WO2007129328A2

WO2007129328A2 - Process for preparing 2-[pyridinyl]sulfinyl-substituted benzimidazoles

Info

Publication number: WO2007129328A2
Application number: PCT/IN2007/000158
Authority: WO
Inventors: Niraj Shyamlal Shah; Shriprakash Dhar Dwivedi
Original assignee: Cadila Healthcare Limited
Priority date: 2006-05-09
Filing date: 2007-04-23
Publication date: 2007-11-15
Also published as: WO2007129328A3

Abstract

A process for the preparation of 2-[(pyridinyl)methyl]sulfinyl-benzimidazole of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1 is selected from the group consisting of hydrogen or substituted or unsubstituted C1-C4 alkoxy; 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.

Description

PROCESS FOR PREPARING 2-[PYRIDINYL]SIJT--FINYL-SUBSTITUTED BENZIMIDAZOLES

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.

Formula (I) Formula (II)

Background and Prior art The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field. There are a large number of patents and patent applications disclosing different substituted 2-(2-pyridinylrnethylsulphinyl)-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, i described in i.e. 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.

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] sulfmyl]-lH-benzimidazole. 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 center in the molecule, these compounds can exist as pairs of enantiomers. Corresponding sulphides of such compounds which already contain a ^■ stereogenic center 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)-lH- benzimidazoles.

The preparation of 2-[(pyridinyl]methyl]sulfmyl-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.

FFoorrmmuullaa ((HII)) Formula (I)

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).

Formula (III)

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. WO91/18895 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.

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- halosuccinamide, 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). Objects of the Invention

It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide a useful alternative.

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

Formula (I) wherein Ri is selected from the group consisting of hydrogen or substituted or unsubstituted Q.Qalkoxy; R₂ and R₄ are independently selected from the group consisting of hydrogen, Ci-C₄alkyl or Q-Qalkoxy; 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

Formula (II) wherein R₁, 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]sulfinyl- 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 C]-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.

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 Ri 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 Ri 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-trifiuoro-ethoxy)-2- pyridinyl]methyl]thio]-lH- benzimidazole to the corresponding (2-[[[3~methyl-4-

(2,2,2-trifluoro-ethoxy)-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 ((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- pyridinyl)methyl]thio]-lH-benzimidazole, to the corresponding ((5-(difluoromethoxy)- 2- [[(3 ,4-dimethoxy-2-pyridinyl)methyl] -sulfinyl] - 1 H-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).

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 in an amount of 0.8 molar equivalent to 2 molar equivalent of the thioether compound of formula (II). Preferably 1.8 molar equivalent to the thioether compound of formula (II).

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

Formula (I) wherein Ri is selected from the group consisting of hydrogen or substituted or unsubstituted Q^alkoxy; R₂ and R₄ are independently selected from the group consisting of hydrogen, Cj-C₄alkyl or Ci-C₄alkoxy; R₃ is selected from the group consisting of substituted or unsubstituted Cj-C₄alkoxy, which comprising the steps of: (a) oxidizing thioether compound of formula (II) in absence of base

Formula (II)

wherein R₁, 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 mild acid (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 tert-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.

Preferably, the invention provides a process for the preparation of Rabeprazole of formula (Ia) and its pharmaceutically acceptable salts, solvents, hydrates thereof, which comprises

(Ia)

(a) oxidizing 2-({[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl} thio)-lH- benzimidazole of formula (Ua) in absence of base with N-halosuccinimide in presence of water

Formula (Ha)

(b) extracting the reaction mixture with aqueous alkaline solution with suitable organic solvent at pH about 11 to 12 and removing the organic layer. (c) extracting the aqueous layer of step (b) with mild base and organic solvent at pH about 8 to 9.5 and removing the aqueous layer.

(d) removing organic solvent to obtain Rabeprazole

(e) optionally converting Rabeprazole to its pharmaceutically acceptable salt, solvates, hydrates thereof. According to the preferred embodiment of the present invention, 2-({[4-(2- methoxyethoxy)-3-methylpyridin-2-yl]methyl} thio)-lH-benzimidazole of formula (Ua) was dissolved in the organic solvent preferably ethereal solvent such diethyl etherl, isopropyl ether, tetrahydrofuran, dioxane; alcoholic solvent such as methanol, ethanol, isopropanol, n-propanol to obtain the solution. The said solution of compound of formula (Ha) is oxidized with N- chlorosuccinimide in presence of water. The reaction is preferably carried out at temperature of -10 to 30° C. More preferably, the reaction is carried out at about -5 to 5° C. The complete reaction time is about 10 to 30 minutes. The ratio of N- chlorosuccnimide is about 0.9 M to 1.1 M equivalent of compound of formula (Ha). Upon completion of the reaction, the reaction mixture is treated with aqueous alkali solution, preferably aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium tert-butoxide, preferably sodium hydroxide; to bring the pH of reaction mass about 11 to 12. More, preferably pH of the reaction mixture maintained about 11.5 to 11.9 to obtain optimum result in terms of better purity and better yield.

Upon extraction, separated organic layer was discarded and aqueous layer containing product was further treated with mild acid solution such as ammonium acetate to bring the pH of aqueous layer about 8 to 9.5. More, preferably pH of aqueous layer is adjusted to about 8 to about 9 at about 5 to 15⁰C. Subsequently, it is extracted with organic solvent to remove aqueous layer. The product remains in organic layer. Rabeprazole is obtained by removal of solvent by distillation or evaporation.

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 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.

Thus, obtain Rabeprazole is converted to its pharmaceutically acceptable salts, solvents, hydrates thereof. Preferably, Rabeprazole sodium salt can be prepared from Rabeprazole by know technique. According to another embodiment of the present invention, there is provided a process for preparing 2-[(pyridinyl)methyl]sulfϊnyl-benzimidazoles of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof in the form of a single enantiomer or in an enantiomerically enriched form

Formula (I) wherein Ri 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, Ci-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.

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(rV)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.

Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that the invention can be embodied in many other forms. 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-yl]methyl} sulfϊnyl)- lH-benzimidazoIe i.e. rabeprazole base

To the solution of 2-({[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl} thio)-lH-benzimidazole (2Og, 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 25⁰C to 35⁰C. Cool the reaction mixture to -5⁰C to -1O⁰C. N-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 -5⁰C to -1O⁰C. Methylene dichloride (100 mL) is added to the reaction mixture followed by addition of sodium thiosulphate solution (2.5g in 25 mL). The layers are separated and organic layer is treated with 2% Sodium hydroxide solution (2g in 100 mL) till the pH is between 10 to 12 or aqueous layer 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 (100 mL) is added to above reaction mixture and stirred for 10 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 added dropwise in n-heptane to isolate the product at 25⁰C to 35⁰C. The product thus obtained is stirred for 30 minutes at same temperature and cooled to 5°C to 1O⁰C and stir for 1 hour. The reaction mass is filtered and washed with n-heptane, dried under vacuum at 25⁰C to 35⁰C to give 2-({[4-(2-methoxyethoxy)-3- methylpyridm-2-yl]methyl}sulfmyl)-lH-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 38⁰C to 42°C. The reaction mixture is cooled to 25⁰C to 35°C and stirred for 30 minutes at same temperature. The reaction mixture is further cooled to 5°C to 1O⁰C and is stirred for 1 hour at the same temperature. The product is filtered at 5⁰C to 10⁰C and washed with chilled isopropyl alcohol. The product is dried under vacuum at 25⁰C to 35°C for 4 hours and 35⁰C to 4O⁰C for 4 hours to get pure rabeprazole free base. Example-2: Preparation of sodium salt of 2-({[4-(2-methoxyethoxy)-3-methyI pyridin-2- yI]methyI}sulfinyl)-lH-benzimidazoIe i.e. rabeprazole sodium

The solution of (2-[[[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl] sulfinyl]-lH-benzimidazole) 120.0 g. in 360.0 ml toluene is taken in round bottom flask and is stirred by maintaining temperature 25⁰C to 35⁰C. 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 10⁰C to 2O⁰C and methanolic sodium hydroxide prepared is added within 1 to 2 hour, maintaining the same temperature and is stirred for 1 hour by maintaining 10⁰C to 2O⁰C temperature. To the solution thus obtained is added 12.0 g of activated charcoal and temperature is raised to 25°C to 35⁰C 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 55⁰C temperature. 120.0 mL of toluene is further added into the reaction mixture and is removed under vacuum below 55⁰C temperature. The reaction mass thus obtained is treated with 300.0 mL of toluene and 18.0 mL of isopropyl alcohol and heated at 6O⁰C and stirred to get clear solution. The clear solution is filtered through celite bed and the bed washed with mixture of hot (55⁰C to 60⁰C) toluene and IPA. 1800.0 mL of fine filtered n-heptane is taken and cooled to 5⁰C to 1O⁰C temperature. The clear solution obtained is added into n-heptane over a period of 1 to 2 hours at 5⁰C to 1O⁰C temperature and is stirred for 1 hour at 5⁰C to 10⁰C temperature. The product is filtered at 5⁰C to 1O⁰C and washed with chilled n-heptane and the cake is sucked dry. The wet cake of Rabeprazole sodium is dried under vacuum at 25⁰C to 35⁰C for 12 hours and then dried under vacuum at 50⁰C to 55⁰C for 12 hours and finally dried under vacuum at 7O⁰C to 75⁰C for 20 - 24 hours to obtain pure rabeprazole sodium. Example-3: Preparation of 2- [(pyridinyI)methyl]sulfinyl-substituted-lH-benzimidazole

To the solution of 2-[(pyridinyl)methyl]thio-substituted-lH-benzimidazole (2Og, 1 mole) in tetrahydrofuran (140 mL, 5 times), process water (25 mL, 1.25 times) is added. The reaction mixture is stirred for 15 minutes at 25⁰C to 35⁰C. Cool the reaction mixture to -5⁰C to -1O⁰C. N-Chlorosuccinimide (10. Ig, 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 -10⁰C. Methylene dichloride (100 mL) is added to the reaction mixture followed by addition of sodium thiosulphate solution (2.5g in 25 mL). The layers are separated and organic layer is treated with 2% Sodium hydroxide solution (2g in 100 mL) till the pΗ is between 10 to 12 or aqueous layer. The aqueous layer and organic layer are separated. The aqueous layer thus obtained is adjusted to pΗ 8 to 9 by adding ammonium acetate solution. Methylene dichloride (100 mL) is added to above reaction mixture and stirred for 10 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 added dropwise in n- heptane to isolate the product at 25°C to 35⁰C. The product thus obtained is stirred for 30 minutes at same temperature and cooled to 5⁰C to 1O⁰C and stir for 1 hour. The reaction mass is filtered and washed with n-heptane, dried under vacuum at 25⁰C to 35⁰C to give 2-[(pyridinyl)methyl]sulfinyl-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-lH- benzimidazole

The solution of 2-[(pyridinyl)methyl]sulfinyl-substituted-lH-benzimidazole 120.0 g. in 360.0 ml toluene is taken in round bottom flask and is stirred by maintaining temperature 25⁰C to 35⁰C. 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 10⁰C to 2O⁰C and methanolic sodium hydroxide prepared is added within 1 to 2 hour, maintaining the same temperature and is stirred for 1 hour by maintaining 1O⁰C to 2O⁰C temperature. To the solution thus obtained is added 12.0 g of activated charcoal and temperature is raised to 25⁰C to 35⁰C 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 55⁰C temperature. 120.0 mL of toluene is further added into the reaction mixture and is removed under vacuum below 55⁰C temperature. The reaction mass thus obtained is treated with 300.0 niL of toluene and 18.0 mL of isopropyl alcohol and heated at 60⁰C and stirred to get clear solution. The clear solution is filtered through celite bed and the bed washed with mixture of hot (55⁰C to 6O⁰C) toluene and isopropylalcohol. 1800.0 mL of fine filtered n-heptane is taken and cooled to 5⁰C to 1O⁰C temperature. The clear solution obtained is added into n-heptane over a period of 1 to 2 hours at 5⁰C to 1O⁰C temperature and is stirred for 1 hour at 5⁰C to 1O⁰C temperature. The product is filtered at 5°C to 1O⁰C and washed with chilled n-heptane and the cake is sucked dry. The wet cake of 2- [(pyridinyl)methyl]sulfinyl-substituted-lH-benzimidazole sodium salt is dried under vacuum at 25⁰C to 35⁰C for 12 hours and then dried under vacuum at 5O⁰C to 55⁰C for 12 hours and finally dried under vacuum at 7O⁰C to 75⁰C for 20 - 24 hours to obtain pure 2-[(pyridinyl)methyl]sulfϊnyl_'Substituted-lH-benzimidazole sodium salt. Example 5:

Preparation of single enantiomer or in an enantiomerically enriched form of 2-

({[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl}suIfinyl)-lH-benzimidazole

2-({[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl}thio)-lH- benzimidazole 5 g was dissolved in 20 niL ethyl acetate. To the solution was added 0.3 ml water. To the mixture was added 5 g (+)-diethyl L-tartrate, 5 g titanium(IV) isopropoxide and 6 ml diisopropyl ethylamine at room temperature. The addition of 3 ml cumene hydroperoxide (80%) was then performed over a period of 90 minutes at 34⁰C. After cooling to room temperature for 120 minutes The mixture was diluted with 6 ml isooctane and 4 ml ethyl acetate whereupon the product was extracted three times with an aqueous ammonia (12%) solution with a total volume of 48 ml. The combined aqueous phases were neutralized by addition of 50 ml concentrated acetic acid. Thereafter, the workup procedure employed extraction, evaporation, sodium hydroxide addition and crystallization procedures yielding 2 g of the title compound.

Claims

We Claim:

1. A process for the preparation of 2-[(pyridinyl)methyl]sulfinyl~benzimidazole of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof

Formula (I) wherein Ri is selected from the group consisting of hydrogen or substituted or unsubstituted Q.Qalkoxy; 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 Q-C₄alkoxy; which comprises oxidizing thioether compound of formula (II) in absence of base

Formula (II) 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.

2. A process as claimed in claim 1, wherein R₄ represents methyl, R₃ represents trifluoroethoxy, R₂ represents hydrogen and Ri represents hydrogen.

3. A process as claimed in claim 1, wherein R₄ represents methyl, R₃ represents methoxy, R₂ represents methyl and Ri represents methoxy.

4. A process as claimed in claim 1, wherein R₄ represents methoxy, R₃ represents methoxy, R₂ represents hydrogen and Ri represents difiuoromethoxy.

5. A process as claimed in claim 1, wherein R₄ represents methyl, R3 represents - OCH₂CH₂CH₂OMe, R₂ represents hydrogen and Ri represents hydrogen.

6. A process as claimed in claim 1, wherein N-halosuccinamide is selected from N- bromosuccinimide, N-chlorosuccinimide or mixtures thereof.

7. A process as claimed in claim 6, wherein said N-halosucciamide is used in an amount of 0.8 molar equivalent to 2 molar equivalent of the thioether compound of formula (II).

8. A process as claimed in any of the preceding claim, wherein oxidation is carried out in a solvent selected from 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.

9. A process for the preparation of substantially pure 2-[(pyridinyl)methyl]sulfinyl- benzimidazoles of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof

Formula (I) wherein Ri 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, Ci-C₄alkyl or Ci-C₄alkoxy; R₃ is selected from the group consisting of substituted or unsubstituted Ci-C₄alkoxy, which comprising the steps of (a) oxidizing thioether compound of formula (II) in absence of base

Formula (II) wherein R₁, R₂, R₃ and R₄ is same as described above, with N-halosuccinimide in presence of water;

(b) treating the product of step (a) 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 mild acid; (e) treating the product of step (d) with suitable organic solvent to extract organic layer, isolating the compound, optionally converting to its pharmaceutically acceptable salt, hydrate, or solvate thereof.

10. A process as claimed in claim 9, wherein said suitable organic solvent is 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.

11. A process as claimed in claim 9, wherein said alkali solution in step (c) is selected from the aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium ter-butoxide.

12. A process as claimed in claim 8, wherein said mild acid is acetic acid.

13. A process for preparing 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of Formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof in the form of a single enantiomer or in an enantiomerically enriched form

Formula (I) wherein Rj is selected from the group consisting of hydrogen or substituted or unsubstituted Q.Qalkoxy; R₂ and R₄ are independently selected from the group consisting of hydrogen, Ci-C₄alkyl or C]-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

Formula (II) wherein Ri, 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.

14. A process as clamed in claim 13, wherein said chiral ligand and a titanium(IV) compound such as preferably titanium(IV)alkoxide, preferably titanium(IV)isopropoxide or titanium(IV)propoxide.

15. A process for the preparation of Rabeprazole of formula (Ia) or a pharmaceutically acceptable salt, hydrate, or solvate thereof

(Ia)

which comprises the steps of

(a) oxidizing thioether compound of formula (Ha) in absence of base

Formula (Ha)

with N-halosuccinimide in presence of water, optionally converting into a pharmaceutically acceptable salt, hydrate, or solvate thereof.

16. A process as claimed in claim 15, wherein said N-halosuccinamide is selected from N-bromosuccinimide, N-chlorosuccinimide or mixtures thereof.

17. A process as claimed in claim 16, wherein said N-halosucciamide is used in an amount of 0.8 molar equivalent to 2 molar equivalent of the thioether compound of formula (II).

18. A process as claimed in claim 15, wherein oxidation is carried out in a solvent selected from 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.

19. A process for the preparation of Rabeprazole or its pharmaceutically acceptable salts, solvents, hydrates thereof, which comprises: (a) oxidizing 2-({[4-(2-methoxyethoxy)-3-methylpyridin-2-yl]methyl} thio)-lH- benzimidazole of formula (Ua) in absence of base with N-halosuccinimide in presence of water

Formula (Ha) (b) extracting the reaction mixture with aqueous alkaline solution with suitable organic solvent at pH about 11 to 12 and removing the organic layer.

(c) extracting the aqueous layer of step (b) with mild base and organic solvent at pH about 8 to 9.5 and removing the aqueous layer.

(d) removing organic solvent to obtain Rabeprazole (e) optionally converting Rabeprazole to its pharmaceutically acceptable salt, solvates, hydrates thereof.

20. A process as claimed in claim 19, wherein said suitable organic solvent is 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.

21. A process as claimed in claim 19, wherein said aqueous alkaline solution is selected from aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium ter- butoxide.

22. A process as claimed in claim 15, wherein said mild acid is selected from acetic acid, ammonium acetate.

23. A process as claimed in claim 19, wherein Rabeprazole prepared is in amorphous form.

24. A process as claimed in any preceding claims, wherein said pharmaceutically acceptable salt is alkali or alkali earth metals selected from Mg, Ca, Na, K or Li salts, preferably Mg or Na salt.

25. A process for the preparation of compound of formula (I) such as herein described in accordance with accompanying text, describes and examples.