WO2009066309A2

WO2009066309A2 - Process for preparation of omeprazole

Info

Publication number: WO2009066309A2
Application number: PCT/IN2008/000445
Authority: WO
Inventors: Dhimant Jasubhai Patel; Mahesh Shankarbhai Patel; Shriprakash Dhar Dwivedi
Original assignee: Cadila Healthcare Limited
Priority date: 2007-07-12
Filing date: 2008-07-11
Publication date: 2009-05-28
Also published as: WO2009066309A9; WO2009066309A3

Abstract

The present invention discloses 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).

Description

PROCESS FOR PREPARATION OF OMEPRAZOLE 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).

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-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-benziniidazole), with the generic name omeprazole, 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]sulfmyl-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] sulfinyl]-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 inclμding 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.

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.

Oxidation

Formula (II) 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 US 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, disadvantageous^, 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. EP 0484265 Al discloses the process for the preparation of omeprazole (see example 32 and 33) by oxidation of 2-(((3,5-dimethyl-4-methoxy-2- pyridinyl)methyl)sulfinyl)-5-methoxy-lH-benzimidazole in suitable organic solvent with 50% H₂O₂ in presence of catalyst like (P(W₃O₁₀)₄.X.H₂O; ammonium Molybdate, having the formula (NH₄)₂MoO₄; sodium tungstate, having the formula Na₂WO₄; phosphomolybdic acid, having the formula H₃(P(Mo₃O_1O)₄-XH₂O; and silicotungstic acid, having the formula H₄(Si(W₃O_1O)₄-XH₂O at lower temperatures. Use of base in the oxidation process is essential. The process is suffering from tedious and costlier work up for the isolation of the product. The use of organic solvent like methylene dichloride and ethyl acetate and then washing with the same solvent at -15⁰C is very tedious workup procedure.

Hence, there is a need to provide a process for improved oxidation which provided direct isolation of omeprazole by filtration and which is free from such tedious and costlier work up thereby avoiding the use of organic solvents as mentioned herein above.

There are some patents related to the purity as well as residual alcohols in omeprazole. U.S. Patent No. 6,191,148 Bl claims 5-methoxy-2-[[4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfmyl]-lH-benzimidazole (omeprazole) of greater than

99.94% purity as determined by high-performance liquid chromatography and having less than 500 parts per million (p.p.m.) of residual ethanol relative to omeprazole.

U.S. Patent No. 6,147,103 and U.S. Patent No. 6,166,213 claims 5-methoxy-2- [[4-methoxy-3 ,5 -dimethyl-2-pyridinyl)methyl] sulfinyl] - 1 H-benzimidazole (omeprazole) containing less than three parts per million (p.p.m) of residual aromatic hydrocarbon solvent and less than 20 p.p.m of residual methanol relative to omperazole.

Thus, there is a need to provide a process for the preparation of omeprazole with higher residual methanol greater than 20 ppm and well within the standards of

ICH guidelines. Also, the purity of omeprazole is very essential and hence, the process of the present invention provides omeprazole with all the known and unknown individual impurities well within the phamacopial limits.

The polymorphism is an important criteria for omperazole. U.S. Patent No. 6,150,380 discloses two polymorphic forms of Omeprazole. Form A and Form B. Form A and Form B are characterized by XRD, Raman Spectra, single crystal, IR etc. analytical evidences. According, to the disclosure in US '380, the single crystal data and the molecular structure prepared according to EP 5129 and as disclosed in Acta Cryst. (1989), C45, 1921-1923 by Ohishi et al. is omeprazole Form-B.

Eur. Patent No. 1,390,360 claims yet another crystalline Form of omeprazole i.e. omeprazole Form C characterized by X-ray powder diffraction pattern exhibiting the d-spacings, single crystal analysis and IR. Also claimed is the process for the preparation of omeprazole Form C by dissolving crude omeprazole in a solvent or a mixture of solvents in which omeprazole is freely soluble, and precipitating Omeprazole Form C with a solvent in which omeprazole is poorly soluble.

WO 2007008588 A2 discloses the process for the preparation of omeprazole Form-B free from Form- A after being kept under stability for 3 to 6 months at 2⁰C to 8⁰C at 60% RH.

Thus, there is still a need to provide a process for preparing omeprazole form-B substantially free from other crystalline forms and having purity of atleast 99.75% by HPLC and meeting the pharmacopial requirements for individual impurities.

Object 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 (I).

Another object of the present invention to provide a process for preparing 2-(2- pyridylmethyl) sulfinyl-lH-benzimidazoles of formula (I), which is simple, easy to handle and cost effective. Description of 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 R₁ 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, C₁-C₄alkyl or C₁-C₄alkoxy; R₃ is selected from the group consisting of substituted or unsubstituted Q-C₄alkoxy; which comprises oxidizing thioether compound of formula (II)

Formula (II) wherein. R₁, R₂, R₃ and R₄ is same as described above, with suitable oxidizing agent formed by the reaction product of hydrogen peroxide and a catalyst in absence of base in a suitable organic solvent at about -1O⁰C to 5O⁰C.

In the case where R₁ represents substituted alkoxy substantially as hereinbefore described, suitable substituents is selected from the group consisting of hydrogen or substituted or unsubstituted Ci-C₄ alkoxy, especially methoxy.

In the case where R₃ represents substituted alkoxy substantially as hereinbefore described, suitable substituents one or more alkoxy substituents, such as C₁-C₃ alkoxy, especially methoxy.

In the preferred embodiment, R₁ 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 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 R₁ 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 R₁ 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 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- pyridinyl)methyl]thio]-lH-benzimidazole, to the corresponding ((5-(difluoromethoxy)-

2- [ [(3 ,4-dimethoxy-2-pyridinyl)methyl] -sulfmyl] - 1 H-benzimidazole or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

According to preferred embodiment the present invention, there is provided an improved process for preparing crystalline omeprazole Form-B having purity of atleast 99.70% but not more than 99.90% by HPLC which comprises:

(a) oxidizing 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]-thio]- lH-benzimidazole of formula (Ha) with an oxidizing agent in presence of catalyst in a suitable organic solvent in absence of base at about O⁰C to 5⁰C

Ha

(b) isolating crude omeprazole by filtration;

(c) treating crude omeprazole with base in a suitable organic solvent;

(d) optionally filtering the reaction mixture;

(e) treating the reaction mixture with weak acid; and

(f) isolating omeprazole crystalline forai-B.

According to the embodiment of the present invention, oxidizing agent can be selected from m-chlorperbenozic acid, hydrogen peroxide, N-chlorosuccinimide, N- bromosuccinimide, vanadium acetlacetonate and the like. The preferred oxidizing agent is 50% solution of hydrogen peroxide.

Suitable catalyst can be selected from (P(W₃O_1O)₄-X-H₂O; ammonium Molybdate, having the formula (NFLO₂MoO₄; sodium Molybdate, having the formula Na₂MoO₄, sodium tungstate, having the formula Na₂WO₄; phosphomolybdic acid, having the formula H₃(P(Mo₃O_1O)₄-XH₂O; and silicotungstic acid, having the formula

H₄(Si(W₃O₁₀)₄.XH₂O, preferably sodium Molybdate, having the formula Na₂MoO₄.

According to the present invention, hydrogen peroxide in presence of suitable catalyst itself generates the oxidizing agent. The reaction is preferably carried out in absence of base in an organic solvent for the oxidation of thioether linkage in order to obtain highly pure 2-[(pyridinyl)methyl]sulfinyl-benzimidazoles of formula (I).

According to another embodiment of the present invention, oxidation of thioether compound of formula (II) is carried out in any solvent, which is 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. The organic solvent used can be selected from alcohol like 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.

Suitable catalyst can be selected from (P(W₃O_1O)₄-X-H₂O; ammonium Molybdate, having the formula (NH₄)₂MoO₄; sodium Molybdate, having the formula Na₂MoO₄, sodium tungstate, having the formula Na₂WO₄; phosphomolybdic acid, having the formula H₃(P(MOaO₁₀)₄.XH₂O; and silicotungstic acid, having the formula H₄(Si(W₃O₁₀)₄.XH₂O, preferably sodium Molybdate, having the formula Na₂MoO₄

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 further provides a process for the preparation of omeprazole of Formula (Ha) and its pharmaceutically acceptable salts, solvents, hydrates thereof, which comprises

(a) oxidizing ((5 -methoxy-2- [ [(4-methoxy-3 ,5 -dimethyl-2 -pyirdyl)methyl] -thio] -IH- benzimidazole of formula (Ha) in with 50% hydrogen peroxide in presence of sodium molybdate in absence of base in methanol at O⁰C to 5⁰C;

Formula (Ha)

(b) isolating crude omeprazole

(c) treating crude omeprazole with base in a suitable organic solvent;

(d) optionally filtering the reaction mixture;

(e) treating the reaction mixture with weak acid; and

(f) isolating pure omeprazole .

Thus obtained Omeprazole consist higher purity i.e. greater than 99.0% but not more than 99.90%.

According to the preferred embodiment of the present invention, ((5-methoxy- 2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]-thio]-lH-benzimidazole of formula of formula (Ha) 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 50% hydrogen peroxide in presence of sodium, molybdate catalyst. The reaction is preferably carried out at temperature of -10 to 50° C. More preferably, the reaction is carried out at about -5° to 10° C. The complete reaction time is about 10 minutes to about 3 hours.

Upon completion of the reaction, the product is isolated by filtration and washed with suitable organic solvent or mixture thereof with water. Suitable organic solvent can be selected from alcoholic solvent like methanol, ethanol, isopropanol, propanol etc, preferably mixture of isopropanol with water to obtain optimum result in terms of better purity and better yield.

The isolated omeprazole crude is treated with base selected from alkali metal or alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide and the like, alkali metal or alkaline earth metal carbonates or bicarbonates like sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide.

The reaction of crude omeprazole with base can be carried out in suitable organic solvent selected from alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; hydrocarbons like toluene, xylene, ethylbenzene; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran; esters like ethyl acetate^ methyl acetate, isopropyl acetate, butyl acetate; dimethylformamide, dimethyl sulfoxide or mixture thereof with water, preferably methanol or mixture thereof with water.

The product, pure omeprazole Form-B is isolated by treating the reaction mixture with weak acid like acetic acid and characterized by known methods like XRD, DSC and IR.

The crystalline omeprazole form-B, characterized by having atleast one of the following properties:

(a) a powder x-ray diffraction (PXRD) pattern substantially in accordance with Figure I; and/or

(b) a powder x-ray diffraction (PXRD) having characteristic peaks at about 9.7, 8.0, 7.9, 7.1, 5.9, 5.6, 5.3, 5.1, and 4.5 d-values ±0.04 (A)

(c) a melting point in the range of about 156⁰C to about 159⁰C; and/or (d) differential scanning calorimetric (DSC) theromgram substantially in accordance with Figure II and having endothermic peak at about 158.3⁰C; and/or

(e) an Infrared (IR) absorption spectrum in potassium bromide comprising peaks at about 545, 821, 1011, 1017, 1202, 1407, 1587, 3006, 3061 ± 5 cm^"1 (f) an Infrared (IR) spectrum substantially in accordance with Figure III.

Thus, crystalline omeprazole Form-B is characterized by a powder x-ray diffraction (PXRD) having characteristic peaks at about 9.7, 8.0, 7.9, 7.1, 5.9, 5.6, 5.3, 5.1, and 4.5 d- values ±0.04 (A).

Further, crystalline omeprazole Form-B is characterized by differential scanning calorimetry analysis having endothermic peak at about 158.3⁰C.

A crystalline omeprazole Form-B is also characterized by IR having characteristic peaks at about 545, 821, 1011, 1017, 1202, 1407, 1587, 3006, 3061 ± 5 cm^"1.

A crystalline omeprazole form-B prepared by the process of the present invention is having particle size distribution D₁₀ less than about 10 μm, D₅₀ less than about 20 μm and D₉₀ less than about 50 μm.

The purity of Omeprazole can be determined by using high-performance liquid chromatography and residual solvent by gas chromatography. It can be performed by using the known methods as disclosed in U.S. Patents No. 6,191,148, 6,166,213 and 6, 147, 103 are incorporated herein as reference.

The HPLC purity of omeprazole form-B obtained in the following examples were determined by following HPLC (high performance liquid chromatography) conditions listed below:

column: - Zorbax SB C8 (150x4.6 mm, 5 μ) flow rate : - 1.0 mL/rnin wavelength : - 280 run oven temp: - 25⁰C

Buffer : - 1.4 g Na₂HPO₄ -> 1000 mL with water, pH 7.8 with OPA (orthophosphoric acid)

Mobile Phase : - Buffer : Acetonitrile:::76:24

Diluent: - Mobile Phase Brief Description of Drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention taken in conjunction with the following accompaying drawings, which respectively show: FIG. I: X-ray diffraction pattern of omeprazole Form-B as obtained in example 3. FIG. II: Differential Scanning Calorimetry analysis of omeprazole Form-B as obtained in example 3. FIG. Ill: Infrared spectra analysis of omeprazole Form-B as obtained in example 3.

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. Example-1:

Preparation of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2- pyridinyl)methyI]sulfinyl]-lH-benzimidazole (Omeprazole)

A mixture of 100.0 g of ((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyirdyl)methyl]-thio]-lH-benzimidazole [prepared as per the known methods in the literature] in 400 mL methanol was prepared and stirred for 15 minutes to get clear solution. The reaction mixture was treated with 10 gm of charcoal and stirred for 30 minutes. The reaction mass was cooled to 5⁰C to 1O⁰C and 1.08 gm of catalyst sodium molybdate in 50 mL of water was added drop wise within 15 minutes. 21.10 gm of 49% hydrogen peroxide was added at 5⁰C to 1O⁰C to obtain clear reaction mass. The reaction mixture was maintained for 5-6 hours at 5⁰C to 1O⁰C. 8.9 gm of sodium thiosulphate in 40 mL of water was added within 30 mins. The pH was adjusted by 10% NaOH solution. The product was filtered, washed with chilled mixture of methanol and water and dried at 5O⁰C to 55⁰C to obtain 78 gm of crude omeprazole.

Example-2: Preparation of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2- py ridiny l)methy 1] sulfiny 1] - IH-

benzimidazole (Omeprazole)

A mixture of 100.0 g of ((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyirdyl)methyl]-thio]-lH-benzimidazole [prepared as per the known methods in the literature] in 400 mL ethanol was prepared and stirred for 15 minutes to get clear solution. The reaction mixture was treated with 10 gm of charcoal and stirred for 30 minutes. The reaction mass was cooled to 5⁰C to 1O⁰C and 1.08 gm of catalyst sodium molybdate in 50 mL of water was added drop wise within 15 minutes. 21.10 gm of 49% hydrogen peroxide was added at 5⁰C to 10⁰C to obtain clear reaction mass. The reaction mixture was maintained for 5-6 hours at 5⁰C to 1O⁰C. 8.9 gm of sodium thiosulphate in 40 mL of water was added within 30 mins. The product was filtered, washed with chilled mixture of ethanol and water and dried at 5O⁰C to 55⁰C to obtain 79 gm of crude omeprazole.

HPLC purity: 99.75%

Example-3: Purification of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-lH-benzimidazole (omeprazole Form-B)

A mixture of 100 gm of omeprazole crude and 160 mL of methanol were taken in round bottom flask. 160 mL water was added to the above reaction mixture at 25⁰C to 35⁰C and stirred for 15 mins. 14.4 gm sodium hydroxide in 160 mL water was added dropwise within 1 hour and stirred for 15 min. The reaction mixture was filtered and washed with 100 mL water. The filtrate was treated with acetic acid to adjust the pH to 7.5 to 7.7 within 20 mins. The product thus obtained was filtered, washed with water and dried at 4O⁰C to 45⁰C to obtain 96 gm omeprazole Form-B. HPLC purity : 99.86%. Individual Impurities are as under: Impurity-A at RRT 0.44 : 0.03%

Impurity-B at RRT 0.46 : Not detected

Impurity-C at RRT 0.80 : Not detected

Impurity-D at RRT 0.90 : 0.11% Impurity-E at RRT 3.26 : Not detected

Total Impurities : 0.14%

Impurity-A: 5-methoxy- 1 H-benzimidazole-2-thiol

Impurity-B: 2-[(R,S)]-[(3,5-dimethylpyridine-2-yl)methyl]sulphinyl]-5-methoxy-lH- benzimidazole Impurity-C : 5 -methoxy-2 [ [4-methoxy-3 ,5 -dimethylpyridiή-2-yl)methyl] sulphanyl] - lH-benzimidazole [Omeprazole Sulfide]

Impurity-D : 5 -methoxy-2 [ [4-methoxy-3 ,5 -dirnethylpyridin-2-yl)methyl] sulphonyl] - lH-benzimidazole [Omeprazole Sulfone]

Impurity-E: 4-methoxy-2-[[(R,S)-(5-methoxy-lH-benzimidazole-2-yl)- sulphinyl]methyl)-3 ,5 -dimethylpyridine- 1 -oxide [Omeprazole N-Oxide]

Advantages of Invention:

1) The present invention provides an improved process for the preparation of Omeprazole Form-B.

2) The present invention provides an improved process for the preparation of Omeprazole Fόrm-B having purity of atleast 99.75% but not more than 99.90% by area percentage of HPLC.

3) The present invention provides an improved process for the purification of crude omeprazole to obtain polymorphic Form-B.

4) Omeprazole Polymorphic Form-B is substantially free from other crystalline forms of Omeprazole.

5) The present invention provides a simple, cost effective and large scale applicable process for the preparation of Omeprazole Form-B having purity greater than 99.70% but not more than 99.90% by area percentage of HPLC as well as meeting with the Pharmacopial limits of individual impurities.

Claims

We claim:

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

Formula (I) wherein R₁ 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, C₁-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)

Formula (II) wherein R₁, R₂, R₃ and R₄ is same as described above, with suitable oxidizing agent formed by the reaction product of hydrogen peroxide and a catalyst in absence of base in a suitable organic solvent at about -1O⁰C to 5O⁰C.

2. A process for preparing crystalline omeprazole Form-B having purity of at least

99.70% but not more than 99.90% by HPLC; which comprises of:

Ha (b) isolating crude omeprazole by filtration;

(c) treating crude omeprazole with base in a suitable organic solvent;

(d) optionally filtering the reaction mixture;

(e) treating the reaction mixture with weak acid; and (f) isolating omeprazole crystalline form-B

3. A crystalline omeprazole form-B according to claim 2, characterized by having at least one of the following properties: (a) a powder x-ray diffraction (PXRD) pattern substantially in accordance with

Figure I; and/or (b) a powder x-ray diffraction (PXRD) having characteristic peaks at about 9.7,

8.0, 7.9, 7.1, 5.9, 5.6, 5.3, 5.1, and 4.5 d-values ±0.04 (A)

(c) a melting point in the range of about 156⁰C to about 159⁰C; and/or

(d) differential scanning calorimetric (DSC) theromgram substantially in accordance with Figure II and having endothermic peak at about 158.3⁰C; and/or

(e) an Infrared (IR) absorption spectrum in potassium bromide comprising peaks at about 545, 821, 1011, 1017, 1202, 1407, 1587, 3006, 3061 ± 5 cm^'1 or

(f) an Infrared (IR) spectrum substantially in accordance with Figure III.

4 A process according to claim 1 or 2, wherein oxidizing agent is selected from m- chloroperbenzoic acid, hydrogen peroxide, N-chlorosuccinimide, N- bromosuccinimide, vanadium acetlacetonate and the like. The preferred oxidizing agent is 50% solution of hydrogen peroxide.

5 A process according to claim 1 or 2, wherein catalyst is selected from (P(W₃O₁₀)₄.X.H₂O; ammonium Molybdate, having the formula (NH₄)₂MoO₄; sodium Molybdate, having the formula Na₂MoO₄, sodium tungstate, having the formula Na₂WO₄; phosphomolybdic acid, having the formula H₃(P(MOsO₁O)₄-XH₂O; and silicotungstic acid, having the formula H₄(Si(W₃O₁₀)₄.XH₂O, preferably sodium Molybdate, having the formula Na₂MoO₄. 6 A process according to claim 1 or 2, wherein suitable organic solvent is selected from alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; hydrocarbons like toluene, xylene, ethylbenzene; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran; esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate; dimethylformamide, dimethyl sulfoxide or mixture thereof with water. 7 A process according to claim 6, wherein suitable solvent is methanol or ethanol or mixture thereof with water. 8 A process according to claim 2, wherein base in step (c) is selected from alkali metal or alkaline earth metal hydroxides, like sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide and the like, alkali metal or alkaline earth metal carbonates or bicarbonates like sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide.

9 A process according to claim 2, wherein suitable organic solvent in step (c) is selected from alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; hydrocarbons like toluene, xylene, ethylbenzene; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran; esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate; dimethylformamide, dimethyl sulfoxide or mixture thereof with water.

10. A process according to claim 9, wherein suitable organic solvent is methanol or ethanol or mixture thereof with water.

11. An improved process according to claim 2, wherein weak acid is acetic acid. 12. A process for the preparation of omeprazole of Formula (Ha) and its pharmaceutically acceptable salts, solvents, hydrates thereof, which comprises (a) oxidizing ((5 -methoxy-2- [ [(4-methoxy-3 ,5 -dimethyl-2-pyirdyl)methyl] -thio] - lH-benzimidazole of formula (Ha) in with 50% hydrogen peroxide in presence of sodium molybdate in absence of base in methanol at O⁰C to 5⁰C;

-

Formula (Ha)

(b) isolating crude omeprazole

(c) treating crude omeprazole with base in a suitable organic solvent;

(d) optionally filtering the reaction mixture; (e) treating the reaction mixture with weak acid; and

(f) isolating pure omeprazole.

13. A process according to claim 12, wherein base in step (c) is selected from alkali metal or alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium hydroxide and the like, alkali metal or alkaline earth metal carbonates or bicarbonates like sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and the like, preferably sodium hydroxide.

14 A process according to claim 12, wherein suitable organic solvent in step (c) is selected from alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; hydrocarbons like toluene, xylene, ethylbenzene; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran; esters like ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate; dimethylformamide, dimethyl sulfoxide or mixture thereof with water. 15. A process according to claim 14, wherein suitable organic solvent is methanol or ethanol or mixture thereof with water.

16. A process according to claim 12, wherein weak acid is acetic acid.

17. Crystalline omeprazole form-B according to claim-2 having purity of atleast

99.75% but not more than 99.90% by area percentage of HPLC and having individual impurities as below: impurity-A not more than about 0.05%, impurity-C not in detectable ^• amount, impurity-D not more than 0.15%, impurity-E not in detectable amount, impurity 8-methoxy-l,3-dimethyl-12-thixopyrido-[r,2':3,4]imdazo[l,2'-a]benzimidazol- 2(12H)-one and impurity 9-methoxy- 1,3 -dimethyl- 12- thioxopyrido[l ',2' :3,4]imidazo[l,2-a]benzimidazole-2[12H]-one not in detectable amount by area percentage of HPLC.

18. Crystalline omeprazole form-B prepared by the process of claim 2 having particle size D₁₀ less than about 10 μm, D₅₀ less than about 20 μm and D₉₀ less than about 50 μm.