FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION (SECTION 10; RULE 13)
"A NOVEL PROCESS FOR THE OPTICAL PURIFICATION OF PROTON PUMP INHIBITORS AND PHARMACEUTIC ALLY ACCEPTABLE SALTS THEREOF."
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a novel process for the optical purification of enantiomerically enriched 2-(pyridinylmethylsulphinyl)-lH-benzimidazole compounds and their pharmaceutically acceptable salts of Formula 1
wherein R1 to R4 may be selected from H, linear or branched (1-4 C) alkyl, linear or branched (1-4 C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs useful as proton pump inhibitors (PPI). Representative compounds of PPI include compounds of the like of lansoprazole, omeprazole, pantoprazole, rabeprazole, lerninoprazole and other structurally related sulfoxides.Particularly, the present invention provides an improved optical purification of enantiomerically enriched preparation of Esomeprazole and pharmaceuticaHy acceptable salts thereof.
BACKGROUND OF THE INVENTION
2-(Pyridinylmethylsulphinyl)-lH-benzimidazole derivatives and other structurally related sulfoxide compounds of formula 1
wherein R1 to R4 may be selected from H, linear or branched (1-4C) alkyl, linear or branched (1-4C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs are useful as proton pump inhibitors that inhibit gastric acid secretion.
Representative compounds of PPI include compounds of the like of lansoprazole, omeprazole, pantoprazole, rabeprazole, lerninoprazole and other structurally related sulfoxides.The compound omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-

pyridinyl)methyl]sulfmyl]-l H-benzimidazole) is well known as an effective gastric acid secretion inhibitor and is useful as an anti-ulcer agent. Omeprazole has two enantiomeric forms R-omeprazole and S-omeprazole shown below and normally exists as a racemic mixture.

U.S. Patent No. 6,262,085 discloses a process for the preparation of the magnesium salt of S-omeprazole using magnesium metal, methanol, and a catalytic amount of methylene dichloride.
U.S. Patent No. 6,747,155 discloses a process for the preparation of the magnesium salt of esomeprazole trihydrate. The '155 patent also discloses a process for the preparation of esomeprazole magnesium dihydrate Form A and Form B.
U.S. 6,894,066 discloses a process for producing the magnesium salt of S- omeprazole with varying percents of crystallinity and varying amounts of residual solvents in the solid.
U.S.Patent No. 5,929,244 discloses a process for the optical purification of single enantiomers of some 2-sulphinyl-l H-benzimidazole derivatives and another structurally related sulphoxide from the respective enantiomerically enriched preparations thereof. However the patent does not disclose a strategy to arrive directly to a desired salt form of 2-sulphinyl-lH-benzimidazole derivatives and other structurally related sulphoxide with enhanced optical purity. The process for the optical purification of (S)(-)Omeprazole free base as disclosed in examples-1, 2, 3 & 8 of US'244 result in a yield of just about 51%, 20%, 42% and 46% respectively. However the process of the present invention provides a simple and cost-effective solution to arrive at Esomeprazole-Mg salt directly with a yield as high as 60%.The process of the present invention does not necessitate the isolation of the free base, instead directly targets the salt of Esomeprazole and succeeds

in arriving directly at Esomeprazole-Mg salt in high yield and purity unlike the prior art processes that attempt to purify the free base first to afford the free base of desired optical purity first , convert it to an alkali metal salt of the like of Na/K and then convert the alkali metal salt to the desired Mg salt Thus the prior art processes involve multiple steps as well as purification steps while the present process results in reduced reaction steps as well as purification steps as it directly affords the desired alkali/alkaline salt of the PP1 in high yields and purity.
PCT publication WO2003089408 teaches a process for the purification of alkali or alkaline earth metal salts of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl)sulfinyl]-lH-benzirnidazole comprising treatment of the said alkali or alkaline earth metal salt having a sulfone impurity with a solvent system comprising an organic solvent selected from ketone and a nitrile, and isolating the alkali or alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyI-2-pyridinylmethyl)sulfinyl]-lH-benzimidazole which is substantially free of sulfone impurity.
PCT publication WO2004052882 provides a process for preparing optically pure PPI having a sulphinyl structure characterized in that the oxidation of the corresponding sulphide is carried out in the presence of a chiral zirconium complex or a chiral hafnium complex, the chiral auxiliary used being an optically pure tartaric acid derivative.
PCT publication WO2007013743 discloses a method of preparing optically pure esomeprazole, and its salt, from omeprazole by applying an improved optical resolution process by dissolving (S)-(-)-binol, a weak base and the racemic form of omeprazole in a mixture of a water-compatible organic solvent and water at a high temperature, cooling the mixed solution to crystallize the inclusion complex of esomeprazole and (S)-(-)-binoI, and removing the (S)-(-)-binol moiety from the crystallized inclusion complex. The present process avoids complex inclusion complex of the like of (S)-(-) binol, instead the present process succeeds in arriving directly to the desired Mg salt of Esomeprazole using simple and commercially available reagents and solvents.

U.S. Patent Application Publication No. 2007/0259921 discloses processes for the preparation of different crystalline forms -J, K, L, M, and N of esomeprazole sodium and a crystalline form of esomeprazole magnesium. The process of the present invention does not necessitate isolation or additional purification of the Na salt, as in the process of present invention, the optically enriched Na salt of the PPI is used directly for further conversion to its pharmaceutically acceptable salt.
There still exists a need of a commercially viable process for making crystalline esomeprazole magnesium hydrates, more particularly the dihydrate and trihydrate forms. Continued efforts in this direction by the present inventors resulted in the present improved process for the preparation of salts of proton pump inhibitors of enhanced optical purity directly unlike the prior art processes which attempted to synthesise the free base of enhanced optical purity first followed by preparation of salts. The novel process as designed by the present invention involves direct preparation of enantiomerically enriched optically pure salts of 2-(pyridinylmethylsulphinyl)-1H-benzimidazoie derivatives and other structurally related sulfoxide compounds of formula 1
wherein R1 to R4 may be selected from H, linear or branched (1-4C) alky], linear or branched (1-4C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs as aqueous solutions of their salts with enhanced optical purity directly and if required converting them into other desired salts.Unlike the prior art processes that follow the conventional prior art strategy of purification of the free base of enhanced optical purity first followed by alkali salt formation and then conversion to its pharmaceutically acceptable salt (alkaline earth/other), the process of the present invention directly aims at obtaining the target salt of enhanced optical purity directly during the workup stage after the enantioselective oxidation of the prochiral sulfide. Thus the process of the present invention is an economically viable process with emphasis on reduced reaction time cycle via fewer reaction steps and consequently lesser

solvents, reduced costs, time and labour and thus economically viable and suitable to be implemented on an industrial scale.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the optical purification of enantiomerically enriched 2-(pyridinylmethylsuIphinyi)-lH-benzimidazole compounds and their pharmaceutically acceptable salts of Formula 1
wherein R to R may be selected from H, linear or branched (1-4 C) alkyl, linear or branched (3-4 C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs useful as proton pump inhibitors. Representative compounds of PPI include compounds of the like of lansoprazole, omeprazole, pantoprazole, rabeprazole, lerninoprazole and other structurally related sulfoxides. Particularly, the present invention provides a novel method for the optical purification of enantiomerically enriched preparation of esomeprazole and pharmaceutically acceptable salts thereof.
The key aspects of the present invention can be summarized by the following:
A. A process for the optical purification of an enantiomerically enriched preparation of
a salt of a compound, according to formula I,
wherein R1 to R4 may be selected from H, linear or branched (I-4C) alkyl, linear or branched (1-4C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs characterized in that the process comprises the steps of
a) providing a solution of an enantiomerically enriched salt of a compound according to formula 1 , in favour of a salt of either its (+) or (-) enantiomer in an organic solvent ,

b) optionally seeding the reaction mass with the salt of its isomer or racemate and
filtering off the precipitated salt of the undesired isomer or racemate,
c) adding water , separating the organic layer and recovering an aqueous solution of
the salt of the desired single enantiomer with enhanced optical purity ,
d) optionally converting the aqueous solution of the salt of the desired single
enantiomer with enhanced optical purity, from step(c) above to another salt of the same
compound.
B. The process according to A above, wherein the optical purification is preferably applied to a salt of a compound of formula (a):

C. The process according to A above, wherein the optical purity of (+) or (-) isomers of
compound of Formula (I) is enhanced.
D. The process according to A above, wherein the enantiomerically enriched
preparation is treated with a mixture of organic solvents.
E. The process according to A above, wherein the organic solvent is a mixture
comprising ketones, esters, alcohols, nitriles, hydrocarbons, ethers and mixtures thereof.
F. The process according to E above, wherein the organic solvent mixture is
preferably a ketone-hydrocarbon-alcohol mixture.
G. The process according to F above, wherein the organic solvent mixture is preferably
a Methyl ethyl ketone-Toluene-Methanol or a 2-butanone-Toluene-Methanol mixture.
H. The process according to A above, wherein the salt is selected from alkali and
alkaline salts.
I. The process according to H above, wherein the salt is preferably a Na or Mg salt.
J. A process for the optical purification of an enantiomerically enriched preparation of a
salt of a compound, according to formula (a)

characterized in that the process comprises the steps of
a) providing a solution of an enantiomerically enriched salt of a compound according
to formula (a), in favour of a salt of either its (+) or (-) enantiomer in an organic solvent,
b) optionally seeding the reaction mass with the salt of its racemate and filtering off the precipitated salt of the undesired isomer or racemate,
c) adding water , separating the organic layer and recovering an aqueous solution of the salt of the desired single enantiomer with enhanced optical purity ,
d) optionally converting the aqueous solution of the salt of the desired single enantiomer with enhanced optical purity, from step(c) above to the desired salt of the same compound.
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Unless defined 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 also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
The present invention provides an improved process for the optical purification of enantiomerically enriched 2-(pyridinylmethylsulphinyl)-lH-benzimidazole compounds and their pharmaceutically acceptable salts of Formula 1
wherein R1 to R4 may be selected from H, linear or branched (1-4C) alky I, linear or branched (1-4C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs useful as proton pump inhibitors. Representative compounds of PP1 include compounds of the like of lansoprazole, omeprazole, pantoprazole, rabeprazole, lerninoprazole and other structurally related

sulfoxides.Particularly, the present invention provides an improved optical purification process of enantiomerically enriched preparation of Esomeprazole and pharmaceutically acceptable salts thereof.
The enantiomerically enriched preparation of compounds of formula 1 may be prepared by any known suitable prior art process such as for example by an enantioselective oxidation process of US Patent 5,948,789.
In a preferred embodiment the alkali or alkaline earth metal salt of S-enantiomer of 5 -methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl) sulfinyl]-lH-benzimidazole was prepared according to the enantioselective catalytic oxidation process known in the art and then purified by purification process of the present invention by treatment with the novel solvent system of the present invention.
In an embodiment of the present invention, optically enriched Esomeprazole was obtained by enantioselective oxidation of its corresponding prochiral sulfide intermediate with Chromium trioxide oxidizing agent in the presence of a chiral Ti (IV) isopropoxide-Diethyltartarate complex and Triethyl amine base in toluene as the reaction solvent.
The reaction mixture after enantiomeric oxidation may be worked up by standard procedures obvious to a person skilled in the art. In a preferred embodiment of the process of the present invention, the reaction was worked up by quenching with methanol and addition of aqueous solution of NaOH in water. The reaction mass was treated with charcoal, filtered under hyflo, water added and the organic layer was separated.DCM was added to the combined water extracts and the pH adjusted to about 7.0 to 8.5 with acetic acid and the organic layer separated.The combined organic layer was dried and vacuum filtered to provide an enantiomeric excess of esomeprazole.
The organic solvent suitable for optical enrichment of the desired PPI may be selected from a group comprising ketones, esters, alcohols, nitrites, hydrocarbons, ethers and the like or mixtures thereof. Preferably the organic solvent is a mixture of a ketone-hydrocarbon-alcohol.

In a preferred embodiment of the process of the present invention, the free esomeprazole base in enantiomeric excess was dissolved in a solvent mixture comprising Ethyl methyl ketone-Toluene.In another preferred embodiment, the free esomeprazole base in enantiomeric excess was dissolved in a solvent mixture comprising 2-butanone-Toluene.The solution was treated with a solution of sodium hydroxide in Methanol and the reaction mixture seeded with Na salt of the undesired R-isomer and the subsequent hazy mixture stirred at 0-5°C and the precipitated (R)-Na salt of omeprazole was then filtered off. The organic filtrate was then treated with water and the aqueous layer containing the desired Na salt of (S)-Omeprazole was separated, filtered through hyflo and used for the next step for conversion to its corresponding Mg salt.
The alkali metal salt of S-enantiomer of S-methoxy-2-[(4-rnethoxy-3,5-dimethyl-2 pyridinylmethyl)sulfmyl]-lH-benzimidazo1e substantially free of sulfone impurity obtained by following the process of the present invention can be converted to alkaline earth metal salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2 5 pyridinylmethyl)sulfinyl]-lH-benzimidazole substantially free of sulfone impurity by reacting with an alkaline earth metal source. The alkaline earth metal source that may be used may be selected from calcium, magnesium or barium salt and the like. For example, magnesium salt of S-enantiomer of 5-methoxy-2-[(4-methoxy-3, 5-dimethyl-2 pyridinylmethy!) sulfinyl]-lH-benzimidazole substantially free of sulfone impurity may be prepared from the sodium salt of S-enantiomer of 5-methoxy-2-[ (4-methoxy-3,5 dimethy3-2-pyridinylmethyl)sulfinylJ-lH-benzimidazole by following the process of the present invention.
The present invention provides enantiomerically enriched optically pure alkali or alkaline earth metal salts of S-enantiomer of 5 methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinylmethyl) sulfnyl]-lH-benzimidazole substantially free of sulfone impurity.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

Examples:
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
Example-l- Esomeprazole-Me.2 H?0
Stage 1: Preparation of Stage-1 Intermediate
2-mercapto-5-methoxy benzimidazole (83.10 gm) was added at 30-35°C to a solution of NaOH (42 gm) in Methanol (200 ml) and Water (100 ml) to form a 1st reaction mass. A solution of 2-Chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride (100 gm) in methanol (50 ml) and water (150 ml) mixture was added to the 1st reaction mass in 90-120 min at 30-35°C and the reaction mass stirred for 10-15 hrs and the reaction followed by TLC and HPLC.The reaction mass was worked up by addition of Water(900 ml), stirred for 2 hours, and filtered, washed with water(2x300 ml); suck dried, filtered and dried at 42-46C for 24-30 hrs in an oven to afford stage-1 intermediate with M/C content < 0.5% and a Dry Wt: - 130 gm
Stage 2: Oxidation of Esomeprazole Stage 1
Stage 1 intermediate (100 gm) in toluene (300 ml) was charged in a 1L 4 necked RBF at 25-30°C and the reaction mass heated to 52-55°C. (-) Diethyl-D-tartarate (12.52 gm) was

added of at 52-55°C reaction mass stirred for 30 min at 50-52°C. followed by addition of Titanium (IV) isopropoxide (8.63 gm) at 52-55°Cand the reaction mass stirred for 60 min at 52-55°C. The reaction mass was cooled to 27-30°C followed by addition of Triethyl amine {6.40 gm) at 27-30°C and addition of cumene hyroperoxide (55.43 gm) drop wise in 90-120 min at 27-30°C, the reaction mass stirred for 2 hr at 27-30°C. Methanol was charged in the reaction mass (100 ml) and used for next step.
Stage 3: Preparation Esomeprazole stage 3 (Eso.sodium salt)
The methanolic reaction mass from Stage-2 was stirred for 30 min, quenched the reaction mass in alkaline water (20 gm NaOH in DM water (400 ml). (pH= 12-13). Activated charcoal (10 gm) and hyflo (10 gm) was charged and the reaction mass stirred for 30 mins at 25-30°C. The reaction mass was stirred for 30 min at 25-30°C. The reaction mass filtered on hyplo bed, water (200 ml)washed .Allowed to settle and organic layer separated.The aq. layer was charged back in 4 L flask. Charged with toluene (100 ml), Stirred for 15 min, allowed to settle and organic layer. (Organic layer contains stage-I) separated. Charged with MDC (300 ml) and a pH=7.0-8.5 was adjusted with aq.acetic acid (50ml acetic acid in 50 ml water) and stirred for 15 min, Allowed to settle and organic layer separated.The Aq. Layer was charged back in 4 n flask, Charged with MDC (100 ml).and stirred for 15 min, Allowed to settle and organic layer separated.The Combined organic layer were washed with DM water (300 ml X 3),stirred for 15 min Allowed to settle and organic layer separated.The combined organic layer dried with sodium sulphate (20 gm), the organic layer filtered, and the organic layer distilled out completely under vacuum to afford the free base residue.. Wt. of residue: 100 gm
The above residue was dissolved in a solution of Sodium hydroxide (13gm) in methanol (75 ml) and charged to a solution of free base in MEK (400 ml) and Toluene (400 ml), solution. The reaction mass was seeded with R-isomer sodium salt (5 mg). and the hazy reaction mass stirred for 5 hr at 20-25°C, cooled to 0-5°C and stirred for 2 hr at 0-5°C. The solid filtered under nitrogen; washed with chilled toluene (50 ml) suck dried and the solid unloaded. Wet wt:-25 gm (R-isomer followed out).The solid dried under vacuum at

50-55°C for 12 hr.Dry wt. =11-12 gm. SOR: -2 to -4°. The filtrate containing S-
isomer was charged back into flask, charged with DM water (500 mi),stirred for 30 min, allowed to settle and the aq.layer separated.The organic layer was charged back into flask, charged with DM water (200 ml),stirred for 30 min,allowed to settle and the aq.layer separated.
The combined aq.layer was filtered through hyflo bed and washed with DM water (100 ml) and the clear filtrate used for the next step.
Stage 4: Preparation of Esomeprazole -Mg.
Charged the clear filtrate in 4 neck RBF followed by magnesium chloride hexahydrate (24.89 gm) in DM water 200 ml, dropwise in 30 min and the reaction mass stirred for 5 hrs.The solid was filtered, washed with DM water (200 ml),suck dried and the wet cake unloaded, charged back into flask along with DM water (1000 ml) and the reaction mass stirred for 3 hr.The solid was filtered , washed with DM water (200 ml), suck dried, washed with Acetone (150 ml), suck dried and unloaded. The wet cake was charged in acetone (450 ml), stirred for 30 mins and the solid filtered, washed with acetone (100 ml), suck dried and unloaded. Wt: - 60 gm.
Example: 2
5-methoxy~2-|(S)-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]
benzimidazole, Magnesium dihydrate.
5-methoxy-2-[(S)-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] thio] Benzimidazole (100 gm, 0.3 mole) was charged in Toluene (300 ml), reaction mass was heated to 55°C, (-) diethyl-D-tartarate (12.52 gm, 0.2 mole) was added, and then titanium (IV) isopropropoxide (8.63 gm, 0.1 mole),followed by addition of triethyl amine 6.4 gm (0.21 mole) at 30°C. Cumene hydroperoxide (55gm, 1.2 mol) at 25-30°C.was slowly added after stirring for 2 hrs, HPLC analysis of the reaction mixture at this stage revealed (94%) of chiral enantiomer. Methanol(50 ml) was charged in the reaction mass, the reaction mass quenched in 50% sodium hydroxide solution (400ml),the product extracted in aq.layer and the aq.layer neutralized by acetic acid (25 ml), the product extracted in

methylene chloride (400 ml) and solvent distilled out under vacuum. To the residue was added 2-butanone (200 ml) and toluene (400 ml) and 17% methanolic sodium hydroxide solution (75ml) and the reaction mass seeded with R-isomer of Esomeprazole (sodium salt). Unwanted sodium salt of R- isomer was precipitated out with a chiral purity of 79%, which was filtered out. HPLC of the filtrate revealed a chiral purity of 99%. The filtrate was charged in water (700 ml) and the product extracted in aq. Layer.An aq. solution of magnesium chloride (28 gm in 400ml of water) was added to the aq. Layer containing Esomeprazole sodium salt and the precipitated product was filtered . The product dissolved in methanol (800 ml) and the solvent distilled out under vacuum followed by removal of insoluble material to afford a residue. Acetone (250 ml) was charged, the precipitated product was filtered as Esomeprazole magnesium salt (58gm) with a chiral HPLC purity of 99.90%.
Example: 3
5-methoxy-2-|(S)-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl| sulfinyl)
benzimidazole, Magnesium dihydrate.
5-methoxy-2-[(S)-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] thio] Benzimidazole (100 gm, 0.3 mole) was charged in Toluene (300 ml), reaction mass was heated to 55°C, (-) diethyl-D-tartarate (12.52 gm, 0.2 mole) was added, and then titanium (IV) isopropropoxide (8.63 gm, 0.1 mole), followed by addition of triethyl amine 6.4 gm (0.21 mole) at 30°C. Cumene hydroperoxide (55gm, 1.2 mol) at 25-30°C.was slowly added after stirring for 2 hrs, HPLC analysis of the reaction mixture at this stage revealed (95%) of chiral enantiomer. Methanol(50 ml) was charged in the reaction mass, the reaction mass quenched in 50% sodium hydroxide solution (400ml),the product extracted in aq.layer and the aq.layer neutralized by acetic acid (25 ml), the product extracted in methylene chloride (400 ml) and solvent distilled out under vacuum. To the residue was added 2-butanone (200 ml) and toluene (400 ml) and 17% methanolic sodium hydroxide solution (75ml) and the reaction mass seeded with R-isomer of Esomeprazole (sodium salt). HPLC of the filtrate revealed a chiral purity of 96%. The filtrate was charged in water (700 ml) and the product extracted in aq. Layer.An aq. solution of magnesium

chloride (28 gin in 400ml of water) was added to the aq. Layer containing Esomeprazole sodium salt and the precipitated product was filtered . The product dissolved in methanol (800 ml) and the solvent distilled out under vacuum followed by removal of insoluble material to afford a residue. Acetone (250 ml) was charged, the precipitated product was filtered as Esomeprazole magnesium salt (58gm) with a chiral HPLC purity of 99.90%.

WE CLAIM:
l.A process for the optical purification of an enantiomerically enriched preparation of a salt of a compound, according to formula I,
wherein R1 to R4 may be selected from H, linear or branched (1-4C) alkyl, linear or branched (1-4C) alkoxy, aryl, aryloxy and their halo or alkoxy substituted analogs characterized in that the process comprises the steps of
a) providing a solution of an enantiomerically enriched salt of a compound according to formula 1 , in favour of a salt of either its (+) or (-) enantiomer in an organic solvent ,
b) optionally seeding the reaction mass with the salt of its isomer or racemate and filtering off the precipitated salt of the undesired isomer or racemate,
c) adding water , separating the organic layer and recovering an aqueous solution of
the salt of the desired single enantiomer with enhanced optical purity ,
d) optionally converting the aqueous solution of the salt of the desired single
enantiomer with enhanced optical purity, from step (c) above to another salt of the same
compound.
2.The process according to Claiml, wherein the optical purification is preferably applied to a salt of a compound of formula (a):

3.The process according to Claim 1, wherein the optical purity of (+) or {-) isomers of compound of Formula (I) is enhanced.
4.The process according to Claim 1, wherein the enantiomerically enriched preparation is treated with a mixture of organic solvents.

5.The process according to Claim 1, wherein the organic solvent is a mixture comprising
ketones, esters, alcohols, nitriles, hydrocarbons, ethers and mixtures thereof.
6. The process according to Claim 5, where in the organic solvent mixture is preferably
a ketone-hydrocarbon-alcohol mixture.
7.The process according to Claim 6, wherein the organic solvent mixture is preferably a
Methyl ethyl ketone-Toluene-Methanol or a 2.butanone-Toluene-Methanol mixture.
8.The process according to Claim 1, wherein the salt is selected from alkali and alkaline
salts.
9.The process according to Claim 8, wherein the salt is preferably a Na or Mg salt.
10. A process for the optical purification of an enantiomerically enriched preparation of
a salt of a compound, according to formula (a)


characterizeq in that the process comprises the steps of

providing a solution of an enantiomerically enriched salt of a compound according to formula (a), in favour of a salt of either its (+) or (.) enantiomer in an organic solvent,
b) optionally seeding the reaction mass with the salt of its racemate and filtering off the precipitated salt of the undesired isomer or racemate,
c) adding water , separating the organic layer and recovering an aqueous solution of the salt of the desired single enantiomer with enhanced optical purity ,
d) optionally converting the aqueous solution • 0f the salt of the desired single enantiomer with enhanced optical purity, from step(c) above to the desired salt of the same compound.