Title of Invention

A PROCESS FOR PREPARING 2-[PYRIDINYL]SULFINYL-SUBSTITUTED BENZIMIDAZOLES

Abstract

A process for the preparation of 2-[(pyridinyl)methyl]sulfinyl-benzimidazole of formula (I) or apharmaceutically acceptable salt, hydrate, or solvate thereof wherein R1 is selected from the group consisting of hydrogen or substituted or unsubstituted C1-C4alkoxy; R2 and R4 are independently selected from the group consisting of hydrogen, C1-C4alkyl or C1-C4alkoxy; R3 is selected from the group consisting of substituted or unsubstituted C1-C4alkoxy is disclosed. The process comprises oxidizing thioether compound of formula (II) in absence of base wherein R1,R2,R3 and R4 is same as described above, with N-halosuccinimide in presence of water, optionally converting into a pharmaceutically acceptable salt, hydrate, or solvate thereof.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patent Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION AN IMPROVED PROCESS FOR OXIDATION OF THIOETHER" We, CADILA HEALTHCARE LTD., a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India. The following specification describes the invention: AN IMPROVED PROCESS FOR OXIDATION OF THIOETHER Field of the Invention: The present invention relates to a process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. More particularly, the present invention relates to the process for oxidation of 2-[(pyridinyl)methyl}thio-substituted benzimidazoles of Formula (II). The present invention further relates to the process for preparing enantioselective synthesis of the single enantiomers of 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (I) a pharmaceutically acceptable salt, hydrate, or solvate thereof in an enantiomerically enriched form. ###STR( )###STR Background and Prior art: There are a large number of patents and patent applications disclosing different substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazoles. This class of compounds has properties making the compounds useful as inhibitors of gastric acid secretion and generally known as proton pump inhibitors. For example the compound (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-lH-benzimidazole), with the generic name omeprazole, is described in EP 5129. It is marketed under the brand name Prilosec® for treatment of duodenal ulcer, gastric ulcer and GERD; maintenance of healing of errosive esophagitis, and long term treatment of pathological hyperscretory conditions Rabeprazole is another compound of the same class and chemically known by 2-[[[(4-(3-methoxypropoxy)-2-methyl-2-pyridinyl]methyl]sulfinyl-lH-benzimidazoles. It was reported in U.S. Pat. No. 5045552 and marketed in the United States under the brand name Aciphex® for healing of erosive or ulcerative GERD, maintenance of healing of GERD and treatment of symptomatic GERD. 2 Pantoprazole is the active ingredient of a pharmaceutical product that is marketed in the United States by Wyeth-Ayerst Inc. under the brand name Protonix®. Pantoprazole is chemically represented (5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-lH-b- enzimidazole. Pantoprazole useful for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis and pathological hypersecretory conditions including Zollinger-Ellison syndrome. Lansoprazole another compound represented by 2-[[[3-methyl-4(2,2,2,-triflouroethoxy)-2-pyridiyl]methyl]sulfinyl]-lH-benzimidazole and reported in U.S Patent No. 4628098. It is marketed under the brand name Prevacid® for short-term treatment of duodenal ulcer, H. Pylori eradication to prevent recurrence of duodenal ulcer and maintenance of healed duodenal ulcers. These compounds as well as structurally related sulphoxides, have a stereogenic centre at the sulphur atom and thus exist as two optical isomers, i.e. enantiomers. If there is another stereogenic centre in the molecule, these compounds can exist as pairs of enantiomers. Corresponding sulphides of such compounds which already contain a stereogenic centre are not pro-chiral compounds, but chiral compounds. However, the sulphur atom in these compounds does not have asymmetry and therefore they are referred to as pro-chiral sulphides in respect of this invention. Even though this class of chiral sulphoxides has been discussed in the scientific literature since the late seventies, there is not yet any efficient asymmetric process described for the synthesis of the single enantiomers thereof. The single enantiomers of pharmacologically active compounds have met an increased interest in the last years because of improved pharmacokinetic and biological properties. Therefore, there is a demand and need for an enantioselective process that can be used in large scale for the manufacture of the single enantiomers of pharmacologically active compounds, such as for instance optically pure, substituted 2-(2-pyridinylmethylsulphinyl)-1 H-benzimidazoles. The preparation of 2-[(pyridinyl]methyl]sulfinyl-susbstituted benzimidazoles of Formula (I) by oxidation of compound of Formula (II) is generally known and is discussed in U.S. patent Nos. 5045552, 4508905 and 4628098. 3 ###STR( )###STR However, it has been reported that the sulfone compound of formula (III) is also generated because of over oxidation of thioether compound of formula (II). ###STR( )###STR Various methods employing various different oxidants to perform this oxidation are known. For example, Canadian Patent No. 1,263,119 describes the use of hydrogen peroxide over a vanadium catalyst (such as vanadium pentoxide, sodium vanadate and vanadium acteylacetonate). Canadian Patent No. 1,127,158 similarly describes the use of peracids, peresters, ozone, etc. European Patent Application, Publication No. 533,264 describes the use of magnesium monoperoxyphthalate as the oxidizing agent. PCT Publication No. W091/18895 describes the use of m-chloroperoxy benzoic acid as the oxidizing agent. GB Pat. No. 2,069,492 generally describes this acid and other peroxy acids in the oxidation of substituted (phenylthiomethyl)pyridines. According to example 32 of 505552, thioether is oxidized by using 0.96 equivalent (on a purity basis) of m-chloroperbenzoic acid, to produce sulfoxide at a yield of 80%, which is not an industrially satisfactory yield. Depending on the reaction conditions, disadvantageously, the reaction does not ceased at the stage of sulfoxide production but further proceeds to a side reaction where a part of the produced sulfoxide is furthermore oxidized to sulfone as shown below. When sulfone is formed, there is a problem not only that the yield of the objective sulfoxide is reduced, but also that is difficult to separate and purify them, since there is a close resemblance in physicochemical property between the two. Additionally, the oxidation is conducted in dichloromethane (methylene chloride), but from a viewpoint of environmental strategies and regulatory aspects, use of halogenated hydrocarbon solvents is preferably avoided.Moreover, m-chloroperbenzoic acid is expensive, it is extremely disadvantageous from a viewpoint of the production cost. 4 US 5374730 relates to omeprazole and lansoprazole, in particular, two novel synthetic methods for their preparation. According to the process, amide analogues of the thioether compounds are oxidized to the corresponding sulfinyl compounds by using hydrogen peroxide as oxidizing agent. US 6313303 Bl discloses the process for preparing Rabeprazole, Lansoprazole and other related compounds by oxidation thioether precursor compound with N-halosuccinimide, l,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate in the presence of a base. Accordingly, use of base in the oxidation process is essential. However, the isolation of the desired compound is tedious and costlier. There has been a long felt need for efficient and safe methods for the selective oxidation of thioether compound of formula (II) The present invention provides efficient, safe and easy to handle process for preparing substituted 2-(2-pyridylmethyl) sulfinyl- lH-benzimidazoles of formula (II). Object of the Invention: It is an object of the invention to provide an improved process for preparing 2-(2-pyridylmethyl) sulfinyl-benzimidazoles of formula (II). Another object of the present invention to provide a process for preparing 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazoles of formula (II), which is simple, easy to handle and cost effective. Detailed Description of the Invention: According to the present invention, there is provided a process for preparing 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof ###STR( )###STR Formula (I) wherein Ri is selected from the group consisting of hydrogen or substituted or unsubstituted Ci.C4alkoxy; R2 and R4 are independently selected from the group consisting of hydrogen, Ci-C4alkyl or Ci-C4alkoxy; R3 is selected from the group consisting of substituted or unsubstituted Ci-C4alkoxy; which comprises oxidizing thioether compound of formula (II) in absence of base 5 ###STR( )###STR Formula (II) wherein Ri, R2, R3 and R4 is same as described above, with N-halosuccinimide in presence of water, optionally converting in to a pharmaceutically acceptable salt, hydrate, or solvate thereof Substantially as hereinbefore described a process according to the present invention can further comprise conversion of a 2-[(pyridinyl)methyl]sulfinyI-substituted benzimidazole compounds of formula (I) to a suitable pharmaceutically acceptable salt, hydrate or solvate thereof, in particular a pharmaceutically acceptable salt form. Suitable salts include those with alkali or alkali earth metals, for example Mg, Ca, Na, K or Li salts, in particular Mg or Na salts. In the case where Ri represents substituted alkoxy substantially as hereinbefore described, suitable substituents include one or more halo substituents, such as one or more fluoro substituents. In the case where R3 represents substituted alkoxy substantially as hereinbefore described, suitable substituents include one or more halo substituents, such as one or more fluoro substituents, or one or more alkoxy substituents, such as C1-C3 alkoxy, especially methoxy. In the preferred embodiment, Ri is selected from hydrogen atom, methoxy group or difluoromethoxy group; represents methyl group or methoxy group; R2 represents methyl group or methoxy group; R3 represents 3-methoxypropoxy group, methoxy group or 2,2,2-trifluoroethoxy group; and R4 represents hydrogen atom or methyl group. A preferred compound prepared according to a process of the present invention is lansoprazole, wherein in formula (I) R4 represents methyl, R3 represents trifluoroethoxy, R2 represents hydrogen and Ri represents hydrogen. A further preferred compound prepared according to a process of the present invention is omeprazole, wherein in formula (I) R4 represents methyl, R3 represents methoxy, R2 represents methyl and Ri represents methoxy. 6 A further preferred compound prepared according to a process of the present invention is pantoprazole, wherein in formula (I) R4 represents methoxy, R3 represents methoxy, R2 represents hydrogen and R1 represents difluoromethoxy. A further preferred compound prepared according to a process of the present invention is rabeprazole, wherein in formula (I) R4 represents methyl, R3 represents –OCH2CH2CH2OMe, R2 represents hydrogen and R1 represents hydrogen. In the preferred embodiment, the present invention provides an improved process for oxidation of (2- [[[4-(3-methoxy-propoxy)3-methyl-2-pyridinyl]methyl]-thio]-lH-benzimidazole, to the corresponding (2-[[[4-(3-methoxy-propoxy)3-methyl-2-pyridinyl] methyl]-sulfinyl]-lH-benzimidazole or a pharmaceutically acceptable salt, hydrate, or solvate thereof In the preferred embodiment, the present invention provides an improved process for oxidation of (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]thio]-lH-benzimidazole to the corresponding (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]-sulfmyl]-lH-benzimidazole or a pharmaceutically acceptable salt, hydrate, or solvate thereof In the preferred embodiment, the present invention provides an improved process for oxidation of ((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]-thio]-lH-benzimidazole, to the corresponding ((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]-sulfinyl]-lH-benzimidazole or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In the preferred embodiment, the present invention provides an improved process for oxidation of ((5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyI)methyl]thio]-lH-benzimidazole, to the corresponding ((5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl]-lH-benzimidazole or a pharmaceutically acceptable salt, hydrate, or solvate thereof According to the embodiment of the present invention, N-halosuccinimide is selected from N-bromosuccinimide, N-chlorosuccinimide or mixtures thereof. The preferred N-halosuccinimide is N-chlorosuccinimide. According to the present invention, N-halosuccinimide in absence of base in presence of aqueous medium in-situ generates hypochlorous or hypobromous acid as a strong oxidizing agent for the oxidation of thioether linkage in order to obtain highly pure 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of formula (II). 7 According to another embodiment of the present invention, oxidation of thioether compound of formula (II) is carried out any solvent inactive to compound of formula (II), or Formula (I). Preferably oxidation is carried out in alcohol selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, hydrocarbon selected from toluene, xylene, ether selected from diethyl ether, diisopropyl ether, tetrahydrofuran, ester selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, dimethylformamide, dimethyl sulfoxide or mixture thereof. In the preferred embodiment of the present invention, N-halosucciamide used in an amount of 1 molar equivalent or less of the thioether compound of formula (I). According to another aspect of the present invention, there is provided a process for process for preparing substantially pure 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof ###STR( )###STR Formula (I) wherein R1 is selected from the group consisting of hydrogen or substituted or unsubstituted Q.C4alkoxy; R2 and R4 are independently selected from the group consisting of hydrogen, C\-C4alkyl or d-C4alkoxy; R3 is selected from the group consisting of substituted or unsubstituted Ci-C4alkoxy, which comprising the steps of 8 (a) oxidizing thioether compound of formula (II) in absence of base ###STR( )###STR wherein R\, R2, R3 and R4 is same as described above, with N-halosuccinimide in presence of water (b) treatment with suitable organic solvent to extract organic layer (c) treating said organic layer with alkali solution to extract aqueous layer (d) adjusting pH of said aqueous layer to about 8 to about 9 with (e) treatment with suitable organic solvent to extract organic layer, isolating the compound, optionally converting to its pharmaceutically acceptable salt, hydrate, or solvate thereof The organic solvent used in the extraction can be selected from halogenated solvent such as methylene dichloride, carbon tetrachloride, chloroform, esters such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, alcohol selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, hydrocarbon selected from toluene, xylene, haptane, hexane, cyclohexane, ether selected from diethyl ether, diisopropyl ether, tetrahydrofuran or mixtures thereof Alkaline solution used in step (c) is selected from the aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium fer-butoxide. After the treatment with Alkaline solution aqueous layer is extracted and further treated with mild acid to bring the pH in the range of about 8 to about 9. Mild acid used for pH adjustment is preferably acetic acid. The substantially pure compound of formula (I) is further isolated by well know techniques used in the art such as filtration, concentration followed by drying. According to another embodiment of the present invention, there is provided a process for preparing 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of Formula (I) or or a pharmaceutically acceptable salt, hydrate, or solvate thereof in the form of a single enantiomer or in an enantiomerically enriched form ###STR( )###STR 9 Formula (I) wherein R1 is selected from the group consisting of hydrogen or substituted or unsubstituted QX^alkoxy; R2 and R4 are independently selected from the group consisting of hydrogen, Q-C4alkyl or Ci-C4alkoxy; R3 is selected from the group consisting of substituted or unsubstituted Q-C4alkoxy, which comprises oxidizing thioether compound of formula (II) in absence of base ###STR( )###STR Formula (II) wherein R1, R2, R3 and R4 is same as described above, with N-halosuccinimide in presence of water, a chiral titanium complex, optionally converting into a pharmaceutically acceptable salt, hydrate, or solvate thereof The titanium complex suitable for catalysing the process of the invention is prepared from a chiral ligand and a titanium(IV) compound such as preferably titanium(IV)alkoxide, and optionally in the presence of water. An especially preferred titanium(IV)alkoxide is titanium(IV)isopropoxide or -propoxide. The amount of the chiral titanium complex is not critical. An amount of less than approximately 0.50 equivalents is preferred and an especially preferred amount is 0.05-0.30 equivalents. Surprisingly, even very low amounts of complex, such as for instance 0.04 equivalents may be used in the processes according to the present invention with excellent result. This improved process has the advantage that the reaction of sulfide of Formula (I) doesn't require any basic conditions during the oxidation, thereby the use of aqueous medium to remove excess of oxidizing agent. The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention. Examples: Example-1: Preparation of 2-({[4-(2-methoxyethoxy)-3-methylpyridin-2-yI]methyI} sulfinyl)-l//- benzimidazole i.e. rabeprazole base 10 To the solution of 2-({[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl}thio)-l#-benzimidazole (20g, 1 mole) in tetrahydrofuran (100 mL, 5 times), process water (25 mL, 1.25 times) is added. The reaction mixture is stirred for 15 minutes at 25°C to 35°C. Cool the reaction mixture to -5°C to -10°C. N-Chlorosuccinimide (10. 1g, 1.3 moles) is added into the reaction mixture within 15-20 minutes and the reaction mixture is stirred 5-10 minutes at -5°C to -10°C. Methylene dichloride (100 mL) is added to the reaction mixture followed by addition of sodium thiosulphate solution (2.5g in 25 mL). The pH of the reaction mass is adjusted between 10 to 12 by adding 2% sodium hydroxide solution (2g in 100 mL). The aqueous layer and organic layer are separated. The aqueous layer thus obtained is adjusted to pH 8 to 9 by adding ammonium acetate solution. Methylene dichloride (60 mL) is added to above reaction mixture and stirred for 15 minutes. The separated organic layer is treated with charcoal and stirred for 1 hour. The reaction mixture is filtered through celite bed and washed with methylene dichloride. The filtrate thus obtained is reduced upto 20-30 mL under reduced pressure. The filtrate thus obtained is added dropwise in n-heptane to isolate the product at 25°C to 35°C. The product thus obtained is stirred for 30 minutes at same temperature and cooled to 5°C to 10°C and stir for 1 hour. The reaction mass is filtered and washed with n-heptane, dried under vacuum at 25°C to 35°C to give 2-({[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl}sulfinyl)-1H-benzimidazole i.e. crude rabeprazole free base. Purification: The solution of crude rabeprazole free base (16 g) in isopropyl alcohol (80 mL) is taken in round bottom flask and stirred for 30 minutes at 38°C to 42°C. The reaction mixture is cooled to 25°C to 35°C and stirred for 30 minutes at same temperature. The reaction mixture is further cooled to 5°C to 10°C and is stirred for 1 hour at the same temperature. The product is filtered at 5°C to 10°C and washed with chilled isopropyl alcohol. The product is dried under vacuum at 25°C to 35°C for 4 hours and 35°C to 40°C for 4 hours to get pure rabeprazole free base. Example-2: Preparation of sodium salt of 2-({[4-(2-methoxyethoxy)-3-methyl pyridin-2-yl]methyl}sulfinyl)-l//-benzimidazole i.e. rabeprazole sodium The solution of (2-[[[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl] sulfinyl]-1/f-benzimidazole) 120.0 g. in 360.0 ml toluene is taken in round bottom flask and is stirred by maintaining temperature 25°C to 35°C. Methanolic sodium hydroxide solution is prepared separately by dissolving 13.82 g sodium hydroxide in 138.0 ml methanol. The reaction vessel is cooled to 10°C to 20°C and methanolic sodium hydroxide prepared is added within 1 to 2 hour, maintaining the same temperature and is stirred for 1 hour by maintaining 10°C to 20°C 11 temperature. To the solution thus obtained is added 12.0 g of activated charcoal and temperature is raised to 25°C to 35°C and stirred for 0.5 to 1.0 hour. The reaction mass is filtered through celite bed and the bed is washed with a mixture of 60.0 ml toluene and 12.0 ml methanol. The mixture of toluene and methanol is then distilled off under reduced pressure below 55°C temperature. 120.0 mL of toluene is further added into the reaction mixture and is removed under vacuum below 55°C temperature. The reaction mass thus obtained is treated with 300.0 mL of toluene and 18.0 mL of isopropyl alcohol and heated at 60°C and stirred to get clear solution. The clear solution is filtered through celite bed and the bed washed with mixture of hot (55°C to 60°C) toluene and IPA. 1800.0 mL of fine filtered n-heptane is taken and cooled to 5°C to 10°C temperature. The clear solution obtained is added into n-heptane over a period of 1 to 2 hours at 5°C to 10°C temperature and is stirred for 1 hour at 5°C to 10°C temperature. The product is filtered at 5°C to 10°C and washed with chilled n-heptane and the cake is sucked dry. The wet cake of Rabeprazole sodium is dried under vacuum at 25°C to 35°C for 12 hours and then dried under vacuum at 50°C to 55°C for 12 hours and finally dried under vacuum at 70°C to 75°C for 20 - 24 hours to obtain pure rabeprazole sodium. Example-3: Preparation of 2-[(pyridinyl)methyl]sulfinyl-substituted-lH-benzimidazole To the solution of 2-[(pyridinyl)methyl]thio-substituted-l//-benzimidazole (20g, 1 mole) in tetrahydrofuran (100 mL, 5 times), process water (25 mL, 1.25 times) is added. The reaction mixture is stirred for 15 minutes at 25°C to 35°C. Cool the reaction mixture to -5°C to -10°C. JV-Chlorosuccinimide (lO.lg, 1.3 moles) is added into the reaction mixture within 15-20 minutes and the reaction mixture is stirred 5-10 minutes at -5°C to -10°C. Methylene dichloride (100 mL) is added to the reaction mixture followed by addition of sodium thiosulphate solution (2.5g in 25 mL). The pH of the reaction mass is adjusted between 10 to 12 by adding 2% sodium hydroxide solution (2g in 100 mL). The aqueous layer and organic layer are separated. The aqueous layer thus obtained is adjusted to pH 8 to 9 by adding ammonium acetate solution. Methylene dichloride (60 mL) is added to above reaction mixture and stirred for 15 minutes. The separated organic layer is treated with charcoal and stirred for 1 hour. The reaction mixture is filtered through celite bed and washed with methylene dichloride. The filtrate thus obtained is reduced upto 20-30 mL under reduced pressure. The filtrate thus obtained is added dropwise in n-heptane to isolate the product at 25°C to 35°C. The product thus obtained is stirred for 30 minutes at same temperature and cooled to 5°C to 10°C and stir for 1 hour. The reaction mass is filtered and washed with n-heptane, dried under vacuum at 25°C to 35°C to give 2-[(pyridinyl)methyl]sulfinyl- 12 substituted-lH-benzimidazole-type compounds i.e. rabeprazole, omeprazole, lansoprazole, pantoprazole and esomeprazole. Example-4: Preparation of sodium salt of 2-[(pyridinyl)methyl]sulfinyl-substituted-l//- benzimidazole The solution of 2-[(pyridinyl)methyl]sulfinyl-substituted-l//-benzimidazole 120.0 g. in 360.0 ml toluene is taken in round bottom flask and is stirred by maintaining temperature 25°C to 35°C. Methanolic sodium hydroxide solution is prepared separately by dissolving 13.82 g sodium hydroxide in 138.0 ml methanol. The reaction vessel is cooled to 10°C to 20°C and methanolic sodium hydroxide prepared is added within 1 to 2 hour, maintaining the same temperature and is stirred for 1 hour by maintaining 10°C to 20°C temperature. To the solution thus obtained is added 12.0 g of activated charcoal and temperature is raised to 25°C to 35°C and stirred for 0.5 to 1.0 hour. The reaction mass is filtered through celite bed and the bed is washed with a mixture of 60.0 ml toluene and 12.0 ml methanol. The mixture of toluene and methanol is then distilled off under reduced pressure below 55°C temperature. 120.0 mL of toluene is further added into the reaction mixture and is removed under vacuum below 55°C temperature. The reaction mass thus obtained is treated with 300.0 mL of toluene and 18.0 mL of isopropyl alcohol and heated at 60°C and stirred to get clear solution. The clear solution is filtered through celite bed and the bed washed with mixture of hot (55°C to 60°C) toluene and isopropylalcohol. 1800.0 mL of fine filtered n-heptane is taken and cooled to 5°C to 10°C temperature. The clear solution obtained is added into n-heptane over a period of 1 to 2 hours at 5°C to 10°C temperature and is stirred for 1 hour at 5°C to 10°C temperature. The product is filtered at 5°C to 10°C and washed with chilled n-heptane and the cake is sucked dry. The wet cake of 2-[(pyridinyl)methyl]sulfinyl-substituted-l//- benzimidazole sodium salt is dried under vacuum at 25°C to 35°C for 12 hours and then dried under vacuum at 50°C to 55°C for 12 hours and finally dried under vacuum at 70°C to 75°C for 20 - 24 hours to obtain pure 2-[(pyridinyl)methyl]sulfinyl-substituted-J//-benzimidazole sodium salt. Dated this the 2nd day of May 2006 H. SUBRAMANIAM Of Subramaniam Nataraj & Associates Attorneys for the Applicants 13 Abstract: The present invention provides a process comprising admixing a thioether with about 0.5 to about 5.0 molar equivalents of an active halogen-containing oxidant preferably N-Bromosuccinimide or Af-Chlorosuccinimide in aqueous media; and recovering a sulfoxide that is preferably rabeprazole, omeprazole, lansoprazole, pantoprazole or esmoprazole. The process further comprises of preparing pure benzimidazoles-type compounds by oxidation of the corresponding sulfide followed by extraction of the sulfone by-product with an aqueous alkaline solution at controlled pH. 14

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