WO2008017020A2

WO2008017020A2 - Process for preparing proton pump inhibitors

Info

Publication number: WO2008017020A2
Application number: PCT/US2007/075053
Authority: WO
Inventors: Vijayabhaskar Bolugoddu; Jaydeepkumar Lilakar Dahyabhai; Ramalinga Reddy Beeravalli; Madhuraju Veeraboina
Original assignee: Dr. Reddy's Laboratories Limited; Dr. Reddy's Laboratories, Inc.
Priority date: 2006-08-03
Filing date: 2007-08-02
Publication date: 2008-02-07
Also published as: WO2008017020A3

Abstract

The present application relates to a process for the preparation of proton pump inhibitors of the benzimidazole-type represented by the general Formula I, Formula I wherein R1 and R2 are the same as or different from each other and are selected from hydrogen, methoxy or difluoromethoxy, R3, R4 and R5 are the same as or different from each other and are selected from hydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy, and their pharmaceutically acceptable salts.

Description

PROCESS FOR PREPARING PROTON PUMP INHIBITORS

The present application relates to a process for the preparation of proton pump inhibitors of the benzimidazole-type, and their pharmaceutically acceptable salts. In particular, the present application relates to a process for the preparation of rabeprazole and its salts free of its sulfone impurity.

BACKGROUND

Proton pump inhibitors of the benzimidazole-type can be represented by the general Formula I.

Formula I

wherein Ri and R₂ are the same as or different from each other and are selected from hydrogen, methoxy or difluoromethoxy, R₃, R₄ and R₅ are the same as or different from each other and are selected from hydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy.

Gastric proton pump inhibitors include substituted 2-(2-pyridylmethyl)- sulfinyl-1 H-benzimidazoles, such as lansoprazole (2-[[[3-methyl-4-(2,2,2-trifluoro- ethoxy)-2-pyridinyl]methyl]sulfinyl]1-H benzimidazole), omeprazole (5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1 H-benzimidazole), pantoprazole (5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1 H- benzimidazole), and rabeprazole (2-[[[4-(3-methoxypropoxy) -3-methyl-2-pyridinyl]- methyljsulfinyl] -1 H-benzimidazole). Rabeprazole is represented by Formula II.

Formula Il Typically, processes for the preparation of benzimidazole type compounds involve oxidation of the corresponding sulfide derivative of Formula III followed by extraction of the product from the reaction medium.

Formula III

However, oxidation reaction to convert the sulfide intermediates of Formula into the sulfoxide compound of Formula I is likely to produce over-oxidation, i.e. oxidation from sulfoxides of Formula I to sulfones represented by general Formula IV.

IV

Since proton pump inhibitors of the benzimidazole-type are very susceptible to degradation under acidic or neutral conditions the reaction mixture is usually worked-up under basic conditions. These basic conditions decompose any unwanted oxidizing agent still present in the reaction mixture and also neutralize any acid formed when the oxidizing agent is consumed in the oxidation reaction.

There is a long felt need in the art to provide an improved process for the synthesis of benzimidazole-type compounds of Formula I, which is more convenient and more efficient than the previously known methods in the literature.

DETAILED DESCRIPTION In one embodiment, the present invention relates to a process for the preparation of proton pump inhibitors of the benzimidazole-type represented by the compounds of Formula I, and their pharmaceutically acceptable salts. In another embodiment, the present invention provides a process for the preparation of rabeprazole and its pharmaceutically acceptable salts.

In an embodiment, the present invention provides a process for the preparation of benzimidazole-type compounds of Formula I, and their pharmaceutically acceptable salts free of their sulfone impurity, which can be practiced on an industrial scale. In another embodiment, the present invention provides a process for the preparation of rabeprazole and their salts free of its sulfone impurity.

In the process of the present application, the steps may be performed under mild conditions providing a low content of by-products and thereby a high yield and high purity of the desired product.

In one embodiment, the present invention provides a process for the preparation of proton pump inhibitors of the benzimidazole-type having Formula (I) and their salts

Formula I wherein R₁ and R₂ are the same as or different from each other and are selected from hydrogen, methoxy or difluoromethoxy, R₃, R₄ and Rs are the same as or different from each other and are selected from hydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy, which process comprises: (a) reacting of the compound of Formula III

Formula III wherein R_1, R_2, R₃, R₄ and R₅ are as described above, with an oxidizing agent in the presence of a suitable organic solvent; (b) quenching of the reaction mass of step (a) using a suitable base and adjusting pH of the reaction mass to about 7 to about 9.5;

(c) extracting the benzimidazole compound of Formula I from the organic layer of step (b) using an aqueous solution of a base; and (d) isolating the benzimidazole by adjusting pH of the aqueous layer of step (c) to about 7 to about 9.

In another embodiment the present invention provides a process for the for the preparation of proton pump inhibitors of the benzimidazole-type having Formula (I) and their salts

Formula I wherein Ri and F^ are the same as or different from each other and are selected from hydrogen, methoxy or difluoromethoxy, R₃, R₄ and R₅ are the same as or different from each other and are selected from hydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy, which process further comprises the step of purifying the product obtained in step (d) from sulphone impurity by treating a solution of the product of step (d) with a base and adjusting the pH to about 7.0 to about 9.5.

Step (a) oxidation of compound of Formula III.

Suitable oxidizing agents which can be used include, but are not limited to metaperoxychlorobenzoic acid, meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, sodium hypochloride, sodium bromite, hydrogen peroxide, sodium meta periodate, iodobenzene, nitric acid, dinitrogen tetraoxide, iodosobenzene, N-halosuccinamide, 1-chlorobenzotriazole, selenium dioxide, manganese dioxide, chromic acid, sulfuryl chloride, and the like, or mixtures thereof.

Suitable solvents which can be used for conducting the reaction include, but are not limited to hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n- hexane and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as N, N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide, acetonitrile and the like or mixtures thereof.

Suitable temperatures for conducting the reaction range from about -50 ⁰C to about 50 ⁰C, or from about -20 ⁰C to about 0 ⁰C.

The amount of oxidizing agent used is less than about 1 molar equivalent or less than about 1.5 molar equivalents of the benzimidazole sulfide compound of Formula III. Usually the amount of oxidizing agent used is such that it results in the maximum conversion of the benzimidazole sulfide compound of Formula III, maximum formation of sulfoxides of Formula I and minimum formation of unwanted sulfones of Formula IV.

Step (b) quenching of the reaction mass of step (a).

Suitably, the reaction mass is treated with a base followed by adjustment of the pH to about 7 to about 9.5 using an acid.

Suitable bases which can be used include, but are not limited to alkali metal hydrides such as lithium hydride, sodium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof. These bases can be used in the form of solids or in the form of aqueous solutions.

Suitably, aqueous solutions containing about 5% to about 50%, or about 10% to about 20%, (w/v) of the base can be used.

Suitable acids which can be used for adjusting the pH include, but are not limited to organic acids like acetic acid, tartaric acid, formic acid, oxalic acid, succinic acid, benzoic acid, para-toluenesulfonic acid, methanesulfonic acid, and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

The organic layer obtained after pH adjustment contains the benzimidazole compound of Formula I, and it may also contain some amount of sulfone compound of Formula IV as an impurity that may be formed in the reaction as a by-product due to further oxidation of the formed sulfoxide of Formula I.

Step (c) extracting the product from the organic layer of step (b).

The organic layer obtained in step (b) is then extracted into an aqueous solution of a base, in which both the benzimidazole compound of Formula I and the sulfone by-product of Formula IV will be present.

Suitably, aqueous solutions containing about 5% to about 50%, or about 10% to about 20%, (w/v) of the corresponding base can be used. The aqueous solution obtained after extraction may then be washed with an organic solvent to remove the organic impurities which do not form an ionic salt, and hence are not soluble in water. Suitable solvents which can be used to wash out the organic impurities include, but are not limited to halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary- butyl ether and the like, or mixtures thereof. The solution obtained can be optionally treated with activated charcoal to enhance the color of the compound followed by filtration through a medium such as through a flux calcined diatomaceous earth (Hyflow) bed to remove the carbon.

Step (d) isolating the benzimidazole having Formula (I).

The pH of the solution obtained in step (c) is then adjusted to about 7 to about 9 using an acid and the product is extracted into an organic solvent.

Suitable acids which can be used for adjustment of pH include, but are not limited to organic acids like acetic acid, tartaric acid, formic acid, oxalic acid, succinic acid, benzoic acid, para-toluenesulfonic acid, methanesulfonic acid, and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

Suitable solvents which can be used for extraction of the product include, but are not limited to halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like, alcohols such as methanol, ethanol, propanol, isopropanol, and the like or mixtures thereof in various proportions.

Optionally, the product is isolated from the organic solvent by concentrating the solution and maintaining further at temperatures lower than the concentration temperatures such as for example below about 10 ⁰C to about 25 ⁰C, for a period of time as required for a complete isolation of the product. The exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry. Isolation of the product may be optionally enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture, or a combination thereof. The solid material isolated is recovered from the final mixture using any of the techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals can be washed with a solvent to wash out the mother liquor. The solid isolated may be further dried. Drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35 ⁰C to about 70 ⁰C.

Purification of the product obtained in step (d). Benzimidazoles which have a certain percentage of the sulfone impurity can be purified by selecting the appropriate pH for isolating the product. The pH range selected is such that at the selected pH range, only the sulfone impurity forms the ionic salt and the product which is in the form of a sulfoxide, does not form salt, and remains in the organic layer.

The pH range for the sulfone impurity to form the salt leaving out the actual sulfoxide product is usually lower than the pH range required for the sulfoxide product to form a salt, and the pH range usually differs for different products. For Example for omeprazole, at a pH range of from about 7.0 to 7.5, only the corresponding sulfone impurity forms the salt, and for rabeprazole, at a pH range of from about 9.0 to about 9.5 only the sulfone impurity forms a salt. Hence, the pH range selected for washing out the impurity will depend upon the benzimidazole that is used.

Suitable bases which can be used include, but are not limited to alkali metal hydrides such as lithium hydride, sodium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof. These bases can be used in the form of solids or in the form of aqueous solutions. Suitably, aqueous solutions containing about 5% to about 50%, or about 10% to about 20%, (w/v) of the corresponding base can be used.

Suitably, pH adjustment is carried out in a heterogeneous medium where the salt of the sulfone impurity formed remains in the aqueous phase and the product in the form of sulfoxide remains in the organic layer.

Suitable organic solvents which can be used during adjustment of the pH include, but are not limited to halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary- butyl ether and the like, alcohols such as methanol, ethanol, propanol, isopropanol, and the like or mixtures thereof in various proportions.

Optionally, the product is isolated from the organic solvent by concentrating the solution and maintaining further at temperatures lower than the concentration temperatures. Isolation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture, or a combination thereof.

The benzimidazole obtained above can be converted to its pharmaceutically acceptable base addition salt by reacting with a suitable base in the presence of a suitable solvent.

Another embodiment of the present invention provides a process for the preparation of rabeprazole having Formula Il

Formula Il and its pharmaceutically acceptable salts free of their sulfone impurity, which process comprises: a) reacting the compound of Formula V

Formula V with an oxidizing agent in the presence of a suitable organic solvent; (b) quenching of the reaction mass of step (a) using a suitable base and adjusting pH of the reaction mass to about 7 to about 9.5;

(c) extracting rabeprazole form the organic layer of step (b) using an aqueous solution of a strong base;

(d) isolating rabeprazole by adjusting pH of the aqueous layer of step c) to about 7 to about 9;

In a further embodiment, the present invention provides a process for the preparation of rabeprazole having Formula Il

Formula Il and its pharmaceutically acceptable salts free of their sulfone impurity, which process further comprises the step of purifying the product obtained in step (d) from sulphone impurity by treating a solution of the product obtained in step (d) with an aqueous base and adjusting the pH to about 9.0 to about 9.5. Step (a) - reaction of the compound of Formula III.

Suitable oxidizing agents which can be used in this step include, but are not limited to metaperoxychlorobenzoic acid, meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, sodium hypochloride, sodium bromite, hydrogen peroxide, sodium meta periodate, iodobenzene, nitric acid, dinitrogen tetraoxide, iodosobenzene, N-halosuccinamide, 1-chlorobenzotriazole, selenium dioxide, manganese dioxide, chromic acid, sulfuryl chloride, and the like, or mixtures thereof.

Suitable solvents which can be used for conducting the reaction include, but are not limited to hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n- hexane and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as N, N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), N.N-dimethylacetamide, acetonitrile and the like or mixtures thereof.

The amount of oxidizing agent used is less than about 1 molar or less equivalent of about 1.5 molar equivalents of the starting material, i.e. the sulfide intermediate of Formula III, which normally results in a less than 100% conversion of starting material.

Step (b) quenching of the reaction mass of step (a).

Suitable acids which can be used for adjusting the pH within the required range include, but are not limited to organic acids like acetic acid, tartaric acid, formic acid, oxalic acid, succinic acid, benzoic acid, para-toluenesulfonic acid, methanesulfonic acid, and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.

Step (c) extracting the product from the organic layer of step (b). The product which remains in the organic layer of step (b) is suitably extracted into an aqueous base.

Suitably, aqueous solutions containing about 5% to about 50%, or about 10% to about 20%, (w/v) of the corresponding base can be used.

During extraction with a strong aqueous base, the unreacted starting material of Formula V remains in the organic layer, and can be suitably recovered form it.

Suitably, the aqueous solution obtained after extraction is further washed with an organic solvent to remove the starting material of Formula V, and other organic impurities which do not form an ionic salt.

Suitable solvents which can be used to wash out the organic impurities include, but are not limited to halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary- butyl ether and the like, or mixtures thereof.

The aqueous solution obtained can be optionally treated with activated charcoal to enhance the color of the compound followed by filtration through a medium such as through a flux calcined diatomaceous earth (Hyflow) bed to remove the carbon.

Step (d) isolation of rabeprazole.

The product may be optionally isolated from the organic solvent by concentrating the solution and maintaining further at temperatures lower than the concentration temperatures such as for example below about 10 ⁰C to about 25 ⁰C, for a period of time as required for a complete isolation of the product. The exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry. Optionally isolation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture, or a combination thereof.

The solid material isolated is recovered from the final mixture using any of the techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals can be washed with a solvent to wash out the mother liquor.

Optionally, the solid isolated may be further dried. Drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35 ⁰C to about 70 ⁰C.

Purification of the product obtained in step (d).

Suitable bases which can be used for the purification include, but are not limited to alkali metal hydrides such as lithium hydride, sodium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof.

These bases can be used in the form of solids or in the form of aqueous solutions.

Suitable acids which can be used for adjusting the pH within the required range include, but are not limited to organic acids like acetic acid, tartaric acid, formic acid, oxalic acid, succinic acid, benzoic acid, para-toluenesulfonic acid, methanesulfonic acid, and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. Suitably, pH adjustment is carried out in a heterogeneous medium where the salt of the sulfone impurity formed remains in the aqueous phase and rabeprazole remains in the organic layer. Suitable organic solvents which can be used during adjustment of the pH include, but are not limited to halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary- butyl ether and the like, alcohols such as methanol, ethanol, propanol, isopropanol, and the like or mixtures thereof in various proportions.

The product can be further purified by recrystallization or slurry, or a combination thereof in suitable solvents.

Suitable solvents which can be used for recrystallization or slurry include, but are not limited to halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like, alcohols such as methanol, ethanol, propanol, isopropanol, and the like or mixtures thereof in various proportions

Rabeprazole obtained above can be converted to its pharmaceutically acceptable base addition salt by reacting with a suitable base in the presence of a suitable solvent by processes known in the art.

In one embodiment, the present invention provides a process wherein the base is sodium hydroxide and the salt obtained is rabeprazole sodium salt prepared by a process comprising the steps of: (a) dissolving rabeprazole in an alcoholic solution of sodium hydroxide.

(b) distilling off the solvent from the solution obtained in step (a), and

(c) isolating rabeprazole sodium.

Suitable alcohols which can be used for preparing the solution of sodium hydroxide include, but are not limited to methanol, ethanol, isopropyl alcohol, n- propanol, and the like or mixtures thereof.

The solution obtained in step (a) after the dissolution of rabeprazole can be optionally filtered to remove the undissolved particles before proceeding to step (b).

The undissolved particles can be removed suitably by filtration, centrifugation, decantation, and other techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Distillation of the solvent in step (b) can be carried out using evaporation, atmospheric distillation, or distillation under vacuum. Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20 ⁰C to about 70 ⁰C. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product. Suitable techniques which can be used for the distillation include, distillation using a rotational evaporator device such as a Buchi Rotovap, spray drying, agitated thin film drying ("ATFD"), and the like.

The residue obtained after distillation in step (b) is further isolated in a combination of an alcoholic solvent and an ether solvent. Suitable alcohols which can be used include, but are not limited to methanol, ethanol, isopropyl alcohol, n- propanol, n-butanol and the like; suitable ether solvents which can be used include, but are not limited to diethyl ether, dimethyl ether, diisopropyl ether, tertiary butyl ether and the like, or mixtures thereof. The isolated solid can be further dried. The drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35 ⁰C to about 70 ⁰C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like.

The dried product can optionally be milled to get the required particle size.

Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities. Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.

Rabeprazole sodium obtained using the process of the present invention has a particle size of less than about 200 μm, or less than about 100 μm.

The Dio, D₅₀ and D₉₀ values are useful ways for indicating a particle size distribution. Dg₀ refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D₅₀ and Di₀ refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining D₁₀, D₅₀ and D₉₀ include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern, Worcestershire, United Kingdom) equipment.

In an embodiment, rabeprazole sodium obtained according to the process of the present invention has D-io less than 50 μm or less than 25 μm, D₅₀ less than 100 μm or less than 150 μm, and D₉₀ less than 500 μm or less than 250 μm. There is no specific lower limit for any of the D values. In an embodiment of the present invention, the crystalline Rabeprazole sodium obtained according to the process of the present invention has degree of crystallinity more than about 70%, or more than about 80%. Crystalline rabeprazole sodium means a substance of rabeprazole sodium with the crystalline structure referred to in the crystallography field as the term means. The term crystalline means a substance different from an amorphous substance.

Another embodiment of the present invention provides a pharmaceutical composition comprising a benzimidazole-type compound or its pharmaceutically acceptable salts prepared according to the process of the present invention along with one or more pharmaceutically acceptable carriers, excipients or diluents. In another embodiment of the present invention provides a pharmaceutical composition comprising rabeprazole or its pharmaceutically acceptable salts prepared according to the process of the present invention along with one or more pharmaceutically acceptable carriers, excipients or diluents.

In an embodiment, the pharmaceutical composition of the present invention may be further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

In an embodiment of the present invention, the compositions of rabeprazole or its pharmaceutically acceptable salts is a useful active ingredient in the range of 20 mg to 350 mg, or 40 mg to 320 mg.

Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are provided only for the purpose of illustration and are not intended to limit the scope of the appended claims in any manner.

EXAMPLE 1

PREPRATION OF RABEPRAZOLE (FORMULA II) 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl] methyl] thio]-H-benzimidazole compound of Formula III (100 g) was charged into a clean and dry 4 neck round bottom flask containing dimethylsulfoxide (200 ml), and chloroform (500 ml) and stirred for about 10 min. The reaction mixture was cooled to a temperature of about -10 ⁰C to about -15 ⁰C. Metaperoxychlorobenzoic acid (60 g) dissolved in chloroform (500 ml) was added slowly over about 90 to about 105 minutes at a temperature of about -10 ⁰C to about -15 ⁰C. The resultant reaction mixture was stirred for about 20 minutes to about 30 minutes followed by decomposition of reaction mass by the addition of basic water (500 ml) (64 g sodium hydroxide dissolved in 500 ml of water). The pH of the reaction solution was adjusted to about 8.5 by addition of acetic acid (63 ml) followed by separation of organic and aqueous layers. The aqueous layer was extracted with chloroform (100 ml) followed by separation of the organic and aqueous layers.

The combined organic layers were extracted with basic water (300, 200 ml) (5 g of sodium hydroxide dissolved in 300 ml water, 3 g of sodium hydroxide dissolved in 200 ml) followed by washing the aqueous layer with chloroform (2x50 ml). The combined aqueous layer was charged into a clean and dry round bottom flask. Activated charcoal carbon (2g) was added into the reaction mass followed by stirring for about 25 minutes to about 30 minutes. The resultant reaction suspension was filtered through celite and the celite was washed with of water (100 ml).

To the resultant clear filtrate, methanol (100 ml) and chloroform (100 ml) were added followed by cooling to a temperature of about 25 ⁰C to about 30 ⁰C. The pH of the reaction solution was adjusted to about 8.6 by the addition of acetic acid (1 1 ml). The organic and aqueous layers were separated and the aqueous layer was extracted with of chloroform (50 ml) and the organic layers were combined.

To the combined organic layer was charged methyltertiarybutylether (450 ml) and stirred for about 45 minutes to about 60 minutes at a temperature of about 0 ⁰C to about 5 ⁰C. The separated solid was filtered and the solid was washed with methyltertiarybutylether (100 ml) to afford 46 g of a crude form of title compound.

Sodium hydroxide flakes (10 g) and water (70 ml) were charged into a clean and dry round bottom flask and stirred for about 5 minutes to 10 minutes. The resultant solution was cooled to a temperature of about 20⁰C to about 25 ⁰C, followed by addition of the above-obtained wet solid. The resultant reaction mixture was stirred for about 25 minutes to about 30 minutes. Methanol (70 ml) was charged to the reaction mixture followed by cooling to a temperature of about 10 ⁰C to about 15 ⁰C. The pH of the reaction solution was adjusted to about 9.3 by addition of acetic acid (14 ml). Water (230 ml) was added in to the reaction mixture and stirred for about 2 hours to 3 hours. The separated solid was filtered and the solid was washed with mixture solution of water (70 ml) and methanol (15 ml).

The obtained wet solid was charged into a clean and dry round bottom flask containing water (230 ml) and stirred for about 5 minutes to about 10 minutes followed by addition of methanol (70 ml). The resultant reaction mixture was stirred for about 30 minutes to about 45 minutes. The solid was filtered and washed with methanol (15 ml) and water (70 ml) mixture solution and again with water (3 x 100 ml).

Methyltertiarybutylether (270 ml) was charged into a clean and dry 4 neck round bottom flask followed by cooling to about 0 ⁰C to about 5 ⁰C. The obtained wet solid was dissolved in dichloromethane (80 ml) and the organic layer was separated. The obtained solution was added into a round bottom flask containing methyltertiarybutylether. The resultant reaction mixture was stirred for about 60 minutes to about 90 minutes at a temperature of about 0 ⁰C to about 5 ⁰C. The separated solid was filtered and the solid was washed with methyltertiarybutylether (15 ml) and suck dried for about 30 minutes to about 45 minutes.

The obtained wet solid was slurry again in methyltertiarybutylether (170ml) for about 30 minutes to about 45 minutes at about 25 ⁰C to about 30 ⁰C. The solid filtered and washed with methyltertiarybutyl (170ml) ether and suck dried for about 45 minutes to about 60 minutes. The solid obtained was dried at about 45 ⁰C to about 50 ⁰C under vacuum for about 5 hours to about 6 hours to afford 29 g of the title compound. Purity By HPLC: 99.91 %. % of sulfone impurity: 0.047%. EXAMPLE 2 PREPRATION OF RABEPRAZOLE (FORMULA II)

Chloroform (325 liters), and meta-chloro-per-benzoic-acid (39.0 kg) were taken into a reactor and the mixture was stirred for about 50 minutes. The meta- chloro-per-benzoic-acid layer which settles at the bottom was separated, and taken into an addition bulb. Chloroform (325 liters), 2-[[[4-(3-methoxypropoxy)-3-methyl-2- pyridinyl] methyl] thio]-H-benzimidazole (65 kg) and DMSO (130 liters) were taken into another reactor and cooled to a temperature of about -12.5 ⁰C. The solution of meta-chloro-per-benzoic-acid prepared above was added to the cooled reaction mass slowly. The reaction mass was maintained at about -12 ⁰C for about 30 minutes.

A solution of water (325 liters) and sodium hydroxide (41 .6 kg) was added to the above reaction mass and stirred for about 10 minutes. The pH of the reaction mass was adjusted to about 8.5 to about 9.0 using acetic acid (44 liters). The organic layer was separated and the aqueous layer was extracted into chloroform (65 liters). The organic layer was then extracted into a solution of sodium hydroxide flakes (3.2 kg) in water (195 liters), followed by extraction with a solution of sodium hydroxide (2.0 kg) in water (130 liters). The combined aqueous layer was washed with chloroform (30 X 2 liters). The aqueous layer was given carbon treatment and filtered through a hyflow bed. The carbon bed was washed with water (65 liters). To the aqueous layer chloroform (65 liters) and methanol (65 liters) were added and the mixture cooled to about 22.5 ⁰C. The pH of the reaction mixture was adjusted to about 8.5 to about 9.0 using a 1 :1 combination of acetic acid and water (20 liters), and the organic layer was separated, and the aqueous layer was extracted into chloroform (30 liters). The combined organic layer was added to methyl tertiary butyl ether (290 liters) cooled to a temperature of about 2 ⁰C to about 5 ⁰C. The reaction mass was maintained at about 2 ⁰C to about 5 ⁰C for about 15 minutes. The separated solid was filtered and washed with methyl tertiarybutyl ether (65 liters).

The wet material and methanol (45 liters) were added to a solution of sodium hydroxide (6.5 kg) in water (45 liters) taken into a reactor. The reaction mass was stirred for about 25 minutes to about 30 minutes for clear dissolution and then cooled to about 12.5 ⁰C. The pH of the solution was adjusted to about 9.3 to about 9.7 using a 1 :1 solution of acetic acid in water (24 liters) followed by addition of water (98 liters). The pH was readjusted to about 9.3 to about 9.7 using a 1 :1 solution of acetic acid in water at about 12 ⁰C to about 15 ⁰C. The reaction mass was maintained at about 12 ⁰C to about 15 ⁰C for about 30 minutes. The separated solid was filtered and washed with a solution of water (45 liters) and methanol (10 liters). The wet solid was again slurried in a combination of water (215 liters) and methanol (45 liters) for about 45 minutes, and then filtered. The filtered solid was washed with a mixture of water (45 liters) and methanol (10 liters), followed by washing with water (195 liters). Metyl tertiary butyl ether (175 liters) was taken into a reactor and cooled to about 2.5 ⁰C. Dichloromethane (52 liters) was added to it followed by addition of the wet material. The reaction mass was stirred for about 30 minutes at the same temperature and them filtered. The filtered material was washed with methyl tertiary butyl ether (10 liters).

The wet material was taken into another 1 10 liters of methyl tertiary butyl ether and stirred for about 40 minutes. The material was then filtered and washed with methyl tertiary butyl ether (25 liters). The wet material was dried at about 47 ⁰C for about 30 minutes to get 19.8 kg of the title compound.

EXAMPLE 3 PREPARATION OF RABEPRAZOLE SODIUM:

Sodium hydroxide flakes (6.0 kg) and methanol (80 liters) were taken into a reactor and stirred for about 1 hour. The mixture was checked for clear dissolution and then rabeprazole (40kg) was added to the solution and stirred at about 25 ⁰C for about 2 hours. The solution was checked for clear dissolution and distilled off completely under a vacuum of about 550 mm/Hg at a temperature of about 50 ⁰C. The residue obtained was cooled to about 25 ⁰C and n-butanol (20 liters) was added and stirred for about 25 minutes. Methyl tertiary butyl ether (160 liters) was then added and stirred at about 25 ⁰C for about 10 minutes. Another 240 liters of methyl tertiary butyl ether was added to it and stirred for about 10 minutes. Rabeprazole sodium pure sample (0.8 kg) was added as a seed to the reaction mass and maintained at about 25 ⁰C for about 12 hours. The reaction mass was then further cooled to about 5 ⁰C and maintained for about 3 hours. The separated solid was filtered and washed with methyl tertiary butyl ether (80 liters) under nitrogen atmosphere. The wet solid was dried at about 25 ⁰C to about 30 ⁰C for about 3 hours and then sieved and then again dried at about 50 ⁰C to about 60 ⁰C for about 4 hours. Finally, the solid was dried at a temperature of about 90 ⁰C to about 95 ⁰C for about 4 hours to about 5 hours. The material was further sifted in a No. 10 mesh, and finally pulverized to yield 36 kg of the title compound. Purity by HPLC: 99.83%. % of sulfone impurity: 0.07%. Particle Size analysis: D₉₀: Less than 70 μm. Water by KF: 5.4% w/w.

Claims

1. A process for preparing proton pump inhibitors of the benzimidazole-type having Formula (I) and their salts

Formula (I) wherein Ri and R₂ are the same as or different from each other and are selected from hydrogen, methoxy or difluoromethoxy, R₃, R₄ and R₅ are the same as or different from each other and are selected from hydrogen, methyl, methoxy, methoxypropoxy or trifluoroethoxy, which process comprises: (a) reacting of the compound of Formula (III)

Formula (III) wherein Ri , R₂, R₃, R₄ and R₅ are as described above, with an oxidizing agent;

(b) quenching of the reaction mass of step (a) using a base and adjusting pH of the reaction mass to about 7.0 to about 9.5;

(c) extracting the benzimidazole formed in the reaction of step (a) from the organic layer of step (b) using an aqueous solution of a base; and

(d) isolating the benzimidazole by adjusting pH of the aqueous layer of step (c) to about 7 to about 9.

2. The process of claim 1 , which further comprises purifying the product obtained in step (d) from sulphone impurity by treating with a base and adjusting the pH to about 7.0 to about 9.5.

3. The process of claim 2, wherein, the benzimidazole obtained is further purified by recrystallization or slurry in an organic solvent.

4. The process of claim 1 , wherein the base in step (a) is sodium hydroxide.

5. The process of claim 1 , wherein the benzimidazole is further converted to its pharmaceutically acceptable salts.

6. The process of claim 5, wherein the pharmaceutically acceptable salt is rabeprazole sodium salt.

7. The process claim 6, wherein said rabeprazole sodium has Dio less than 50 μm or less than 25 μm, D₅₀ less than 100 μm or less than 150 μm, and D₉₀ less than 500 μm or less than 250 μm.

8. The process of claim 1 , wherein the benzimidazole is selected from rabeprazole, omeprazole, pentoprazole and lasoprazole.

9. The process of claim 8, wherein the benzimidazole is rabeprazole.

10. The process of claim 1 , wherein the pH range in step (a) is from about 8.0 to about 9.5.

1 1. The process of claim 1 , wherein the pH range in step (b) is from about 8.0 to about 9.5.

12. The process of claim 12, wherein the pH range is from about 9.0 to about 9.5.

13. The process according to any of the claims mentioned above, wherein said benzimidazole compound obtained has a purity of more than about 99.5% by HPLC.

14. The process of claim 13, wherein said benzimidazole compound is rabeprazole.

15. The process according to any of the claims mentioned above, wherein said benzimidazole compound obtained has less than 0.15% by HPLC of the sulfone impurity.

16. The process of claim 15, wherein said benzimidazole compound is rabeprazole.

17. The process according to any of the claims mentioned above, further comprising conversion of the product into its pharmaceutically acceptable salts.

18. A pharmaceutical composition comprising a benzimidazole compound obtained according to the process described in any of the above mentioned claims or its pharmaceutically acceptable salts prepared according to the process given in any of the above claims along with one or more pharmaceutically acceptable carriers, excipients or diluents.

19. The pharmaceutical composition of claim 18, wherein said benzimidazole compound is Rabeprazole or its pharmaceutically acceptable salts.

20. The pharmaceutical composition of claim 19, wherein said rabeprazole or its pharmaceutically acceptable salts is in the range of 20 mg to 350 mg.

21. The pharmaceutical composition of claim 19, wherein said rabeprazole or its pharmaceutically acceptable salts is in the range of 40 mg to 320 mg.