FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of Esomeprazole or its pharmaceutically acceptable salt thereof. The present invention involves novel intermediates in the preparation of Esomeprazole or its salt. The present invention further relates to a pharmaceutical composition comprising Esomeprazole or its salt with excipients.

BACKGROUND OF THE INVENTION:

Substituted sulfoxide compounds or their enantiomers (viz., Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole and llaprazole) are known inhibitors of gastric acid secretion and are used as anti-ulcer agents. The sulfur atom of the sulfoxide group in asymmetrically substituted sulfoxide is chiral. This type of chiral sulfoxides has been discussed in the scientific literature since the late seventies, even though there is no literature evidence for efficient asymmetric process for the synthesis of the single enantiomers thereof.

The single enantiomers of pharmacologically active compounds have met an increased interest in recent years because of improved pharmacokinetic and biological properties. Therefore, there is a demand for an enantioselective process that can be used in large scale manufacture of the single enantiomers of pharmacologically active compounds, such as for instance optically pure, substituted 2-(2- pyridinylmethylsulphinyl)-1 H-benzimidazoles. (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-IH-benzimidazole (Esomeprazole) represented by Formula -I,

The resolution processes of racemates of substituted sulfoxides are disclosed in DE 4035455. According to the disclosed process racemic sulfoxide is converted to a diastereomeric mixture, followed by separation of diastereomers and isolation of desired isomer from the separated diastereomer.

US5948789 (1255/DEL/1995) discloses a process for the enantioselective synthesis of Esomeprazole by asymmetric oxidation of pro-chiral sulphide. In this patent the oxidation is carried out in an organic solvent with an oxidizing agent in the presence of a chiral titanium complex, optionally in the presence of a base, wherein the titanium complex has been generated in situ and it afforded either as a single enantiomer or enantiomerically enriched with S-isomer of omeprazole. However the workup, isolation and purification process given are time consuming, cumbersome/tedious and resulting in overall lower yield.

The resolution processes disclosed in the prior art processes are lengthy and tedious. They involve multiple steps during synthesis and purification to obtain the desired products. Hence, there is a need for an improved and effective enantioselective process for large scale production of Esomeprazole or its salt.

SUMMARY OF THE INVENTION:

In one aspect of the present invention provides a novel process for the preparation of Esomeprazole or pharmaceutically acceptable salts thereof wherein the process comprising:

a. reacting 4-chloro-2,3,5-trimethyl-pyridine-l-oxide of formula IX with sodium methane thiolate to give 2,3,5-trimethyl-4-methylsulfanyl-pyridine-1-oxide of formula — VIII, followed by oxidation with an oxidizing agent to obtain 4-methanesulfonyl-2,3,5- trimethyl-pyridine-l- oxide of formula- VII,

b. acetylating the 4-methanesulfonyl-2,3,5-triimethyl-pyridine-l-oxide of Formula-VII followed by hydrolysis to obtain alcohol derivative of 2-hydroxymethyl-3,5-dimethyl-4- methanesulfonyl-pyridine of Formula -V,

c. chlorinating the 2-hydroxymethyl-3,5-dimethyl-4-methanesulfonyl-pyridine of Formula -V with a chlorinating agent to obtain 2-chloromethyl-4-methanesulfonyl- 3,5 -dimethyl pyridine of Formula-IV or its salt,

d. condensing the compound of Formula — IV or its salt with 2-mercapto-5-methoxy-1 H- benzimidazole in the presence of a base in a solvent to obtain 2-[[(4- methanesulfonyl-3,5-dimethyl-2-pyridinyl)methyl]thio]-5-methoxy-1 H-benzimidazole of Formula-Ill,

e. stereoselectively oxidizing the benzimidazole sulphide of formula-Ill using an optically active reagent in presence of a base, metal catalyst and oxidizing agent in a solvent to obtain (S)-[[(4-methanesulfonyl-3,5-dimethylpyridinyl)-2-methyl]sulfinyl]-
5- methoxy-1 H-benzimidazole of Formula- II,

f. reacting benzimidazole sulfoxide of Formula-II with methanol or in combination with other solvent in the presence of a base to get Esomeprazole of Formula — I, and

g. optionally converting to its pharmaceutical^ acceptable salt thereof.

In another aspect of the present invention provides a process for the preparation of Esomeprazole magnesium, comprising the steps of:

a. reacting benzimiazole sulfoxide of formula-II with methanol or combination with other solvent in the presence of base,

b. converting to sodium salt of Esomeprazole,

c. treating the sodium salt of esomeprazole with magnesium source, and

d. isolating Esomeprazole magnesium.

According to the present invention the process for producing Esomprazole is as illustrated by the following Scheme-I.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a novel, process for the preparation of Esomeprazole or pharmaceutically acceptable salts thereof.

One embodiment of the present invention is to provide a process for producing Esomeprazole or pharmaceutically acceptable salts thereof comprising the steps of:

a. reacting 4-chloro-2,3,5-trimethyl-pyridine-l-oxide of formula — IX with sodium methane thiolate to give 2,3,5-trimethyl-4-methylsulfanyl-pyridine-1-oxide of formula — VIII, followed by oxidation with an oxidizing agent to obtain 4-methanesulfonyl-2,3,5- trimethyl-pyridine-l- oxide of formula- VII,

b. acetylating the 4-methanesulfonyl-2,3,5-triimethyl-pyridine-l-oxide of Formula — VII followed by hydrolysis to obtain alcohol derivative of 2-hydroxymethyl-3,5-dimethyl-4- methanesulfonyl-pyridine of Formula -V,

c. chlorinating the 2-hydroxymethyl-3,5-dimethyl-4-methanesulfonyl-pyridine of Formula -V with a chlorinating agent to obtain 2-chloromethyl-4-methanesulfonyl- 3,5 -dimethyl pyridine of Formula-IV or its salt,

d. condensing the compound of Formula-IV or its salt with 2-mercapto-5-methoxy-1 H- benzimidazole in the presence of a base in a solvent to obtain 2-[[(4- methanesulfonyl-3,5-dimethyl-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole of Formula-Ill,

e. stereoselectively oxidizing the benzimidazole sulphide of formula-Ill using an optically active reagent in presence of a base, metal catalyst and oxidizing agent in a solvent to obtain (S)-[[(4-methanesulfonyl-3,5-dimethylpyridinyl)-2-methyl]sulfinyl]- 5- methoxy-1 H-benzimidazole of Formula- II,

f. reacting benzimidazole sulfoxide of Formula-ll with methanol or in combination with other solvent in the presence of a base to get Esomeprazole of Formula-I, and

g. optionally converting to its pharmaceutically acceptable salt thereof.

According to the present invention 4-chloro-2,3,5-trimethyl-pyridine-1-oxide of formula-IX is reacted with sodium methane thiolate optionally in the presence of a phase transfer catalyst in a solvent, preferably water at 60-80°C to give 2,3,5-trimethyl-4-methylsulfanyl-pyridine-1- oxide of formula-VIII, which is further treated in situ with an oxidizing agent optionally in the presence of a metal catalyst at ambient temperature. The reaction mass is optionally seeded with desired product and maintained for about 8-15hrs for complete precipitation of product. The product 4-methanesulfonyl-2, 3, 5-trimethyl-pyridine-1 -oxide of formula-VII is recovered by filtration.

According to the present invention compound of Formula-VII is acetylated using acetic anhydride followed by hydrolysis in the presence of an aqueous base to obtain 2- hydroxymethyl-3,5-dimethyl-4-methanesulfonyl-pyridine of Formula-V. This compound is further reacted with chlorinating agent by adding over the period of 30-90 minutes at 10- 20°C and get 2-chloromethyl-4-methanesulfonyl-3, 5-dimethyl pyridine of Formula-IV. Condensing the compound of Formula-IV or its salt with 2-mercapto-5-methoxy-1 H- benzimidazole in the presence of a base in a solvent at ambient temperature to gives 2-[[(4- methanesulfonyl-3,5 -dimethyl-2-pyridinyl)methyl]thio]-1 H-benzimidazole of Formula-Ill.

According to the present invention, compound of formula-Ill is oxidized selectively in a solvent in presence of (-)-diethyl-d-tartrate and Ti(IV)isopropoxide and a base at 40-60°C to get (S)-[[(4-methanesulfonyl-3,5-dimethyl-2-pyridinyl)methyl]thio]-5-methoxy-1H-
benzimidazole of Formula-ll. This compound of Formula-ll is reacted with methanol in presence of base at ambient temperature to give Esomeprazole of Formula-I. The obtained Esomeprazole is optionally converted to its pharmaceutical^ acceptable salt thereof.

According to the present invention, the reaction of step a) is optionally carried out in the presence of phase transfer catalyst selected from tetra butyl ammonium bromide, tetra ethyl ammonium bromide, tetra butyl ammonium acetate, tetra butyl ammonium fluoride, benzyl trimethyl ammonium chloride and the like.

The oxidizing agent used in the step a) is selected from metachloroperbenzoic acid, hydrogen peroxide, cumenehydroperoxide or sodium hypo halide. The solvent selected from water, chlorinated solvents such as methylene dichloride.

The acetylating agent used in the present invention is acetic anhydride, acetyl chloride in presence of acetic acid at 60°C to reflux temperature of the solvent. The acetyl derivative formed is in situ subjected to hydrolysis reaction in the presences of alkali or alkaline hydroxides like sodium hydroxide, lithium hydroxide, Potassium hydroxide, magnesium hydroxide, calcium hydroxide, preferably aqueous sodium hydroxide. The solvent selected from water, alcohols such as methanol, ketones such as acetone, methyl ethyl ketone or ethers such as tetrahydrofuran and mixture there of.

The chlorinating reagents used in the present invention include but not limited to thionylchloride, paratoluenesulfonyl chloride, alkane sulfonyl chloride such as methane sulfonyl chloride or ethane sulfonyl chloride, POCI3, PCI5, oxalyl chloride and the like. The solvents used in the chlorinating step include but not limited to dimethyl formamide, chloroform, methylene dichloride, carbon tetrachloride or toluene and the like.

The solvents used during the condensation process in step d) of the present invention are selected from water, alcohols such as methanol, ethanol, isopropanol and the like, ketones such as acetone, methylethylketone, methylisobutylketone and the like, nitriles such as acetonitrile or mixtures thereof. The base used during the condensation process of the invention is selected from inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium bicarbonate, potassium tertiary-but oxide and the like.

According to the present invention, oxidizing agents used for stereoselective oxidation of compound of formula II wherein the oxidizing agent selected from cumene hydro peroxide, metachloroperoxy benzoic acid, tert-butyl hydro peroxide, benzoyl peroxide, sulpholane and the like. The solvents used in the process step are selected from water, hydrocarbons such as toluene, chloroform, dichloromethane, dichloroethane and the like, ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether, methyl tertiary butyl ether, ketones such as acetone, methylethylketone, methylisobutylketone and the like, esters such as ethyl acetate, isopropyl acetate and the like, nitriles such as acetonitrile and the like or mixtures thereof. Ethyl acetate and tetrahydrofuran are the preferred solvent and ethyl acetate is most preferred solvent for oxidation reaction as oxidation in ethyl acetate gives the most easy reaction work up option and also results in highly pure product in high yield. As the oxidation reaction progresses product continue to get precipitated and therefore, isolated by filtration after the completion of reaction. No extractive and evaporative workup is required. The base used in the present step includes but not limited to triethylamine, diisopropylamine, N,N-diisopropylethylamine, dicyclohexylamine, cyclohexylamine, tributylamine, n-butylamine or diisopropyl ethylamine, preferably N, N-diisopropylethylamine.

The optically active reagent used in the present invention is selected from but not limited to enantiomerically pure mandelic acid, tartaric acid, diethyl tartaric acid,
phenylethylamine, cinchonine, cinchonidine or brucine and the like. The metal catalyst is selected from barium acetate, strontium acetate, titanium, vanadium, molybdenum or zirconium, preferably Ti (IV) isopropoxide and the like.

The suitable base used in the replacement of mesyl group in step (f) is selected from but not limited to sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like. The solvents used in the present step is selected from dimethylsulfoxide, dimethylformamide, dimethyl acetate, N-methyl pyrrolidone, methanol, and the like, dioxane, toluene, xylene, tetrahydrofuran, dichloromethane, acetonitrile, sulpholane and the like or mixtures thereof. Most preferred bases for replacement of mesyl group and methoxilation reaction are sodium methoxide, sodium tertiary butoxide and potassium tertiary butoxide in combination with methanol.

Another embodiment of the present invention provides a process for the preparation of Esomeprazole magnesium, comprising the steps of:

a. reacting benzimiazole sulfoxide of formula-II with methanol or combination with other solvent in the presence of base,

b. converting to sodium salt of Esomeprazole,

c. treating the sodium salt of esomeprazole with magnesium source, and

d. isolating Esomeprazole magnesium.

According to the present invention compound of formula-ll is reacted with methanol in the presence of a base at 50-60° for about 3-4 hrs, after completion of the reaction water is added, pH is adjusted to acidic followed by extraction in to a solvent. To this solution sodium hydroxide is added and distilled out the solvent to get crude sodium salt of Esomeprazole, which is isolated as a solid by treating with solvent. The obtained Esomeprazole sodium is dissolved in water followed by treating with magnesium source to get magnesium salt of Esomeprazole.

According to the present invention the base used in the replacement of mesyl group in compound of formula-II is selected from but not limited to sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like. The other solvents used in the present step is selected from dimethylsulfoxide, dimethylformamide, dimethyl acetate, N- methyl pyrrolidone, methanol, and the like, dioxane, toluene, xylene, tetrahydrofuran, dichloromethane, acetonitrile, sulpholane and the like or mixtures thereof. Most preferred bases for replacement of mesyl group and methoxilation reaction are sodium methoxide, sodium tertiary butoxide and potassium tertiary butoxide in combination with methanol.

The solvent used for the extraction is selected from dichloromethane or chloroform, ethyl acetate or toluene. The sodium salt is isolated in ethyl acetate, dichlormethane, acetone, acetonitrile, tetrahydrofuran, toluene or hydrocorbon solvent such as hexane. The magnesium source is selected from magnesium chloride hexahydrate, magnesium hydroxide, magnesium metal or magnesium methoxide.

In most of the prior art processes oxidation step is the final step in the synthesis sequence resulting in esomeprazole product. Esomeprazole acid being an oily liquid, removal of excess oxidizing agents, chiral auxiliary/catalysts and other reaction biproducts from reaction mass and isolation of esomeprazole from reaction mixture requires extractive workup involving multiple extractions followed by concentration and acid base treatments generating lot of environmentally hazardous waste. Concentration of unstable esomeprazole base solutions results in significant decomposition of product affecting the yield and quality. The unstable oily esomeprazole acid limits the purification options and therefore it requires conversion into some salt with a base. Contrary to this the oxidation product of instant invention is a stable crystalline solid which can be isolated by simple filtration and if desired, optionally purified by a simple crystallization to improve the chromatographic and chiral purity.

According to present invention the pharmaceutically acceptable salt is selected from sodium, magnesium, potassium, cesium, calcium, barium, lithium and alkyl ammonium salt.

Yet another embodiment of the present invention is to provide pharmaceutical composition comprising: (a) a therapeutically effective amount of Esomeprazole or its pharmaceutically acceptable salt; and (b) at least one pharmaceutically acceptable carrier.

The following non-limiting examples illustrate specific embodiments of the present invention. They should not construe it as limiting the scope of present invention in any way.

EXAMPLES:

EXAMPLE-I: 4-Methanesulfonyl-2, 3, 5-triimethyl-pyridine 1 -oxide (Formula-VII) Mixture of 4-chloro-2, 3, 5-triimethyl-pyridine-l -oxide (100g), aqueous sodium methane

thiolate (~20%w/w, 306g) and tetra butyl ammonium bromide (5g) were heated to 70-750C and maintained at the same temperature for about 2 to 3 hours. The progress of reaction is monitored by TLC. After completion of reaction, the reaction mixture is cooled to ambient temperature (25-35°C) and sodium tungustate dihydrate (5g) was added at 25-35°C. Subsequently, ~30%w/w hydrogen peroxide (420ml) was added slowly to the reaction mixture at 25-350C and maintained at the same temperature for 2-3 hrs. 4-Methanesulfonyl- 2, 3, 5-triimethyl-pyridine 1 -oxide seed (0.2g) was added and stirring was continued at 25- 35° C for 6-8 hrs to precipitate the product. Further, the reaction mass is cooled to 10-15oC and maintained for 2-3 hrs to complete the precipitation. The product was filtered, washed with cold water (100ml). Product was dried at 25-350C for 2-3 hours to obtain 105 g of the title compound.

EXAMPLE-2: 2-Chloromethyl-4-methanesulfony -3, 5 -dimethyl pyridine Hydrochloride (Formula-IV)

A solution of (4-Methanesulfonyl-2,3,5-trimethyl-pyridine)-1-oxide (105g) in acetic acid (130ml) was slowly added to preheated (65-80°C) acetic anhydride (210 ml), followed by heating to reflux and maintaining at the same temperature for about 40-60 minutes. The reaction mass was concentrated by distillation under reduced pressure. Water (300ml) was added to the concentrate at 25- 35°C and aqueous sodium hydroxide solution (~185ml) added to adjust the pH of reaction mass to ~13.5. Stirring was continued at 25-35°C for about one hour to complete the reaction. Reaction mass pH was adjusted to ~9.5 with hydrochloric acid and product extracted with dichloromethane (650ml). Part of the dichloromethane (~300 ml) was recovered to dehydrate the solution. Dimethylformamide (2 ml) added and followed by dropping of thionyl chloride (75g) over 30-60 minutes.
Stirring of reaction mass continued for 2-3 hours at 25-35°C. Dichloromethane is recovered and the product residue slurried in ethyl acetate (400ml). Product was filtered and washed with ethyl acetate (100ml). The wet product was then dried at 25-35°C to yield 83.2 g of the title compound as hydrochloride salt.

EXAMPLE-3: 2-[[(4-methanesulfonyl-3, 5 -dimethyl-pyridine-2-yl) methyl] thio]-5- methoxy-1H-benzimidazole (Formula- III):

To a mixture of water (400ml) and acetone (160 ml) 2-mercapto-2-methoxy-1 H- benzimidazole (66.5g), 2- chloromethyl-4-methanesulfonyl-3, 5-dimethyl pyridine hydrochloride (100g) was added at 10-20°C. Aqueous sodium hydroxide solution (10% w/w, ~ 550ml) was added at the same temperature to adjust the pH of reaction mass to ~12.5. Stirring was continued for 2-3 hrs at 25-35°C while maintaining the pH. The obtained solid was filtered and washed with water (500ml) and dried at 50-65°C for about 10-12 hours to get 117.5 g of title compound as monohydrate.

EXAMPLE-4: (S)-2-[[(4-Methanesulfonyl-3, 5-dimethylpyridinyl)-2-methyl] sulfinyl)-5- methoxy-1 H-benzimidazole (Formula-ll).

A mixture of 2-[[(4-methanesulfonyl-3,5-dimethylpyridinyl)-2-methyl]thio)-5-methoxy-1H- benzimidazole monohydrate (104g) and cyclohexane (900 ml) was heated to reflux and water was removed azeotropically. Cyclohexane was recovered completely by distillation and ethyl acetate (980ml), (-)-diethyl-d-tartrate (33g) and water (1.0 ml) was added under nitrogen atmosphere. The reaction mass is heated to 55 - 60°C and Ti (IV) isopropoxide (23gm) was added at 55 - 60°C. Stirring continued at the same temperature for about 45-60 min. The reaction mixture was cooled to 25-35°C and diisopropylethylamine (34.2g) was added and maintained at the same temperature for 20-30 min. Cumene hydro peroxide (~80%w/w) dissolved in ethyl acetate (48.4g in 250ml) was then added slowly at 25-35°C over 1.5-2.0 hours. Progress of reaction was followed by TLC. After completion of reaction (sulphide starting material less than 4%, normally -3%), the reaction mixture was cooled to 2-5°C and stirring continued at 2-5°C for 1-2 hours. Product was filtered and washed with pre-cooled ethyl acetate (100ml). Wet product was dried at 50-55°C for ~6 hours to get 86.4 g of title compound having chromatographic purity (by HPLC 99.1%) and chiral purity (by HPLC 96.4%).

EXAMPLE- 5: (S)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl) -1 H-benzimidazole sodium (Esomeprazole sodium).

Potassium tertiary butoxide (85.5 g) was added slowly to pre-cooled methanol (500ml, 5- 10°C). The content was heated to 25-35°C and (S)-2-[[(4-methanesulfonyl-3,5- dimethylpyridinyl)-2-methyl]sulfinyl]-5-methoxy-1 H-benzimidazole (100 g) added in small lots. Reaction mass was further heated to 64-66°C and maintained at the same temperature for 6-8 hours to complete the replacement reaction. The reaction mass was cooled to ~45°C and concentrated by distilling off the solvent under reduced pressure.
Water (800ml) and methylene dichloride (200ml) was added to the concentrated residue slowly at 25-35°C. Reaction mass was stirred for 5-10 minutes, settled and then collected the aqueous layer. The aqueous solution was subjected to carbon treatment and to the clear solution methylene dichloride (400 ml) was added. The contents were cooled to 10-15°C and pH adjusted to 7.7-8.2 with dilute acetic acid (1:2 acetic acid and water) at the same temperature. Methylene dichloride layer was separated and the product was re-extracted from aqueous layer with methylene dichloride (150ml) at 25-35°C. The combined methylene dichloride extract was dried over anhydrous sodium sulfate, and to the resulting dry solution methanolic sodium hydroxide solution (12.2 g in 100ml methanol) was added, stirred for 30-45 minutes and filtered through hyflow bed. The solution was concentrated at below 45°C and there after codistilled with ethyl acetate to complete the removal of methanol/ methylene dichloride at the same temperature. Ethyl acetate (500ml) was added to the concentrate at 25-35°C and stirred at 25-35°C for about 3- 4 hours. Product was filtered and washed with ethyl acetate (100ml). Wet product was dried at 25-35°C for 8-9 hours to get 78.4 g of title compound (Esomeprazole sodium).

EXAMPLE-6: Purification of (S)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl) -1 H-benzimidazole sodium (Esomeprazole sodium).

Esomeprazole sodium crude (100 g) is added at 25-35°C to acetone (800 ml) and the slurry was heated to 50-55°C and maintained for about 1 hour 30 minutes at the same temperature. The slurry was cooled to 10-15°C and maintained for about 2-3 hours at the same temperature. The product cake was filtered and washed with pre-cooled acetone (100ml). The wet product was dried at 50-55°C for about 6-8 hours to get pure 88 g of Esomeprazole sodium.

Example-7: Magnesium salt of (S)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl) -1H-benzimidazole (Amorphous Esomeprazole magnesium).

Esomeprazole sodium (100g) was dissolved in water (500ml) and filtered through a candle filter to get particle free solution. Magnesium chloride hexahydrate (33g) was dissolved in water (600ml) and filtered. The magnesium chloride hexahydrate aqueous solution was added to esomeprazole sodium at 8-12°C over 15-30 minutes and continued stirring for 30- 45 minutes at the same temperature. The precipitated product was filtered and washed with water (200ml). Product was dried at 35-45°C until water content was 6.0-8.5% w/w, to give amorphous Esomeprazole magnesium (74.3g).

EXAMPLE-8: (S)-2-[[(4-Methanesulfonyl-3, 5-dimethylpyridinyl)-2-methyl] sulfinyl)-5- methoxy-1 H-benzimidazole (Formula-II).

A mixture of 2-[[(4-methanesulfonyl-3,5-dimethylpyridinyl)-2-methyl]thio)-5-methoxy-1H- benzimidazole monohydrate (104g) and cyclohexane (900 ml) was heated to reflux and water was removed azeotropically. Cyclohexane was recovered completely by distillation and tetrahydrofuran (1200ml), (-)-diethyl-d-tartrate (109.3g) and water (2.38 g) was added under nitrogen atmosphere. The reaction mass is heated to 57 - 62°C and Ti (IV) isopropoxide (75.3gm) was added at 57 - 62°C. Stirring continued at the same temperature for about 40-50 min. The reaction mixture was cooled to 28-32°C and diisopropylethylamine (34.4g) was added and maintained at the same temperature for ~20 min. Cumene hydro peroxide (~80%w/w) dissolved in tetrahydrofuran (50.5g in 280ml tetrahydrofuran) was then added slowly at 28-32°C over 70-80 minutes. Progress of reaction was followed by HPLC. After completion of reaction (~ 75 minutes, sulphide starting material less than 5%), reaction mass was diluted with toluene (500 ml) and the product was extracted with aqueous ammonia solution (1x800 ml, 2x250 ml). The aqueous extracts were combined and washed with toluene (200 ml). The aqueous solution was cooled to 8-12°C and pH was adjusted to 7.8-8.2 with aqueous acetic acid (1:1v/v).
The precipitated product was filtered and washed with water (2x200ml). Wet product was dried at 50-55°C for ~6 hours to get 82.4 g of title compound having chromatographic purity (by HPLC 98.3%) and chiral purity (by HPLC 94.8%).

EXAMPLE- 9: (S)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl) -1 H-benzimidazole sodium (Esomeprazole sodium).

Potassium tertiary butoxide (91.3 g) was added slowly to a pre-cooled (5-10°C) mixture of acetonitrile (180 ml) and dimethylformamide (180 ml). Methanol (100ml) was added and the contents was heated to 25-35°C and (S)-2-[[(4-methanesulfonyl-3,5-dimethylpyridinyl)-2- methyl]sulfinyl]-5-methoxy-1 H-benzimidazole (100 g) added in small lots. Reaction mass was further heated to 56-60°C and maintained at the same temperature for 3-4 hours to complete the replacement reaction. The reaction mass was cooled to ~5°C and water (1180ml) was added slowly at 5-8°C. Reaction mass was stirred for 5-10 minutes, and methylene dichloride (200ml) was added. Reaction mass was settled and then collected the aqueous layer. The aqueous solution was subjected to carbon treatment and to the clear solution ethyl acetate (400 ml) was added. The contents were cooled to 10-15°C and pH adjusted to 7.7-8.2 with aqueous acetic acid (1:1v/v) at the same temperature. Ethyl acetate layer was separated and the product was re-extracted from aqueous layer with ethyl acetate (250ml) at 25-35°C. The combined ethyl acetate extract was dried over anhydrous sodium sulfate, and to the dried solution methanolic sodium hydroxide solution (12.2 g in 100ml methanol) was added. The solution was stirred for 30-45 minutes and there after it was concentrated at below 45°C and there after co distilled with ethyl acetate to complete the removal of traces of methanol at the same temperature. Ethyl acetate (500ml) was added to the concentrate at 25-35°C and stirred at 25-35°C for about 2- 3 hours. Product was filtered and washed with ethyl acetate (100ml). Wet product was dried at 25-35°C for 8-9 hours to get 68.6 g of title compound (Esomeprazole sodium).

EXAMPLE-10: (S)-5-methoxy-2-[[(4-methoxy-3, S-dimethyl-2-pyridinyl) methyl] sulfinyl) -1 H-benzimidazole sodium (Esomeprazole sodium).

Sodium methoxide (96 g) was added slowly to pre-cooled methanol (550ml, 5-10°C).
The content was heated to 25-35°C and (S)-2-[[(4-methanesulfonyl-3, 5-dimethylpyridinyl)-2- methyl] sulfinyl]-5-methoxy-1 H-benzimidazole (100 g) was added in small lots. Reaction mass was further heated to reflux and continued reflux for 6-8 hours to complete the replacement reaction. The reaction mass was cooled to ~45°C and concentrated by distilling off the solvent under reduced pressure. Water (900ml) and methylene dichloride (200ml) was added to the concentrated residue slowly at 25-35°C.
Reaction mass was stirred for 5- 10 minutes, settled and then collected the aqueous layer.
To the aqueous solution methylene dichloride (400 ml) was added. The contents were cooled to 10-15°C and pH adjusted to 7.7-8.2 with aqueous acetic acid (1:1 v/v) at the same temperature. Methylene dichloride layer was separated and the product was re-extracted from aqueous layer with methylene dichloride (2x150ml) at 25-35°C. The methylene dichloride extracts were combined and dried over anhydrous sodium sulfate. To the resulting dry solution methanolic sodium hydroxide solution (12.2 g in 100ml methanol) was added and stirred for 10-20 minutes. The solution was concentrated at below 45°C and there after co distilled with ethyl acetate to complete the removal of methanol/ methylene dichloride at the same temperature. Ethyl acetate (500ml) was added to the concentrate at 25-35°C and stirred at 25-35°C for about 3- 4 hours. Product was filtered and washed with ethyl acetate (100ml). Wet product was dried at 25-35°C till constant weight to get 73.5 g of title compound (Esomeprazole sodium).

Example-11: Magnesium salt of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl) -1H-benzimidazole (Amorphous Esomeprazole magnesium).

Magnesium chloride hexahydrate (33.4g) was dissolved in water (500ml) and filtered through a micron filter. The solution was cooled to 4-8°C and an aqueous solution of esomeprazole sodium (100g esomeprazole sodium dissolved in 500 ml water) was added slowly at 4-8°C over 25-35 minutes and continued stirring for 40-45 minutes at the same temperature. The precipitated product was filtered and washed with pre-cooled water (4x250ml, 4-8°C). Product was dried at 38-43°C until water content was 6.0-8.5% w/w, to give amorphous Esomeprazole magnesium (84.6g).

We Claim:

1. A process for producing Esomeprazole or pharmaceutically acceptable salts thereof comprising the steps of:

a. reacting 4-chloro-2,3,5-trimethyl-pyridine-l-oxide of formula IX with sodium methane thiolate to give 2,3,5-trimethyl-4-methylsulfanyl-pyridine-1-oxide of formula — VIII, followed by oxidation with an oxidizing agent to obtain 4- methanesulfonyl-2,3,5-trimethyl-pyridine-l- oxide of formula- VII,

b. acetylating the 4-methanesulfonyl-2,3,5-triimethyl-pyridine-1-oxide of Formula VII followed by hydrolysis to obtain alcohol derivative, 2- hydroxymethyl-3,5-dimethyl-4-methanesulfonyl-pyridine of Formula –V

c. chlorinating the 2-hydroxymethyl-3,5-dimethyl-4-methanesulfonyl-pyridine of Formula — V with a chlorinating agent to obtain 2-chloromethyl-4- methanesulfonyl-3,5 -dimethyl pyridine of Formula — IV or its salt

d. condensing the compound of Formula — IV or its salt with 2-mercapto-5- methoxy-1 H-benzimidazole in the presence of a base in a solvent to obtain 2-[[(4-methanesulfonyl-3,5-dimethyl-2-pyridinyl)methyl]thio]-5-methoxy-1H- benzimidazole of Formula-Ill,

e. stereoselectively oxidizing the benzimidazole sulphide of formula-Ill using an optically active reagent in presence of a base, metal catalyst, and oxidizing agent in a solvent to obtain (S)-[[(4-methanesulfonyl-3,5- dimethylpyridinyl)-2-methyl]sulfinyl]-5-methoxy-1H-benzimidazole of Formula- II,

f. reacting benzimidazole sulfoxide of Formula-II with methanol or in combination with other solvent in the presence of a base to get Esomeprazole of Formula I, and

g. Optionally converting to its pharmaceutical^ acceptable salt thereof.

2. The process according to claim 1, wherein the oxidizing agent in step a) is selected from metachloroperbenzoic acid, hydrogen peroxide, cumenehydroperoxide or sodiumhypohalite.

3. The process according to claim 1, wherein the chlorinating agent in step c) selected from thionylchloride, paratoluenesulfonyl chloride, methane sulfonyl chloride or ethane sulfonyl chloride, POCI3, PCI5 or oxalyl chloride.

4. The process according to claim 1, wherein the chlorination in step c) is carried out in a solvent selected from chloroform, methylenedichloride, carbontetrachloride, or toluene.

5. The process according to claim 1, wherein the base in step d) is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate.

6. The process according to claim 1, wherein the solvent used in step d) is selected from water, methanol, ethanol, isopropanol, acetone, methylethylketone, methylisobutylketone, acetonitrile or mixtures thereof.

7. The process according to claim 1, wherein the oxidizing agent in step e) is selected from cumene hydrogen peroxide, metachloroperbenzoicacid, tert-butyl hydroperoxide, benzoyl peroxide or sodium hypohalite.

8. The process according to claim 1, wherein the solvent in step e) is selected from water, hydrocarbons, ethers, ketones, esters, nitriles or mixture thereof.

9. The process according to claim 1, wherein the base in step e) is selected from triethylamine, diisopropylamine, N, N-diisopropylethylamine, dicyclohexylarnine, cyclohexylamine, tri-butylamine, n-butylamine or diisopropyl ethylamine.

10. The process according to claim 1, wherein the optically active reagent in step e) is selected from enantiomerically pure mandelic acid, tartaric acid, diethyl tartaric acid, phenylethylamine, cinchonine, cinchonidine or brucine.

11. The process according to claim 1, wherein the metal catalyst in step e) is selected from barium acetate, strontium acetate, titanium (IV) isopropoxide, vanadium pentoxide, vanadylacetylacetonate, molybdenum (V) isopropoxide or zirconium(IV)isopropoxide.

12. The process according to claim 1, wherein the base in step f) is selected from sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tertiary butoxide, potassium tertiary butoxide

13. The process according to claim 1, pharmaceutical acceptable salt is selected from sodium, magnesium, potassium, cesium, calcium, barium, lithium or alkyl ammonium salt.

14. A process for the preparation of Esomeprazole magnesium, comprising the steps of:

a. reacting benzimiazole sulfoxide of formula-II with methanol or combination with other solvent in the presence of base,

b. converting to sodium salt of Esomeprazole,

c. treating the sodium salt of Esomeprazole with magnesium source, and

d. isolating Esomeprazole magnesium.

15. The process according to claim 14, where in the combination solvent with methanol is selected from dimethylsulfoxide, dimethylformamide, dimethyl acetate, N-methyl pyrrolidone, methanol, and the like, dioxane, toluene, xylene, tetrahydrofuran, dichloromethane, acetonitrile or mixture thereof.

16. The process according to claim 14, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tertiary butoxide or potassium tertiary butoxide.

17. The process according to claim 14, wherein the magnesium source is selected from magnesium chloride, magnesium hydroxide or magnesium methoxide.

18. A pharmaceutical composition comprising: (a) a therapeutically effective amount of Esomeprazole or its pharmaceutically acceptable salt; and (b) at least one pharmaceutically acceptable carrier.