanesulfonamide of Formula V;

d) nitration of N-(2-phenoxy-phenyl)-methanesulfonamide of Formula V with
nitric acid in a suitable solvent to give N- (4-nitro-2-phenoxy-phenyl)-
methanesulfonamide of Formula I.
Step a) involves condensation of phenol with 1-chloro-2-nitrobenzene of Formula II in the presence of a strong base in a suitable solvent to give 2-phenoxynitrobenzene of Formula III.
Suitable solvents which can be used for this stage include any solvent or mixture of solvents, in which the required compounds are soluble. Examples include, without limitation: aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like; ketonic solvents such as acetone, methyl isobutyl ketone and the like; or mixtures thereof.
Suitable inorganic bases which can be used in this reaction include, but are not limited to hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like.

The temperature for conducting the reaction can range from about 60-130° C, or about 110-115° C, or at the reflux temperature of the solvent used.
The intermediate compound of Formula III in step a) may or may not be isolated. The same can be converted in situ to compound of Formula IV in step b).
Step b) involves reduction of 2-phenoxynitrobenzene of Formula III in the presence of a suitable reducing agent in a suitable solvent to give 2-phenoxyaniline of Formula IV;
Suitable solvents which can be used for this stage include any solvent or mixture of solvents, in which the required compounds are soluble. Examples include, without limitation: aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like; ketonic solvents such as acetone, methyl isobutyl ketone and the like; or mixtures thereof.
Suitable reducing agents which can be used include, but are not limited to: metal hydrogenation catalysts such as nickel, palladium, platinum, iridium, ruthenium and the like, in combination with hydrogen; or a transition metal in combination with HCI, such as iron and HCI, zinc and HCI, tin and HCI and the like.
The temperature for conducting the reaction can range from about 50 to 120 °C, or about 80 to 110 °C under hydrogen gas pressures ranging from about 2 to 8 kg/cm2, or about 4 to 5 kg/cm2.
The intermediate compound of Formula IV in step b) may or may not be isolated. The same can be converted in situ to the compound of Formula V in step
c)
Step c) involves condensation of 2-phenoxyaniline of Formula IV with
methane sulfonyl chloride in the presence of a base in a suitable solvent to give N-(2-phenoxy-phenyl)-methanesulfonamide of Formula V.
Suitable solvents which can be used for this stage include any solvent or mixture of solvents, in which the required compounds are soluble. Examples include, without limitation: aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like; ketonic solvents such as acetone, methyl isobutyl ketone and the like; or mixtures thereof.

The basic reagents which can be used in the reaction include, but are not limited to: organic bases like d-Cioalkyl amines; inorganic bases selected from hydroxides of alkali-metals such as lithium hydroxide, sodium hydroxide, potassium and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like.
The temperature for conducting the reaction can range from about -10 to 20 °C, or about 0 to 20 °C.
Step d) involves nitration of N-(2-phenoxy-phenyl)-methanesulfonamide of Formula V with nitric acid in a suitable solvent to give N- (4-nitro-2-phenoxy-phenyl)-methanesulfonamide of Formula I.
Suitable solvents which can be used for this stage include any solvent or mixture of solvents, in which the required compounds are soluble. Examples include, without limitation: aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like; ketonic solvents such as acetone, methylisobutylketone and the like or mixtures thereof.
The temperature for conducting the reaction can range from 0-100° C, or 20-80° C, or 45-50° C.
Suitably, one or more sequential steps a) to d) are carried out in situ. In one embodiment of the invention, steps a) to c) are carried out in situ followed by isolation of the compound of Formula V.
The whole process is represented schematically in Scheme 2.


The simple and improved process of the present invention is eco-friendly, industrially well-suited, commercially viable, reproducible and cost effective with improved yield.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are not intended to limit the scope of the appended claims in any manner.
EXAMPLES
EXAMPLE 1
PREPARATION OF 2-PHENOXYNITROBENZENE
120 g of phenol and 75.3 g of potassium hydroxide was charged in a 4
neck round bottom flask containing 300 ml of toluene under stirring. 150 g of 1-
chloro-2-nitrobenzene was charged to the reaction mass at 44 °C. The reaction
mixture was heated to 120 °C and maintained for 12 hours. Reaction completion
was confirmed using thin layer chromatography. After the reaction was completed,
the reaction mass was cooled to about 30 °C and 450 ml of water was charged to
the reaction mass. This reaction mass was then cooled to 28 °C and the organic

layer was separated. The aqueous layer was extracted with 75 ml of toluene and proceeded to next stage with total organic layer.
EXAMPLE 2 PREPARATION OF 2-PHENOXYANILINE
330 ml of the organic layer obtained from Example 1, containing 2-phenoxynitrobenzene was taken into a Parr hydrogenator/autoclave vessel. 5 g of Raney nickel was charged and 5 kg/cm2 hydrogen pressure was applied. The reaction mixture was heated to 96 °C and maintained at the same pressure for about 20 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 29 °C. The catalyst was recovered by vacuum filtration and washed with 100 ml of toluene. The filtrate was washed with 100 ml of water. Aqueous layer was then extracted with 50 ml of toluene and total organic layer washed with 100 ml of 5% aqueous sodium hydroxide solution. Separated the organic layer and proceeded to the next step.
EXAMPLE 3 ALTERNATE PROCESS FOR THE PREPARATION OF 2-PHENOXYANILINE
445 ml of organic layer obtained by a process similar to Example 1 containing 2-phenoxynitrobenzene was taken into a 4 neck round bottom flask. 62 g of finely divided iron powder followed by 150 ml of water was added to it and the mixture was heated to a temperature of 88 °C. A mixture of 33 ml of 36% aqueous hydrochloric acid and 50 ml of water was added to the reaction mass for 60-90 minutes at 88 °C. The reaction mass was stirred at 88 °C for 2 hours. The reaction mass was then cooled to 80 °C and another 62 g of iron powder was added to it. Again the reaction mass was heated to 89 °C and a mixture of 33 ml of 36 % aqueous hydrochloric acid and 50 ml of water was added to the reaction mass in 90 minutes at the same temperature. The reaction suspension to was then cooled to 77 °C and then added 62 g of iron powder to it. Again the reaction mass was heated to reflux and a mixture of 33 ml of 36 % aqueous hydrochloric acid and 50 ml of water was added to the reaction mass in 60 minutes at reflux. The reaction mass was maintained at a temperature of 89 °C for 10 hours and the reaction

completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 28 °C and the catalyst was recovered by vacuum filtration and washed with 150 ml of toluene. The aqueous layer was separated and extracted with 75 ml of toluene. Total organic layer washed with 150 ml of 5% aqueous sodium hydroxide solution. The organic layer was separated and proceeded to next step. (Volume about 840 ml).
EXAMPLE 4
PREPARATION OF N-(2-PHENOXY-PHENYL) METHANESULFONAMIDE
750 ml of organic layer obtained from Example 3, containing 2-phenoxyaniline was taken into a four necked round bottom flask. 108.6 g of triethyl amine was added to it and stirred for 10 minutes at 27 °C. The reaction mixture was then cooled to 8 °C. 118 g of methane sulfonyl chloride was added to the reaction suspension at 6 °C in about one hour and maintained at same temperature for 2 hours. The reaction completion was checked using thin layer chromatography and after the reaction was completed, 1590 ml of water cooled to a temperature of 5 °C was added to the reaction mass. The reaction mass was then stirred for 30 minutes at 6 °C. The separated solid was filtered and washed with 795 ml of water. The solid was dried at 70 °C for 6 hours to afford 203 g (% of yield: 90%) of the title compound.
EXAMPLE 5
PREPARATION OF N-(4-NITRO-2-PHENOXYPHENYD-METHANESULFONAMIDE
50 g of N-(2-phenoxyphenyl)-methane sulfonamide obtained above was taken into a four necked round bottom flask containing 350 ml of ethylene dichloride. The contents were heated to 48 °C and 18.7 g of 70% nitric acid was added to the reaction mass at for 30 minutes at the same temperature. The reaction suspension was stirred at 48 °C for 3 hours and confirmed the reaction completion by thin layer chromatography. 200 ml of water was added to the reaction mass and the reaction mass was cooled to 30 °C. The bottom organic layer was separated and washed with 100 ml of 5% aqueous sodium thiosulfate pentahydrate solution at 30 °C. The organic layer was then washed with 100 ml of

5% aqueous sodium thiosulfate solution at 30 °C. The organic layer was then distilled off completely under a vacuum of 300 mm Hg at 60° C. 125 ml of methanol was charged to the residue and stirred for 45 minutes at 48 °C. The reaction mass was then cooled to 4 °C and stirred for 30 minutes. The reaction mass was then filtered and the separated solid was washed with 50 ml of methanol chilled to a temperature of 5 °C. The wet solid was then taken into a separate flask containing 200 ml water and 50 ml ethylene dichloride. 11 ml of 50% aqueous sodium hydroxide solution was added to the reaction suspension in 30 minutes. The aqueous layer was separated and heated to 60 °C. The clear solution thus obtained was optionally treated with activated charcoal. Again pH of the reaction mass was adjusted to 1.59 with 36% aqueous hydrochloric acid solution. The contents were stirred for 45 minutes at 3 °C. The separated solid was filtered and washed with 50 ml methanol. The solid was dried at about 72 °C for about 8 hours to afford 48.8 g (% yield 83.36) of the title compound. Purity by HPLC: 99.92%.




We Claim:
1. A process for preparing nimesulide comprising:
a) condensing phenol with 1-chloro-2-nitrobenzene to give 2-phenoxynitro benzene;
b) reducing 2-phenoxynitrobenzene to give 2-phenoxyaniline; and
c) condensing 2-phenoxyaniline with methanesulfonyl chloride to give N-(2-phenoxy-phenyl)-methanesulfonamide.

2. The process of claim 1, wherein one or more of products from a), b) or c) are not isolated prior to further reaction.
3. The process of claim 1, wherein one or more of products from a) and b), or one or more of products from b) and c), or one or more of products from a) and c), are not isolated prior to further reaction.
4. The process of claim 1, wherein no product from a), b), and c) is isolated prior to further reaction.
5. The process of claim 1, wherein condensation in a) occurs in the presence of potassium hydroxide.

6. The process of claim 1, wherein reduction in b) occurs in the presence of a hydrogenation catalyst and hydrogen or a transition metal and hydrochloric acid.
7. The process of claim 1, wherein reduction in b) occurs in the presence of nickel and hydrogen, or iron and hydrochloric acid.
8. The process of claim 1, wherein condensation in c) occurs in the presence
of triethylamine.
9. The process of any one of claims 1-8, wherein a solvent comprises an aromatic hydrocarbon.
10. The process of any one of claims 1-9, wherein a solvent comprises toluene.


Documents:

1077-CHE-2005 AMENDED PAGES OF SPECIFICATION 26-07-2011.pdf

1077-CHE-2005 AMENDED CLAIMS 26-07-2011.pdf

1077-che-2005 correspondence others 29-07-2011.pdf

1077-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 26-07-2011.pdf

1077-che-2005 form-3 29-07-2011.pdf

1077-che-2005 other patent document 29-07-2011.pdf

1077-CHE-2005 POWER OF ATTORNEY 26-07-2011.pdf

1077-che-2005-abstract.pdf

1077-che-2005-claims.pdf

1077-che-2005-correspondnece-others.pdf

1077-che-2005-description(complete).pdf

1077-che-2005-drawings.pdf

1077-che-2005-form 1.pdf

1077-che-2005-form 3.pdf

1077-che-2005-form 5.pdf

1077-che-2005-other document.pdf


Patent Number 248768
Indian Patent Application Number 1077/CHE/2005
PG Journal Number 34/2011
Publication Date 26-Aug-2011
Grant Date 23-Aug-2011
Date of Filing 05-Aug-2005
Name of Patentee HONDA MOTOR CO., LTD.
Applicant Address 1-1 MINAMIAOYAMA 2-CHOME, MINATO-KU, TOKYO, JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 TAKADA, YASUHIRO C/O KABUSHIKI KAISHA HONDA GIJUTSU KENKYUSHO 4-1, CHUO 1-CHOME WAKO-SHI SAITAMA 351-0193 JAPAN
2 YOKOMORI, TETSUHITO C/O KABUSHIKI KAISHA HONDA GIJUTSU KENKYUSHO 4-1, CHUO 1-CHOME WAKO-SHI SAITAMA JAPAN
3 SUGIUCHI, TADASHI C/O KABUSHIKI KAISHA HONDA GIJUTSU KENKYUSHO 4-1, CHUO 1-CHOME WAKO-SHI SAITAMA JAPAN
4 ANNO, MAMI C/O KABUSHIKI KAISHA HONDA GIJUTSU KENKYUSHO 4-1, CHUO 1-CHOME WAKO-SHI SAITAMA JAPAN
PCT International Classification Number F02M 35/10
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2004-248581 2004-08-27 Japan