CLIAMS:We claim:

1. A process for preparation of Iguratimod of formula-I comprising;

Formula-I

a) reducing nitro compound of formula-II, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl with hydrogen in presence of solid catalyst consisting essentially of Raney Nickel to obtain amino compound of formula-III, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl; and
b) further converting the compound of formula-III into Iguratimod of formula-I.

Formula-II Formula-III

2. The process as claimed in claim 1, wherein the R is methyl.

3. The process as claimed in claim 1, wherein, the reaction of step a) is performed in a solvent at temperature range of 20°C to reflux temperature of the solvent.

4. The process as claimed in claim 3, wherein the solvent is selected from the group consisting of water, alcohols, esters, aromatic hydrocarbons and polar aprotic solvents or mixture thereof.

5. The process as claimed in claim 4, wherein, the ester solvent is ethyl acetate or methyl acetate.
6. The process as claimed in claim 1, wherein the Raney Nickel is used in the range of 10 gm to 30 gm per mole of nitro compound of formula –II.

7. The process as claimed in claim 1, wherein the Raney Nickel is reused or recycled.

8. The process as claimed in claim 1, wherein the reaction is performed under pressure ranging from 1 kg/cm2 to 25 kg/cm2.

9. A process for preparation of amino compound of formula-III comprising;
reducing nitro compound of formula-II, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl with hydrogen in presence of solid catalyst consisting essentially of Raney Nickel to obtain amino compound of formula-III, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl.

10. The process as claimed in claim 9, wherein the amino compound of formula-III is further converted to Iguratimod.

Dated this the 29th day of April, 2014

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates
,TagSPECI:FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:
“A PROCESS FOR THE PREPARATION OF IGURATIMOD”
2. APPLICANT:
(a) NAME: IPCA LABORATORIES LIMITED

(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: 48, Kandivali Industrial Estate, Charkop, Kandivali (West),
Mumbai – 400 067, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

Field of the invention:
The present invention relates to a new process for preparation of Iguratimod of formula-I. More particularly, the invention relates to preparation of intermediate of formula-III useful in the preparation of Iguratimod.

Background of Invention:
Iguratimod, chemically known as N-[(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl] methanesulfoanamide, is an anti inflammatory agent used for the treatment of rheumatoid arthritis. Preparation of Iguratimod was first reported in the US4954518.. As per the teachings of US4954518 and Chem.Pharm.Bull., 2000, 48, 131-139, Iguratimod was prepared starting from 3-nitro-4-phenoxy anisole or 3-nitro-4-phenoxy phenol. The intermediate, 3-amino-4-phenoxyanisole, was generally prepared by reducing 3-nitro-4-phenoxyanisole with iron powder and HCl. The US‘518 patent reported the preparation of the intermediate, 3-amino-4-phenoxyanisole, by reducing 3-nitro-4-phenoxyanisole with iron powder and 4N HCl in ethanol-water solvent mixture. After completion of reaction, the reaction mixture was hot filtered and the filtrate was diluted with water to isolate the 3-amino-4-phenoxyanisole.

Another document, , Chem Pharm Bull (2000), 48(1), 131-9 also reported reduction of 3-nitro-4-phenoxyanisole using iron powder and 4NHCl in 50% ethanol to prepare 3-amino-4-phenoxyanisole. After completion of reaction, the reaction mixture was filtered and the filtrate was diluted with water to precipitate the reduction product and the product was further recrystallised from toluene to afford 3-amino-4-phenoxyanisole.

Recently published Chinese application, CN102807515 (published in 2012) also reported preparation of 3-amino-4-phenoxyanisole from 3-nitro-4-phenoxyanisole using iron powder and concentrated HCl in ethanol solvent.

Preparation of 3-amino-4-phenoxyanisole from 3-nitro-4-phenoxyanisole using iron powder and HCl as mentioned in the above documents involves formation of large quantity of slimy sludge, which causes slow filtration and often the reduced product gets trapped in the sludge. In order to recover the product from sludge, more washings/extractions are required which leads to increased time cycle and consumption of more solvents and thus escalates the cost of the manufacture.

To some extent this problem was solved in another patent, US53044644, which reported reduction of 3-nitro-4-phenoxyanisole with hydrogen in presence of 5% palladium on carbon (5%Pd/C) catalyst at room temperature. After completion of reaction, the catalyst was separated by filtration and the filtrate was subjected to concentration to get the product. The product was further subjected to flash chromatography to isolate pure 3-amino-4-phenoxyanisole.

When the present inventors prepared 3-amino-4-phenoxyanisole as per the reaction conditions mentioned in the US‘644 patent, there was formation of an impurity in substantial quantity (15.84 % impurity at 25.17 RT ) was observed in the reduced product. Therefore, it was evident that an additional flash chromatography step is necessary to obtain pure product, if palladium on carbon catalyst is used for reduction of 3-nitro-4-phenoxyanisole.

Though there is no filtration problem observed in this process but additional problems arised from this process are particularly related to process economics. One major drawback is cost of palladium on carbon catalyst which is highly expensive therefore, it is economically unviable to use this process on industrial scale to prepare an intermediate having less commercial value. The second major drawback is incorporation of additional step-flash chromatography- to get purified product. Incorporation of flash chromatography to purify the crude on industrial scale is not viable.

Therefore, there is very much necessity to develop an improved industrially feasible and economically viable process to prepare the intermediate, 3-amino-4-phenoxyanisole, to overcome the problems of the prior art. The present invention addresses the need by providing an alternative industrially feasible economical process to prepare the intermediate, 3-amino-4-phenoxyanisole and further converting the intermediate into Iguratimod.

Summary of Invention:
Accordingly the present invention provides a cost-effective process for preparation of Iguratimod and also provides a process for preparation of its intermediates, 3-amino-4-phenoxyphenol or its derivatives.

According to one aspect, the present invention provides a process for preparation of Iguratimod of formula-I comprising;

Formula-I

a) reducing nitro compound of formula-II, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl with hydrogen in presence of a solid catalyst consisting essentially of Raney Nickel to obtain formula-III, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl; and
b) further converting the compound of formula-III into Iguratimod of formula-I.

Formula-II Formula-III

In a preferred embodiment, the reduction of nitro compound of formula-II, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl, is carried out at temperature range of 20°C to reflux temperature of the solvent used.

According to another aspect, the present invention provides a process for preparation of amino compound of formula-III wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl comprising;
reducing nitro compound of formula-II, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl with hydrogen in presence of solid catalyst consisting essentially of Raney Nickel to obtain the amino compound of formula-III.

Description of drawings:
Fig 1 depicts the sample analysis of 3-amino-4-phenoxyanisole prepared according to the process described in stage VI of the instant invention
Fig 2 depicts the sample analysis of 3-amino-4-phenoxyanisole prepared according to the process described in US53044644

Detailed description of the invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. The term "consists essentially of” means excluding other materials that contribute to function.

Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

It has bow been found that an improved economical process to prepare the amino compound of formula-III from nitro compound of formula-II and further conversion of the amino compound of formula-III into Iguratimod. The various aspects of the invention are described in detail with the preferred embodiments/conditions hereafter.

Accordingly, in one aspect, the present invention provides a process for preparation of amino compound of formula-III comprising; reducing nitro compound of formula-II, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl with hydrogen in presence of solid catalyst consisting essentially of Raney Nickel to obtain formula-III, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl.

According to another aspect, the present invention provides a process for preparation of Iguratimod of formula-I comprising; reducing nitro compound of formula-II, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl with hydrogen in presence of solid catalyst consisting essentially of Raney Nickel to obtain formula-III, wherein R is selected from hydrogen, a linear or branched (C1-C8)-alkyl, cycloalkyl and aryl; and further converting the compound of formula-III into Iguratimod of formula-I.

In a preferred embodiment, the present invention provides a process for preparation of Iguratimod wherein R denotes methyl as per the Scheme-I mentioned below.

Scheme-1:

In another preferred embodiment the reduction of nitro compound of formula-II is carried by reacting with hydrogen in presence of Raney Nickel catalyst at temperature ranging from ambient temperature to reflux temperature of the solvent used. However the preferred temperature range varies between 40°C and 80°C.

The reduction reaction is carried out preferably in autoclave under hydrogen pressure. The nitro compound of formula-II is dissolved in the solvent and added Raney Nickel catalyst into the solution. Then the mixture is purged with nitrogen under stirring to expel dissolved air, closed autoclave and then applied hydrogen pressure. The hydrogen pressure may be maintained between 1 kg/cm2 and 25 kg/cm2 to complete the reaction. However preferred range of the hydrogen pressure is from 5 to15 kg/cm2.

A wide range of solvents may be used for conducting the reduction reaction. The solvents include, but not limited to, water, alcohols, esters, aromatic hydrocarbons and polar aprotic solvents or mixtures thereof.

Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, iso butanol and tertiary butanol etc. Esters include ethyl acetate, methyl acetate, n-butyl acetate or iso butyl acetate. Polar aprotic solvents include dimethyl sulfoxide or dimethyl formamide. Aromatic hydrocarbons include toluene or xylene. However preferred solvent is ethyl acetate or methylacetate.

Raney Nickel catalyst is used in catalytic amount to complete the hydrogenation reaction. The amount may be used from 1 gm per mole of the substrate, nitro compound of Formula-II, to 40 gm per mole of substrate. However preferred range of the quantity is 10 gm to 30 gm per mole of substrate.

After completion of reaction, vented the hydrogen pressure and the catalyst is separated by conventional methods such as settling the mass followed by siphoning the reaction mass or by direct filtration. Usually the reaction mass is filtered and washed with same solvent used for reduction. Then the product, amino compound of Formula-III, is isolated from the filtrate by concentration under vacuum.
The separated Raney Nickel catalyst may be reused or recycled for use in the next batch.

The amino compound of Formula-III, may, optionally, be purified by crystalliation before subjecting for further reaction to prepare Iguratimod.

In a preferred embodiment, Iguratimod is prepared from the amino compound of Formula-III as mentioned below.

The amino compound of Formula-III is reacted with methane sulfonyl chloride in presence of pyridine in methylenedichloride solvent to obtain corresponding sulfonyl derivative of the amino compound of Formula –IV. The sulfonyl compound of Formula –IV is further reacted with aminoacetonitrile hydrochloride in presence of anhydrous aluminium chloride (AlCl3) in nitrobenzene solvent followed by reacting with dry HCl to obtain compound of Formula-V. The compound of Formula –V is further reacted with sodium formate in presence of pivaloyl chloride in acetone solvent to obtain the compound of Formula-VI. The compound of Formula-VI is reacted with aluminium chloride in presence of sodium iodide in acetonitrile solvent to get the phenolic compound of Formula-VII. Finally the phenolic compound of Formula-VII is subjected to cyclisation by reacting with dimethyl formamide dimethylacetal in dimethylformamide solvent to form Iguratimod. The product may be purified by known methods such as crystallization or base-acid treatment.

The following examples, which include preferred embodiments, is intended 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.

Stage I: Preparation of N-(4-methoxyphenyl)acetamide
Added 500 g (3.31 mol) N-(4-hydroxyphenyl)acetamide into NaOH solution (prepared from 278.20 g (6.95 mol) NaOH and 3500 ml water). Then added 835.29 g (6.62 mol) of dimethyl sulphate slowly at room temperature (30-35°C) over a period of 3-4hrs and maintained the reaction mixture for 17-20 hrs at 30-35°C till completion of reaction. After completion of the reaction, the reaction mass was filtered, washed with 1500 ml of water and dried the cake. Dry wt. of N-(4-methoxyphenyl)acetamide 460 g (84% Yield).

stage II: N-(4-methoxy-2-nitrophenyl)acetamide
Added 611 g (6.877 mol) of HNO3 drop wise in to an aqueous solution of N-(4-methoxyphenyl)acetamide (prepared by mixing 400 g (2.42 mol) N-(4-methoxyphenyl)acetamide and 3200 ml of water) over a period of 3-4 hrs at 0-5°C. Maintained the reaction mass at 30-35°C for 8-10 hrs till completion of the reaction. After completion, the mass was cooled to 0-5°C and further maintained for 2-3 hrs. Filtered the reaction mass and the cake thus obtained was washed with 4000 ml of water and dried. Dry wt. of N-(4-methoxy-2-nitrophenyl)acetamide: 417 g (82% Yield).

Stage III: 4-Methoxy-2-nitroaniline
Charged 400 g (1.9 mol) of 4-methoxy-2-nitroaniline into 1200 ml of water and stirred well to make solution. Then added NaOH solution (prepared by adding 228.57 g (5.71 moles) NaOH and 400 ml of water) drop wise over a period of 1-1.5 hrs. Maintained the reaction mass at 55-60°C for 4-6 hrs till completion of reaction. After completion of reaction, the mass was cooled to 0-5°C for 2-3 hrs. Filtered the reaction mixture and washed the solids with water (4000 ml) to obtain N-(4-methoxy-2-nitrophenyl)acetamide. Dry wt: 263 g (82% Yield).
Stage IV: 4-Chloro-3-nitroanisole
Charged 125 g (0.744 mol) of 4-amino-3-nitroanisole into mixture of 500 mL water and 500 ml of conc.HCl at room temperature (30-35°C). In a separate flask, prepared NaNO2 solution by dissolving 179.68 g (2.6 mol) of NaNO2 in 187.5 ml of water. Then added the NaNO2 solution slowly into 4-amino-3-nitroanisole into mixture to prepare diazonium salt at -5 to 5°C.

In another 10 lit 4-neck RB flask, charged 257.81 g (2.6 mol) of CuCl and 800 ml of Conc. HCl at room temperature. Then charged the above diazonium salt drop wise to the CuCl solution at -5 to 5°C. After addition, raised the reaction mass temperature to 55-60°C and maintained for 4-6 hrs till completion of reaction. After completion of reaction, the mass was cooled to 25-30°C. Charged 1250ml of water and 500 ml of methylene dichloride in to the reaction mass, stirred at room temperature for 15 min and separated layers. Extracted the aqueous layer with 250 ml methylenedichloride twice. Then the organic layer was subjected to distillation under vacuum to get 124.5 gm of 4-Chloro-3-nitroanisole. Yield: 89%.

Stage V: 3-Nitro-4-phenoxy anisole
Dissolved 100g (0.53 mol) 4-Chloro-3-nitroanisole in 100 ml of dimethyl formamide at room temperature. Then added 75.19g (0.8 mol) of phenol dissolved in 100 ml of dimethyl formamide slowly into above prepared 4-Chloro-3-nitroanisole solution. The reaction mixture was heated to 80-900C and added 119.45g (1.07 mol) of potassium tert. butoxide in 3 lots (each in 15 min. of interval). Then raised the temperature of reaction mixture to 120-130°C and maintained the same temperature for 2-3hrs till completion of the reaction. After completion of reaction, cooled the reaction mass to 25-30°C and filtered to separate the solid potassium tert. butoxide and washed the solids with ethylacetate. Distilled the ethylacetate to obtain solids followed by the dissolution of solids in 1000 ml of water. The aqueous solution was extracted with 500 ml of methylene dichloride. Separated layers and the aqueous layer was further extracted with 500 ml methylene dichloride thrice. The combined methylene dichloride layer was washed with 500 ml of 2% HCl solution four times. The obtained methylene dichloride layer was washed with 500 ml of 2% sodium hydroxide solution four times. Then washed the organic layer with 1000 ml of water thrice till neutral pH is obtained. Then the organic layer was subjected to distillation to get 106g of 3-Nitro-4-phenoxy anisole. Yield : 81%.

Stage VI: 3-Amino-4-phenoxy anisole
22 g (10%) of Raney Nickel was added into a solution of 220 g (0.898 mol) of 3-Nitro-4-phenoxy anisole dissolved in 1100 ml of ethylacetate in autoclave. Flushed the reaction mass with nitrogen, applied hydrogen pressure at 10-12 Kg/cm2 and heated the reaction mass to 40-45°C. Maintained the reaction mass for 12-15 hrs at 40-45°C till completion of reaction. After completion, filtered the Raney Nickel catalyst through hyflo bed (36.65 g) under Nitrogen atmosphere and washed the hyflo bed with ethyl acetate (220 ml). The obtained ethyl acetate filtrate was subjected for distillation to get 187 g of 3-Amino-4-phenoxy anisole. Yield: 97%
Impurity: 0.1%

Stage VII & VIII: 3-Methyl sulfonyl amino-4-phenoxy anisole
Added 125 g (0.58 mol) of 3-Amino-4-phenoxy anisole in 500 ml of methylenedichloride at room temperature and stirred for 10 minutes. Then added pyridine-methylenedichloride solution (prepared by mixing 137.79 g of (1.74 mol) of pyridine in 125 mL of methylenedichloride) into the above prepared 3-Amino-4-phenoxy anisole solution and cooled to 0-5°C. In a separate flask, prepared methanesulphonyl chloride solution by dissolving 73.258 g (0.64 mol) of methanesulphonyl chloride in 125 ml methylenedichloride and added this solution to the above reaction mixture at 0-5°C slowly over a period of 1-2hrs. After completion of addition, raised the temperature to 25-30°C and maintained for 4-6 hrs till completion of reaction. After completion of reaction, added 1250ml of water and adjusted the pH of reaction mixture to 2.5-3.0 by using 210 ml of 4N hydrochloric acid. Separated layers and washed the organic layer with 2500ml of water till neutral pH is obtained. Separated the layers and organic layer was subjected to distillation under vacuum to obtain crude 3-methyl sulfonyl amino-4-phenoxy anisole. The crude was recrystallised using 500 ml of ethanol solvent to get 114 g of pure 3-methyl sulfonyl amino-4-phenoxy anisole.
Yield :75.8 %

StageIX:alpha-amino-2-methoxy-4-methanesulfonylamino-5-Phenoxy acetophenone hydrochloride
Charged 99.89 g (0.748 mol) of anhydrous AlCl3 into 110 ml of nitrobenzene and stirred well. To this mixture, added amino acetonitrile hydrochloride-nitrobenzene solution (prepared by mixing 41.57 g (0.449 mol) of amino acetonitrile hydrochloride and 110 ml of nitrobenzene) and heated the reaction mixture to 40-45°C on water bath for 1hr. In a separate flask, prepared a solution by dissolving 110 g (0.374 mol) of 3-Methyl sulfonyl amino-4-phenoxy anisole in 110 ml of nitrobenzene and added this solution into the above reaction mixture at 10-15°C. Then purged HCl gas into the reaction mixture at 10-15°C over a period of 6-8hrs and maintained the reaction mixture at 10-15°C for 20-24 hrs till completion of reaction. After completion, quenched the reaction mixture with 990 ml 4N HCl solution at 0-5°C over a period of 2 hrs and maintained the reaction mixture at 0-5°C for further 4-5 hrs. Filtered the slurry and washed the cake with 330ml of water. Transferred the wet cake into 330ml ethyl acetate and stirred at 65-70°C for 2 hrs. Then cooled and filtered the slurry followed by washing the cake with 110 ml of ethyl acetate. Cake was dried to get alpha-amino-2-methoxy-4-methanesulfonylamino-5-phenoxy acetophenone hydrochloride. Dry wt: 122.75 g (85 % Yield).

StageX:alpha-formamido-2-methoxy-4-methylsulfonylamino-5-benzeneacetophenone
Charged 81.03 g (1.192 mol) of sodium formate into a mixture of 200 ml acetone and 75.85 g (0.62 mol) of pivaloyl chloride and maintained for 4-5hrs at 30°-35C. Then added slowly 100 g (0.259 mol) of alpha-amino-2-methoxy-4-methanesulfonylamino-5-Phenoxy acetophenone hydrochloride dissolved in 100ml of acetone to the above reaction mixture and maintained the reaction mass for 24-30 hrs at 30°-35C till completion of reaction. After completion of reaction, cooled the reaction mass to 0-15°C and added 900 ml of water drop wise over a period of 2-3 hrs and maintained at 0-5°C for 5-6hrs. The reaction mass, in slurry form, was filtered and washed the cake with 300 ml of water followed by washing with 100 ml of chilled isopropanol. The wet cake was dried to get 68.6 g of alpha-formamido-2-methoxy-4-methylsulfonylamino-5-benzeneacetophenone. Yield: 70%.

StageXI:alpha-formamido-2-hydroxy-4-methanesulfonyl-amino-5-phenoxyacetophenone
48.73g (0.365 mol) of AlCl3 was added into 120 ml of acetonitrile at 10- 15 °C in 4 lots at an interval of 5 minutes. Then added 31g (0.21 mol) of sodium iodide in the reaction mixture followed by addition of 60 g (0.16 mol) alpha-formamido-2-methoxy-4-methylsulfonylamino-5-benzeneacetophenone. Then flushed with additional 30 ml of acetonitrile and maintained the mass at 10- 15 °C for 20-25 hrs till completion of reaction. After completion of reaction, added 540ml of 1% sodium sulfite solution in to the above reaction mixture over a period of 2-3hrs at 0-5°C and maintained at 0-5 °C for 24 hrs. The reaction mass was filtered and washed the cake with 180 ml of water. The obtained cake was dried to get 49.85 g of alpha-formamido-2-hydroxy-4-methanesulfonyl-amino-5-Phenoxyacetophenone. Yield: 86 %.

StageXII:3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy) -4H-1-(benzopyran)-4-one (Crude)
Charged 45 g (0.124 mol) of the above prepared alpha-formamido-2-hydroxy-4-methanesulfonyl-amino-5-Phenoxyacetophenone into 90 ml of dimethylformamide (DMF) at 25-30°C. The reaction mass is cooled to 5-10°C and added 44.56 g (0.37 mol) of N,N-Dimethylformamide dimethyl acetal and maintain the temperature for 10-15 min. Raised the temperature of reaction mixture to 15-20°C and maintained for 24-26 hrs till completion of reaction. After completion of reaction, added 225ml of methylene dichloride into the reaction mass drop wise over a period of 1hr at 0- 5°C followed by the addition of 450 ml water at 0- 5°C over the period of 1hr. Then adjusted the pH of reaction mass to 2-3 with 100 ±10 ml of 10% HCl solution. Stirred the mass for another 2-3hrs at 0-5°C. Filtered the reaction mass and washed the obtained cake with 225 ml of water followed by washing with 270 ml of a mixture of solvent (Solvent mixture: MDC: Water: Ethanol ( 90 ml: 90 ml: 90 ml). The wet cake was dried to obtain 3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy) -4H-1-(benzopyran)-4-one. Wt: 39 g: Yield: 84 %. Purity by HPLC: 99.5%

StageXIII:3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy) -4H-1-(benzopyran)-4-one (Pure)
Added 38g (0.101 mol) of the crude 3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy) -4H-1-(benzopyran)-4-one into 760 ml acetonitrile water mixture (acetonitrile: 380 ml and water: 380 ml). Then adjusted pH of the reaction mass to 10-10.5 with 210 ml of 10% sodium carbonate solution. Filtered the reaction mass over Whatmann 41 paper followed by over micron 0.45 mm and washed with 19 ml of water. The filtrate was acidified to pH 1.5-2.0 with 288 ml of 10% hydrochloric acid to precipitate solids and the slurry was further equilibrated for 2-3hrs at 0-5°C. Filtered the slurry and washed the solids with 380ml of DM water. Dry wt. of purified 3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy)-4H-1-(benzopyran)-4-one: 35 g. Yield: 94%. Purity by HPLC: 99.8%