FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - AN IMPROVED PROCESS FOR PREPARATION OF
ILAPRAZOLE.
2. Applicant(s)
(a) NAME : AJANTA PHARMA LTD
(b) NATIONALITY : An Indian Company
(c) ADDRESS: Ajanta House, Charkop, Kandivali (W), Mumbai - 400067,
Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Uaprazole.
BACKGROUND OF THE INVENTION
Proton pump inhibitors (or "PPIs") are a class of pharmaceutical compounds which inhibit gastric acid secretions by inhibiting H+ZK+ adenosine triphosphatase. Uaprazole, chemically, 2[[(4-methoxy-3-methyl-2-pyridinyl)-methyl] sulfinyl]-5-(1H-p yrrol-1-yl) lH-benzimidazole is a new proton pump inhibitor having the structural Formula I.

(0 Uaprazole is developed by II-Yang pharma and disclosed first time in US patent 5703097 (hereafter referred as '097). '097 disclose different methods for preparation of Uaprazole. The closest method to the present invention disclosed in '097 is as follows:

In this method, 5-(lH-pyrrol-1-yl)-1H-benzo[d]imidazole-2-thiol is reacted with 2-(chloromethyl)-4-methoxy-3-methylpyridine in presence of suitable organic solvent and base. Then the obtained compound is oxidised with oxidizing agent to obtain Uaprazole. This method involves two steps for preparation of Uaprazole in which the sulfanyl intermediate is isolated. But. this patent is silent about the

purity of the Ilaprazole. This method for preparation of Ilaprazole increases impurity formation. Also, use of expensive organic solvent increases the cost of the reaction.
Indian patent application 462/CHE/2010 (Applicant: Nandepu Venkateswara Rao; date of filing: Feb 23, 2010) discloses process for the preparation of "Prazole" precursor, which comprises the condensation reaction of substituted 2-chloromethylpyridine hydrochloride with substituted 2-mercapto benzimidazole in presence of water and base to avoid formation of dialkylated impurity. But, this patent application does not mention about the yield of the reaction product. Use of water as a solvent in the reaction may lead to incomplete reaction. Therefore, there is a need to develop an economically feasible process for preparation of Ilaprazole which results in high yield, easy isolation process and less reaction steps.
The present inventors have developed an improved process for preparation of Ilaprazole employing mixed solvent system in the condensation reaction in the process for preparation of Ilaprazole which overcomes the drawbacks of the prior art processes.
The present inventors have developed an improved process for preparation of Ilaprazole without using expensive reagents and solvents which provide good yield and high purity.
OBJECT OF THE INVENTION
It is an object of the present invention is to provide an improved process for the preparation of Ilaprazole without using expensive reagents and solvents.
It is another object of the present invention is to provide an improved process for the preparation of Ilaprazole which gives reaction product in high yield and high purity.

It is a yet another object of the present invention to provide an improved process for the synthesis of Ilaprazole that is substantially free of impurities.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided a process for the preparation of Ilaprazole comprising the steps of
a) condensation of 5-(lH-pyrrol-l-yl)-lH-benzo[d]imidazole-2-thiol of formula (II) with 2-(chloromethyl)-4-methoxy-3-methylpyridine of formula (III) in presence of mixed solvent system and base to form 2-{[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfanyl}-5-(lH-pyrrol-l-yl)-lH-benzimidazole of formula (IV);
b) optionally isolation of compound of formula (IV);
c) oxidation of compound of formula (IV) with suitable oxidizing agent; and
d) isolation of pure Ilaprazole with one or more solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Ilaprazole with good yield and high purity.
According to an embodiment of the invention, there is provided an improved process for the preparation of Ilaprazole comprising the steps of
a) condensation of 5-(1H-pyrrol-l-yl)-1H-benzo[d]imidazole-2-thiol of formula (II) with 2-(chloromethyl)-4-methoxy-3-methylpyridine of formula (III) in presence of mixed solvent system and base to form 2-{[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfanyl}-5-(1H-pyrrol-l-yl)-1H-benzimidazole of formula (IV);
b) optionally isolation of compound of formula (IV);
c) oxidation of compound of formula (IV) with suitable oxidizing agent; and
d) isolation of pure Ilaprazole with one or more solvent.

The condensation of 5-(lH-pyrrol-l-yl)-lH-benzo[d]imidazole-2-thiol of formula (II) with 2-(chloromethyl)-4-methoxy-3-methylpyridine of formula (III) is carried out in presence of mixed solvent system and a base to form 2-{[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfanyl}-5-(lH-pyrrol-1-y1)-1H-benzimidazole of formula (IV).
The mixed solvent system comprises of one or more organic solvent and water. The organic solvent is selected form the group comprising of 1, 4-dioxane, tetrahydrofuran, dimethylacetamide, N-Methyl-2-pyrrolidone (NMP) and ethyl acetate. The solvent is added in the range of 2 to 5 times.
Base is selected from the group comprising of sodium carbonate, Sodium acetate, calcium carbonate, cesium carbonate, potassium t-butoxide. The reaction is carried out at 0 to 100 °C. The obtained compound of formula (IV) is optionally isolated.
The compound of formula (IV) is oxidised with suitable oxidizing agent to obtain Ilaprazole. Sodium hypochlorite is preferably employed for the oxidation reaction. The reaction is carried out at -5 to 27 °C temperature.
The obtained crude Ilaprazole is purified with one or more suitable solvent.
Solvents are selected from Diisopropyl ether, Dichloromethane, ethyl acetate, acetone, methyl ethyl ketone, methanol and ethanol.

The reaction for the preparation of Ilaprazole in accordance with the present invention can be summarized as follows:

The following examples illustrate the invention without however implying a limitation.
Step-I Preparation of 2-((4-methoxv-3-methylpyridin-2-yl) methylthio)-5-(1H-pyrrol-1-yl)-1H-benzo[d]imidazole; compound of formula (IV).
Example 1
To a mixture of 5-(lH-pyrrol-1-yl)-1H-benzo[d]imidazole-2-thiol; compound of formula (II) (100 g, 0.47 mol) in dioxane (300 ml), 3N aqueous sodium carbonate (600 ml) was added at 25°C to 30°C under stirring. To above reaction mixture, aqueous solution of 4-methoxy-3-methyl-2-chloromeihyl pyridine hydrochloride; compound of formula (III) (106.4 g, 0.51 moles) was added over a period of 30 to 45 min. The resulting suspension was stirred at 25°C to 30°C up to completion of the reaction. The reaction mixture was adjusted to pH 7-8 by addition of 50 % aqueous acetic acid and diisopropyl ether (200 ml) was added to above

suspension. After stirring, solid was isolated and washed with water. The wet compound was dried under vacuum at 65°C to 70°C for 4 to 5 hr to obtain 150 gm of the off-white colored title compound; i.e Compound of formula (IV). (HPLC purity-99%).
Example 2
To a mixture of 5-(lH-pyrrol-l-yl)-lH-benzo[d]imidazole-2-thiol; compound of formula (II) (100 g, 0.47 mol) in dimethyl acetamide (400 ml), 3N aqueous sodium carbonate (600 ml) was added at 25°C to 30°C under stirring. To above reaction mixture, aqueous solution of 4-methoxy-3-methyl-2-chloromethyl pyridine hydrochloride; compound of formula (III) (106.4 g, 0.51 moles) was added over a period of 30 to 45 min. The resulting suspension was stirred at 25°C to 30°C up to completion of the reaction. The reaction mixture was adjusted to pH 7-8 by addition of 50 % aqueous acetic acid and diisopropyl ether (200 ml) was added to above suspension. After stirring, solid was isolated and washed with water. The wet compound was dried under vacuum at 65°C to 70°C for 4 to 5 hr to obtain 150 gm of the off-white colored title compound i.e compound of formula (IV). (HPLC purity - 98.5 %)
Example 3
To a mixture of 5-(lH-pyrrol-l-yl)-3H-benzo[d]imidazole-2-thiol; compound of formula (II) (100 g, 0.47 mol) in dimethyl acetamide (500 ml), sodium acetate was added (114 g, 1.41 moles) at 25°C to 30°C under stirring. To above reaction mixture, 4-methoxy-3-methyl-2-chloromethyl pyridine hydrochloride; compound of formula (III) (106.4 g, 0.51 moles) was charged portion wise. The resulting suspension was stirred at 25°C to 30°C up to completion of the reaction. The reaction mixture was diluted by water (500 ml), adjusted pH 7-8 by addition of 50 % aqueous acetic acid and diisopropyl ether (200 ml) was added to above suspension. After stirring, solid was isolated and washed with water. The wet compound was dried under vacuum at 65°C to 70°C for 4 to 5 hr to obtain 150 gm

of the off-white colored title compound i.e compound of formula (IV). (HPLC purity-98.6%)
Step-2 Preparation of Ilaprazole; compound of formula (I).
To a mixture of compound obtained in step-1; i.e compound of formula (IV) (100 g, 0.28 moles) and THF (300 ml), 6N aqueous solution of NaOH (190 ml) was slowly added under N2 atmosphere and the resulting suspension was cooled to -10 to -5°C. To above suspension, mixture of sodium hydroxide (34.3 g), water (143 ml) and 4 % sodium hypochlorite (1064 g) was added slowly at -10 to -5°C under stirring. After completion of reaction, the reaction mixture was quenched by addition of solution of sodium thiosulphate (141.7 g) in water (142 ml) at -10 to -5°C and allowed to warm at 25-30°C. The reaction mixture was neutralized up to pH-8-9 by addition of aqueous ammonium acetate (462 g) and stirred for 15 min. The product was extracted by ethyl acetate (500 ml x 2) and organic layer was isolated. Combined organic layer was decolorized by charcoal and distilled out completely to get solid material. Diisopropyl ether (200 ml) was added to residue and stirred for 30 min, solid was separated by filtration and washed with diisopropyl ether (50 ml) to obtain 90 g light brown solid product i.e compound of formula (I).
Step-3 Purification of Ilaprazole; compound of formula (1).
Example 1
The Ilaprazole obtained in step-2 was dissolved in dichloromethane (360 ml); charcoal (9 g) was added, stirred for 30 min and filtered through celite. To the filtrate, Diisopropyl ether (1800 ml) was added slowly at 25-30°C under stirring. Solid precipitate was stirred further for 3 hours at 25-30°C. The solid product was isolated by filtration, washed with diisopropyl ether (100 ml) and dried under vacuum at 50-60°C for 4-5 hours to obtain pure Ilaprazole of off-white color (Yield: 65 g; purity by HPLC- 98.5 %).

Example 2
The Ilaprazole obtained in step-2 was dissolved in ethyl acetate (1350 ml); charcoal (9 g) was added, stirred for 30 min and filtered through celite. Excess of ethyl acetate (900 ml) was distilled out from filtrate and diisopropyl ether (1800 ml) was added slowly to residue at 25-30°C under stirring. Solid precipitate was stirred further for 3 hours at 25-30°C. The solid product was isolated by filtration. washed with diisopropyl ether (100 ml) and dried under vacuum at 50-60 C for 4-5 hours to obtain pure 65 g of off-white product (purity by HPLC- 98.8 %).
Example 3
The Ilaprazole obtained in step-2 was dissolved in acetone (270 ml), charcoal (9 g) was added, stirred for 30 min and filtered through celite. Diisopropyl ether (1800 ml) was added slowly to filtrate at 25-30°C under stirring. Solid precipitate was stirred further for 3 hours at 25-30°C. The solid product was isolated by filtration, washed with diisopropyl ether (100 ml) and dried under vacuum at 50-60 °C for 4-5 hours to obtain pure 65 g of off-white product (purity by HPLC-98.5 %).
Example 4
The Ilaprazole obtained in step - 2 was dissolved in methyl ethyl ketone (360 ml), charcoal (9 g) was added, stirred for 30 min and filtered through celite. Diisopropyl ether (1800 ml) was added slowly to filtrate at 25-30°C under stirring. Solid precipitate was stirred further for 3 hours at 25-30°C. The solid product was isolated by filtration, washed with diisopropyl ether (100 ml) and dried under vacuum at 50-60 °C for 4-5 hours to obtain pure 65 g of off-white product (purity by HPLC-98.0%).

Example 5
The Ilaprazole obtained in step-2 was suspended in methanol (360 ml) stirred for 30 min. Diisopropyl ether (1800 ml) was added slowly to suspension at 25-30°C under stirring. Solid precipitate was stirred further for 3 hours at 25-30°C. The solid product was isolated by filtration, washed with diisopropyl ether (100 ml) and dried under vacuum at 50-60 °C for 4-5 hours to obtain pure 58 g of off-white product (purity by HPLC- 99.0 %).
Example 6
The Ilaprazole obtained in step-2 was suspended in ethanol (360 ml) stirred for 30 min. Diisopropyl ether (1800 ml) was added slowly to suspension at 25-30°C under stirring. Solid precipitate was stirred further for 3 hours at 25-30°C. The solid product was isolated by filtration, washed with diisopropyl ether (100 ml) and dried under vacuum at 50-60 C for 4-5 hours to obtain pure 62 g of off-white product (purity by HPLC- 98.4 %).
One-pot preparation of Ilaprazole
To a mixture of 5-(lH-pyrrol-l-yl)-lH-benzo[d]imidazole-2-thiol (100 g, 0.47 mol) in THF (300 ml), 3N aqueous sodium carbonate (600 ml) was added at 25°C to 30°C under stirring. To above reaction mixture, aqueous solution of 4-methoxy-3-methyl-2-chloromethyl pyridine hydrochloride (106.4 g, 0.51 moles) was added over a period of 30 to 45 min. The resulting suspension was stirred at 25-30°C up to completion of the reaction. The reaction mixture was cooled to -10 to -5°C and solution of sodium hydroxide (55.8 g, 1.39 moles), water (100 ml) and 4 % of sodium hypochlorite (1732 g, 0.93 mole) was added slowly at -10 to -5°C under stirring. After completion of reaction, the reaction mixture was quenched slowly by addition of solution of sodium thiosulphate (230 g, 0.93 mole) in water (200 ml) at -10 to -5°C and allowed to warm at 25-30°C. The reaction mixture was neutralized up to pH 8-9 by addition of aqueous ammonium

acetate (716 g, 9.3 moles) in water (500 ml) and stirred for 15 min. The product was extracted by ethyl acetate (600 ml x 2). Combined organic layer was decolorized by charcoal and distilled out completely to get solid material. Diisopropyl ether (200 ml) was added to residue and stirred for 30 min, solid was separated by filtration and washed with diisopropyl ether (50 ml) to obtain crude 120 g light brown solid product. The crude product was purified by any method disclosed in step-3 to obtain pure Ilaprazole.

We Claim
1. An improved process for the preparation of Ilaprazole comprising the steps of
a) Condensation of 5-(lH-pyrroI-1 -yl)-1 H-benzo[d]irmdazole-2-thioi of formula (II) with 2-(chloromethyl)-4-methoxy-3-methylpyridine of formula (III) in presence of mixed solvent system and base to form 2-{[(4-methoxy-3-methylpyridin-2-yl)methyl] sulfanyl }-5-(1H-pyrrol-l-yl)-lH-benzimidazole of formula (IV);
b) optionally isolation of compound of formula (IV);
c) oxidation of compound of formula (IV) with suitable oxidizing agent; and
d) isolation of pure Ilaprazole with one or more solvent.

2. The process for the preparation of Ilaprazole as claimed in claim 1 wherein the mixed solvent system used in step (a) comprises one or more organic solvent and water.
3. The process for the preparation of Ilaprazole as claimed in claim 2 wherein the organic solvent is selected from 1, 4-dioxane, tetrahydrofuran, dimethylacetamide. N-Methyl-2-pyrrolidone (NMP), ethyl acetate.
4. The process for the preparation of Ilaprazole as claimed in claim 1 wherein the base used in step (a) is selected from sodium carbonate, sodium acetate, calcium carbonate, cesium carbonate, potassium t-butoxide.
5. The process for the preparation of Ilaprazole as claimed in claim 1 wherein the oxidizing agent used in step (c) is Sodium hypochlorite.

6. The process for the preparation of Ilaprazole as claimed in claim 1 wherein the solvents used in step (d) is selected from Diisopropyl ether, Dichloromethane, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol.