WO2008045777A2

WO2008045777A2 - A process for the preparation of benzimidazole derivatives and their salts

Info

Publication number: WO2008045777A2
Application number: PCT/US2007/080544
Authority: WO
Inventors: Vijaya Kumar Kotagiri; Pravinchandra Jayantilal Vankawala; Uday Kumar Neelam; Sudhakar Reddy Baddam; Ravi Ram Chandrashekar Elati; Naveen Kumar Kolla; Jaydeepkumar Lilakar Dayabhai; Ramchandra Reddy Pingili; Srinivas Gangula; Vijaykumar Reddy Jonnalagadda; Pallvi Thakur; Anitha Neredla; Venkata Rambabu Kammili
Original assignee: Dr. Reddy's Labortories, Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2006-10-06
Filing date: 2007-10-05
Publication date: 2008-04-17
Also published as: EP2069329A2; WO2008045777A3; EP2069329A4

Abstract

The present relates to a process for the preparation of 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazole derivatives and their pharmaceutically acceptable salts substantially free from their sulfide and the sulfone impurities.

Description

A PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVES AND

THEIR SALTS

TECHNICAL FIELD

This application relates to a process for the preparation of 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives and their pharmaceutically acceptable salts.

INTRODUCTION

2-(2-pyridylmethyl) sulfinyM H-benzimidazole derivatives are gastric proton pump inhibitors. Examples include lansoprazole, omeprazole, pantoprazole, and rabeprazole. This class of benzimidazole may be represented by the Formula I

Formula I where Ri represents a hydrogen atom, a methoxy group, or a difluoromethoxy group, R₂ represents a methyl group, or a methoxy group, R₃ represents a 3-methoxypropoxy group, a methoxy group, or a 2,2,2-trifluoroethoxy group, and R₄ represents a hydrogen atom or a methyl group.

2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives may be prepared by a reaction of the mercaptobenzimidazole derivative of Formula III

Formula III where R1 has the same meaning as described earlier; with a substituted pyridine derivative of Formula IV or its acid addition salt

Formula IV where R2, R3, and R4 have the same meaning as described earlier and X is a halogen atom; in the presence of a base to get the intermediate of the Formula II,

Formula Il where R1 , R2, R3, R4 have the same meaning as described earlier. Upon oxidation of the thioether group, the intermediate of the Formula II, gives the 2-(2-pyridylmethyl) sulfinyM H-benzimidazole derivative of Formula I as a sulfoxide.

One issue known in the art is the undesirable formation of the sulfone compound of the Formula V, produced by over oxidation of the sulfide intermediate of Formula V.

Formula V where R1 , R2, R3, R4 have the same meaning as described earlier.

The sulfone and related impurities may be difficult to remove due to similarity of their structures, and physiochemical properties to the target compounds. It is thus desirable to control sulfone formation.

WO2004/11029, WO200463118, WO2005/077936, WO2006049486, WO2007068925, WO2007/026188, and US6423846 have described methods, which, to some extent, tried to address the issue. However, there is a continuing need for an industrially viable process with reduced sulfone formation and commercially acceptable yield.

SUMMARY

There is provided a process for the preparation of benzimidazoles and their pharmaceutically acceptable salts in high yields substantially free from their sulfide and the sulfone impurities.

In one embodiment, there is provided a process for the preparation of the sulfide intermediate of the general Formula Il

Formula Il where Ri represents a hydrogen atom, a methoxy group, or a difluoromethoxy group, R₂ represents a methyl group, or a methoxy group, R3 represents a 3-methoxypropoxy group, a methoxy group, or a 2,2,2-trifluoroethoxy group, and R₄ represents a hydrogen atom or a methyl group; the process including reacting a mercaptobenzimidazole of the Formula III with a pyridine derivative of the Formula IV or its acid addition salt in the presence of from about 2.0 to about 4.0 equivalents of a base.

Formula Formula IV

In another embodiment, there is provided a process for the preparation of 2-(2- pyridylmethyl) sulfinyl-1 H-benzimidazoles of Formula I, which process includes, -A-

a) reacting the sulfide intermediate of the Formula Il with about 0.8 to about 1.25 equivalents of an oxidizing agent in the presence of less than or about 2.25 equivalents of a base; and b) isolating said 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazoles at a pH of about 6.0 to about 10.0.

Various embodiments and variants, including embodiments for specific bezimidazoles, are provided.

DETAILED DESCRIPTION

As set forth above, the process for the preparation of the sulfide intermediate of the Formula II.

Formula Il includes reacting a mercaptobenzimidazole of the Formula III with the pyridine derivative of the Formula IV or its acid addition salt in the presence of from about 2.0 to about 4.0 equivalents of a base.

Formula III Formula IV

Suitable solvents that can be used for this reaction include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles such as acetonitrile, priopionitrile, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; and water or mixtures thereof or their combinations with water in various proportions. In one embodiment, the preferred solvents include water, and ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; or mixtures thereof, or their mixture with water in various proportions. In another embodiment the particularly preferred solvents include water, and acetone or a combination thereof.

Suitable temperatures at which the reaction may be conducted range from about -10 ⁰C to about 50 ⁰C₁ and more particularly from about 10 ⁰C to about 30 ⁰C.

Suitable bases that can be used include, but are not limited to: organic bases such as pyridine, triethylamine, ethylamine, dicyclohexylamine, diisopropyl ethylamine, and the like; 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. The preferred bases are alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; the particularly preferred bases are sodium hydroxide and potassium hydroxide.

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

The mole ratio of the base used may range from about 2.0 to about 4.0 equivalents based on the starting pyridine derivative, including any and all intermediate values. While the invention described herein is not limited to any specific theory, it is believed, that the base is used generally in an amount slightly excessive relative to the equivalent amount. One equivalent of the base is consumed for breaking the hydrochloride salt of the pyridine derivative, and one equivalent is required for conducting the reaction. Excess amount of base other than these two equivalents may convert the formed sulfide intermediate into its sodium salt, thereby making it soluble in water, which may get washed away during work-up.

The sulfide intermediate of the Formula Il prepared using the process described herein is substantially pure, i.e. it contains less than about 0.5%, or less than about 0.1 % of the corresponding process-related impurities as characterized by a high performance liquid chromatography ("HPLC") chromatogram obtained from a mixture comprising the desired compound and one or more of the impurities.

In one embodiment, the sulfide intermediate is 5-difluoromethoxy-2(3,4- dimethoxy-pyridin-2-ylmethyl thio)-1 H-benzimidazole of Formula Ha,

Formula Ha and the process for its preparation comprises reacting 5-difluoromethoxy-2-mercapto benzimidazole of Formula Ilia with 2-chloromethyl-3,4-dimethoxy-pyridine hydrochloride of Formula IVa in the presence of 2.0 to 3.0 equivalents of a base, or alternatively, from about 2.0 to about 2.5 equivalents of a base.

Formula Ilia Formula IVa

Suitable solvents that can be used for the reaction include, but are not limited to: water, alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; or mixtures thereof or their combinations with water in various proportions. The preferred solvents include water, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like, or their mixtures. The particularly preferred solvents include water, acetone, and methanol, or their mixtures in various proportions.

Suitable temperatures at which the reaction may be conducted range from about -10 ⁰C to about 50 ⁰C, more particularly from about 10 ⁰C to about 30 ⁰C.

Suitable bases that can be used include, but are not limited to: alkali metal hydroxides such as, sodium hydroxide, lithium hydroxide, potassium hydroxide and the like; alkali metal hydrides such as lithium hydride, sodium hydride 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. The preferred bases include alkali metal hydroxides such as, sodium hydroxide, lithium hydroxide, and potassium hydroxide. The particularly preferred bases include sodium hydroxide and potassium hydroxide.

The 5-difluoromethoxy-2(3,4-dimethoxy-pyhdin-2-ylmethyl thio)-1 H- benzimidazole of Formula Ma obtained according to the process described herein has a purity of more than 99.0% or more than about 99.5% by HPLC, and has the percentage of all the individual process related impurities less than 0.5%.

In another embodiment, the sulfide intermediate is 2-[4-(3-methoxypropoxy)-3- methyl-pyridin-2-ylmethylsulfanyl]-1 H-benzimidazole of Formula lib

Formula lib and the process for its preparation include reacting 2-mercaptobenzimidazole of Formula NIb with 2-chloromethyl-4-(3-methoxypropoxy)-3-methyl-pyridine of Formula IVb in the presence of from about 2.0 to about 3.0 equivalents of a base; or from about 2.0 to 2.5 equivalents of a base.

Formula 1Mb Formula IVb

Suitable solvents that can be used for the reaction include, but are not limited to: water, alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like;, and the like; nitriles such as acetonitrile, priopionitrile, and the like; or mixtures thereof or their combinations with water in various proportions. The preferred solvents are ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like and water, or mixtures thereof.

Suitable temperatures at which the reaction may be conducted range from about -10 ⁰C to about 50 ⁰C₁ or from about 10 ⁰C to about 30 ⁰C.

Suitable bases that can be used include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal hydrides such as lithium hydride, sodium hydride and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like. These bases can be used in the form of solids or in the form of aqueous solutions. The preferred bases are alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide.

The 2-[4-(3-methoxypropoxy)-3-methyl-pyridin-2-ylmethylsulfanyl] -1 H- benzimidazole of Formula lib obtained according to the process described herein, may have a purity of more than 99.0% by HPLC, or more than about 99.5% by HPLC, and has the percentage of all the individual process related impurities less than 0.5%. As set forth above, there is provided a process for the preparation of 2-(2- pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives of the Formula I, the process including: a) reacting the sulfide intermediate of the Formula Il with from about 0.8 to about 1.25 equivalents of an oxidizing agent in the presence of less than or about 2.25 equivalents of a base; and b) isolating the product at a pH of about 6.0 to about 10.0.

Suitable solvents that can be used for the reaction include, but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and the like; nitriles such as acetonitrile, priopionitrile, and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; and mixtures thereof or their combinations with water in various proportions. The preferred solvents include nitriles such as acetonitrile, propionitrile and the like. The particularly preferred solvent is acetonitrile.

Suitable temperatures which can be used for conducting the reaction range from about -10 ⁰C to about 50 °C, or from about 10 ⁰C to about 30 ⁰C.

Suitable oxidizing agents that can be used for the reaction include, but are not limited to sodium hypochloride, sodium hypobromite, calcium hypochlorite, perphthalic acid, meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, permaleic acid, , 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. The preferred oxidizing agent is sodium hypochlorite. Suitable bases that can be used include, but are not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal hydrides such as lithium hydride, sodium hydride and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like. These bases can be used in the form of solids or in the form of aqueous solutions. The preferred base is sodium hydroxide.

The product formed in the above reaction mass is isolated after adjusting the pH to a suitable value. Selection of the pH range at which the product can be isolated is very important, since the percentage of the sulfone impurity in the final product and the yield of the product is dependant on the pH at which the product is isolated.

Suitable acids that 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 pH range for the sulfone impurity to form the salt leaving out the actual sulfoxide product is usually lower the pH range required for the sulfoxide product to form a salt.

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

The product obtained above can be further purified by recrystallization or slurry, or a combination thereof in suitable solvents. The product can be obtained in the form of a crystalline or an amorphous form by appropriate methods known to a person skilled in the art.

Suitable solvents that 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.

2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives of Formula I prepared using the process of the present invention is substantially pure, i.e. it contains less than about 0.5%, or less than about 0.1 % of the corresponding process related impurities such as the corresponding sulfide or sulfone impurities as characterized by a high performance liquid chromatography ("HPLC") chromatogram obtained from a mixture comprising the desired compound and one or more of the impurities.

In an embodiment, the 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole is pantoprazole and the process includes: a) reacting 5-difluoromethoxy-2(3,4-dimethoxy-pyridin-2-ylmethyl thio)-1 H- benzimidazole with about 0.9 to about 1.03 equivalents of an oxidizing agent in the presence of about 1.0 to about 2.0 equivalents of a base; and b) isolating the product at a pH of about 6.0 to about 7.0.

Suitable solvents that can be used for the reaction include, but are not limited to nitriles such as acetonitrile, priopionitrile, and the like; alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate, and the like;; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; and mixtures thereof or their combinations with water in various proportions. The preferred solvents include nitriles such as acetonitrile, propionitrile and the like. The particularly preferred solvent is acetonitrile.

Suitable temperatures which can be used for conducting the reaction range from about -10 ⁰C to about 50 ⁰C, or from about 10 ⁰C to about 30 ⁰C. Suitable oxidizing agents that can be used for the reaction include, but are not limited to sodium hypochlorite, sodium hypobromite, calcium hypochlorite, perphthalic acid, permaleic acid, sodium meta periodate, meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, hydrogen peroxide, iodobenzene, nitric acid, dinitrogen tetraoxide, iodosobenzene, N-halosuccinamide, 1 -chlorobenzotriazole, selenium dioxide, manganese dioxide, chromic acid, sulfuryl chloride, and the like or mixtures thereof. The preferred oxidizing agent is sodium hypochlorite.

Suitable bases that can be used include, but are not limited to alkali metal hydroxides such as sodium hydroxide; lithium hydroxide, potassium hydroxide and the like; alkali metal hydrides such as lithium hydride, sodium hydride and the like;; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like. These bases can be used in the form of solids or in the form of aqueous solutions. The preferred base is sodium hydroxide.

The product formed in the above reaction mass is extracted after adjusting the pH to a suitable value. Selection of the pH range at which the product can be isolated is very important, since the percentage of the sulfone impurity in the final product and the yield of the product is dependant on the pH at which the product is isolated.

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

For pantoprazole, at a pH range of from about 6.0 to about 7.0, only the corresponding sulfone impurity forms the salt, but the sulfoxide product does not form a salt. Hence a pH range of about 6.0 to about 7.0, or more specifically from about 6.5 to about 7.0 gives good results for pantoprazole. At this pH, the salt of the sulfone impurity formed remains dissolved in the aqueous phase and the product in the form of sulfoxide remains isolated in the aqueous phase.

The product isolated in the aqueous layer 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.

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

Suitable solvents that can be used for recrystallization or slurry include, but are not limited to esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane 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.

Pantoprazole obtained above has a purity of more than about 99%, and contains less than about 0.5%, or less than about 0.1 % of the corresponding process related impurities such as the corresponding sulfide or sulfone impurities as characterized by high performance liquid chromatography ("HPLC") chromatogram.

In another embodiment, the 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole is lansoprazole and the process comprises: a) reacting 2-[[{4-(2,2,2-trifluroethoxy)-3-methyl pyridine-2-yl}methyl]thio]-1 H- benzimidazole with about 0.9 to about 1.20 equivalents of an oxidizing agent in the presence of less than about 2.0 equivalents of a base; and b) isolating the product at a pH of about 9.0 to about 10.0. Suitable solvents that can be used for the reaction include, but are not limited to nitriles such as acetonitrile, priopionitrile, and the like; alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; and mixtures thereof or their combinations with water in various proportions. The preferred solvents include nitriles such as acetonitrile, propionitrile and the like. The particularly preferred solvent is acetonitrile.

Suitable temperatures that can be used for conducting the reaction range from about -10 ⁰C to about 50 ⁰C, or from about 10 ⁰C to about 30 ⁰C.

Suitable oxidizing agents that can be used for the reaction include, but are not limited to sodium hypochlorite, sodium hypobromite, calcium hypochlorite, perphthalic acid, permaleic acid, meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, 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. The preferred oxidizing agent is sodium hypochloride.

Suitable bases that can be used include, but are not limited to alkali metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide and the like; alkali metal hydrides such as lithium hydride, sodium hydride and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like. These bases can be used in the form of solids or in the form of aqueous solutions. The preferred base is sodium hydroxide.

The product formed in the above reaction mass is extracted after adjusting the pH to a suitable value. Selection of the pH range at which the product can be isolated is very important, since the percentage of the sulfone impurity in the final product and the yield of the product is dependant on the pH at which the product is isolated. Suitable acids that 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.

For lansoprazole, at a pH range of from about 9.0 to about 10.0, only the corresponding sulfone impurity forms the salt, but the sulfoxide product does not form a salt. Hence a pH range of about 9.0 to about 10.0, or more specifically from about 9.5 to about 10.0 gives good results for lansoprazole. At this pH, the salt of the sulfone impurity formed remains dissolved in the aqueous phase and the product in the form of sulfoxide remains isolated in the aqueous phase.

The product obtained after isolation typically has a moisture content of more than about 20%, or more than about 5 %.

The product obtained above can be further purified by recrystallization or slurry, or a combination thereof in suitable solvents to reduce the content of water as well as to remove the process related impurities. The product can be obtained in the form of a crystalline or an amorphous form by appropriate methods known to a person skilled in the art.

Suitable solvents that can be used for recrystallization or slurry include, but are not limited to esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like, alcohols such as methanol, ethanol, propanol, isopropanol, ethers such as dimethylether, diethylether, diisopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, 1 ,4-dioxane and the like or mixtures thereof or their combination with water in various proportions without limitation.

Suitably, isolation of the product is carried out by saturating a solution of lansoprazole in any of the above mentioned solvents with an anti-solvent, suitable anti- solvents that can be used for saturation include but are not limited to protic solvents such as water, alcoholic solvents such as methanol, ethanol and the like. Mixtures of any of these solvents are also contemplated. The temperature for saturation can range from about -20 ⁰C to about 35⁰C.

In an embodiment, the purification is carried out using tetrahydrofuran as solvent and water as the anti-solvent which helps in controlling the moisture content of the isolated solid to less than about 1 % or less than about 0.5%.

Lansoprazole obtained above has a moisture content of less than about 0.5%, or less than about 0.1 %. It has a purity of more than about 99%, and contains less than about 0.5%, or less than about 0.1 % of the corresponding process related impurities such as the corresponding sulfide or sulfone impurities as characterized by high performance liquid chromatography ("HPLC") chromatogram.

Lansoprazole obtained using the process of the present invention is also free of impurities at relative retention time of 1 .3, 3.8, 4.0 RRT as measured by HPLC method given below.

The above-mentioned impurity is analyzed by the high performance liquid chromatography (HPLC) method using a column YMC-PAK AQ-302, Ci₈, 150x4.6 mm, 5 μ or equivalent while the other parameters are as shown in table 1 ). Tabie 1

In another embodiment, the 2-(2-pyridyl methyl) sulfinyl-1 H-benzimidazole is rabeprazole and the process comprises: a) reacting 2-[4-(3-methoxypropoxy)-3-methyl-pyridin-2-ylmethylsulfanyl]-1 H- benzimidazole with about 0.9 to about 1.20 equivalents of an oxidizing agent in the presence of less than or about 2.25 equivalents of a base; and b) isolating the product at a pH of about 8.0 to about 9.0.

Suitable solvents that can be used for the reaction include, but are not limited to alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; nitriles such as acetonitrile, priopionitrile, and the like; and mixtures thereof or their combinations with water in various proportions. The preferred solvents include nitriles such as acetonithle, propionitrile and the like. The particularly preferred solvent is acetonitrile.

Suitable oxidizing agents that can be used for the reaction include, but are not limited to sodium hypochlorite, sodium hypobromite, calcium hypochlorite, perphthalic acid, permaleic acid, meta-chloroperbenzoic acid, peracetic acid, trifluoroperacetic acid, 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. The preferred oxidizing agent is sodium hypochlorite.

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

The percentage of sulfone impurity formed in the reaction mass is less than about 1 %, or less than about 0.5%.

The product formed in the above reaction mass is extracted after adjusting the pH to a suitable value. Selection of the pH range at which the product can be isolated is very important, since the percentage of the sulfone impurity in the final product and the yield of the product is dependant on the pH at which the product is isolated. 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.

For rabeprazole, at a pH range of from about 8.0 to about 9.0, only the corresponding sulfone impurity forms the salt, but the sulfoxide product does not form a salt. Hence a pH range of about 8.0 to about 9.0, or more specifically from about 8.0 to about 8.5 gives good results for rabeprazole. At this pH, the salt of the sulfone impurity formed remains dissolved in the aqueous phase and the product in the form of sulfoxide remains isolated in the aqueous phase.

The product isolated in the aqueous layer 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 suitable solvent to wash out the mother liquor.

Suitable solvents which can be used for recrystallization or slurry include, but are not limited to esters such as ethyl acetate, propyl acetate and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane 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 has a purity of more than about 99%, and contains less than about 0.5%, or less than about 0.1 % of the corresponding process related impurities such as the corresponding sulfide or sulfone impurities as characterized by high performance liquid chromatography ("HPLC") chromatogram.

The 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives obtained above can be converted to their pharmaceutically acceptable base addition salts by reacting with a suitable base in the presence of a suitable solvent by processes known in the art.

In an embodiment, 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole is pantoprazole, the pharmaceutically acceptable base is sodium hydroxide and the salt obtained is pantoprazole sodium sesquihydrate prepared by a process comprising the steps of: a) dissolving pantoprazole in an aqueous solution of sodium hydroxide containing a water soluble organic solvent; b) distilling off the solvent from the solution obtained in step a); and c) isolating pantoprazole sodium sesquihydrate form an ester solvent, or an ethereal solvent in the presence of specific amount of water.

Suitably, pantoprazole is added to an aqueous solution of sodium hydroxide containing a water soluble organic solvent. Suitable water soluble organic solvents which can be used include, but are not limited to nitriles such as acetonitrile, propionitrile and the like; alcohols such as methanol, ethanol, propanol, isopropanol, and the like or mixtures thereof in various proportions.

The solution obtained 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. The solution obtained may also 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. The carbon treatment can be conducted either at the dissolution or concentration temperatures, or after cooling the solution to lower temperatures.

Distillation of the solvent 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 10° C to about 70° C. Typically, lower temperatures of the order of less than about 30 ⁰C or less than about 20 °C are used to control the moisture content of the reaction mass for forming the sesquihydrate in step c).

Suitable techniques which can be used for the distillation include, distillation using a rotational evaporator device such as a Buchi Rotovap, or spray drying, or agitated thin film drying ("ATFD"), and the like.

The residue obtained after distillation in step b) is further isolated in an ether or an ester solvent. Suitable ether and ester solvents which can be used include, but are not limited to ethers such as methyl tertiary-butyl ether, dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 1-4-dioxane, and the like; and esters such as esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like or mixtures thereof.

The mixture may be suitably heated further to higher temperatures to get a clear solution, in case a clear solution is not obtained directly.

The moisture content of the solution containing pantoprazole sodium and the ether or ester solvent is adjusted to about 1.6% to about 2 % for getting the required sesquihydrate. lsolation of the product is performed by maintaining the solution obtained further at temperatures lower than the temperatures used for preparing the solution such as for example below about 5 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.

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° C to about 70° C. 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.

In an embodiment, 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole is rabeprazole and the pharmaceutically acceptable base is sodium hydroxide and the salt obtained is rabeprazole sodium prepared by a process that includes 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 from a combination of an alcohol and an ether solvent.

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, centhfugation, 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° C to about 70° C. 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 2-(2-pyridyl methyl) sulfinyl-1 H-benzimidazole obtained using the above process is substantially free of its sulfide starting material and the corresponding sulfone impurity. By "substantially free", it is meant that 2-(2-pyridylmethyl) sulfinyl-1 H- benzimidazole or their pharmaceutically acceptable salts prepared according to the process of the present invention contain less than about 0.15%, or less than about 0.1% of each of the sulfide and the sulfone impurities.

Another embodiment provides a pharmaceutical composition that includes a therapeutically effective amount of pure benzimidazole derivatives and its salts prepared according to the processes of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

The pharmaceutical composition comprising pure benzimidazole derivatives or their pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers of this invention may 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 formulations described herein 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 the compositions, benzimidazole derivatives or their pharmaceutically acceptable salts is a useful active ingredient in the range of 5 mg to 100 mg, or 20 mg to 50 mg.

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

EXAMPLE 1 : PREPARATION OF 5-DIFLUOROMETHOXY-2(3,4-DIMETHOXY- PYRIDIN-2-YLMETHYL THIO)-1 H-BENZIMIDAZOLE (PANTOPRAZOLE SULFIDE) (FORMULA Ma)-USING 2.1 EQUIVALENTS OF SODIUM HYDROXIDE:

Sodium hydroxide (37.4 g) and water (1000 ml) were taken into a clean and dry 4 neck round bottom flask and stirred for about 10 minutes. 5-difluoromethoxy-2- mercaptobenzimidazole (96.4 g) and 2-Chloromethyl-3, 4-dimethoxy-pyridine hydrochloride (100 g) dissolved in 500 ml of water was added slowly over about 2-3 hours at about 25-30⁰C. The resultant reaction mixture was stirred for about 2 hours. The separated solid was filtered and washed with water (500 ml). The obtained solid was again taken into a fresh round bottom flask containing water (500 ml) and stirred for about 20 minutes. The solid was filtered and suction dried for about 30 minutes. The obtained solid was dried under a vacuum of about 650 mm/Hg and a temperature of about 50 ⁰C for 5 hours to afford 159 g (% Yield: 97.5) of the title compound. Purity By HPLC: 99 %.

EXAMPLE 2: PREPARATION OF PANTOPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE IN THE PRESENCE OF 1.0 EQUIVALENT OF SODIUM HYDROXIDE

50 g of pantoprazole sulfide was taken into a clean and dry 4 neck round bottom flask containing 500 ml acetonitrile and stirred for about 10 minutes. A mixture of 88.5 ml of 1 1.4 % aqueous sodium hypochlorite solution and a solution of sodium hydroxide (5.4 g) in 20 ml of water was added slowly at 25-30 ⁰C. The resultant reaction mixture was stirred for 30-45 minutes at 25-30 ⁰C followed by quenching the reaction mass by addition of 1 liter of water and stirring for about 30 minutes at 25-30 ⁰C. The resultant reaction mixture was filtered and the filtrate was added into the fresh round bottom flask and cooled to 0-5 ⁰C. The pH of the solution was adjusted to 6.5 by addition of 70 ml I normal hydrochloric acid solution and then stirred for about 2 hours at 0-5 ⁰C. The separated solid was filtered and the wet solid was dried at 45 ⁰C for 7-8 hours to afford 46.2 g (% Yield: 93%) of the title compound. Purity By HPLC: 98.5%.

EXAMPLE 3: PREPARATION OF PANTOPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE IN THE PRESENCE OF 1.0 EQUIVALENT OF SODIUM HYDROXIDE:

Acetonitrile (120 liters) was taken into a reactor and pantoprazole sulfide (30 kg) was added to it. The mixture was stirred for about 30 minutes and checked for clear dissolution. A solution of water (13 liters) and sodium hydroxide (3.27 kg) was prepared and added to a 10.6% aqueous sodium hypochlorite solution (54.63 kg). This solution was stirred fro about 15 minutes and added to the above solution of pantoprazole sulfide at 25 to 30 ⁰C. The reaction mass maintained at 25 to 35 ⁰C for 45 minutes. Reaction completion was checked using thin layer chromatography. After the reaction is completed, water (100 liters) and hyflow (20 kg) was added to it. The reaction mass was filtered and the filtered bed was washed with water (610 liters). The filtrate was taken into another reactor and cooled to about 0 to 5 ⁰C, and a solution of hydrochloric acid (6 liters) in water (54 liters) was added to it to adjust the pH to about 6.3. The reaction mass was further maintained at about 0 to 5 ⁰C for 1 hour and then centrifuged. The filtered solid was washed with water (60 liters), and the wet material was dried at about 45 ⁰C for 8 hours. The dry material was taken into another reactor and ethyl acetate (52 liters) was added to it. The reaction mass was stirred for about 30 minutes and then cooled to about 0 to 5 ⁰C. The reaction mass was maintained at 0 to 5 ⁰C for about 1 hour and then filtered in a centrifuge. The filtered material was washed with ethyl acetate (26 liters) and spin dried for 2 hours. The wet material was further dried at bout 45 ⁰C for 8 hours to yield 21.7 kg of the title compound (% yield 72.83). Purity By HPLC: 99.7%. % of sulfone impurity: 0.02%. % of pantoprazole sulfide: 0.04%. % of N-oxide impurity: Less than 0.003.

EXAMPLE 4: PREPARATION OF PANTOPRAZOLE SODIUM SESQUIHYDRATE:

A solution of sodium hydroxide (2.41 kg) in water (4.8 liters) was prepared and added to acetonitrile (10 liters) at 25 to 35 ⁰C. The mixture was stirred for about 10 minutes and pantoprazole (22 kg) obtained above was added to it. The reaction mass was stirred for about 1 hour at 25 to 35 ⁰C and checked for clear dissolution. Carbon (1.0 kg) was added to it and stirred for about 60 minutes. The reaction mass was filtered and the filtered bed was washed with acetonitrile (22 liters). The filtrate was distilled off completely at about 18 ⁰C under a vacuum of 650 mm/Hg. The obtained residue was cooled to 25 to 35 ⁰C and ethyl acetate (1 10 liters) was added to it. The reaction mass was stirred for about 20 minutes. The reaction mass was then stirred for about 5 hours at 25 to 35 ⁰C and pure pantoprazole sodium sesquihydrate (0.1 1 kg) was added as seeding material. The reaction mass was further maintained at 25 to 35 ⁰C for about 5 hours, and then further cooled to about 0 to 5 ⁰C. The reaction mass was stirred at 0 to 5 ⁰C for about 3 hours and then filtered. The filtered solid was washed with ethyl acetate (22 liters), and dried at about 50 ⁰C under a vacuum of about 650 mm/Hg for 12 hours to yield 19.5 kg of the title compound. Purity By HPLC: 99.93%. Impurity 1 (pantoprazole sulfide): 0.01 %. Impurity 1 (pantoprazole sulfone): 0.04%.

EXAMPLE 5: PREPARATION OF LANSOPRAZOLE USING 1.2 EQUIVALENTS OF SODIUM HYPOCHLORITE IN THE PRESENCE OF 1.2 EQUIVALENTS OF SODIUM HYDROXIDE:

2-[[{4-(2,2,2-trifluoroethoxy)-3-methyl pyridine-2-yl}methyl]thio]-1 H-benzimidazole (10 kg) and acetonitrile (60 liters) were taken into a reactor and stirred for about 10 minutes. A solution of sodium hydroxide (1.4 kg) in water (4 liters) was prepared and cooled to 0 to 5 ⁰C. 7.91 % aqueous sodium hypochlorite solution (30.1 kg) was added to it and stirred at 0 to 5 ⁰C for about 15 minutes. The sodium hypochlorite solution was added to the above reaction mass slowly at 25 to 35 ⁰C and maintained for about 2 hours at the same temperature. Reaction completion was checked using thin layer chromatography. After the reaction was completed, water (20 liters) was added to it and cooled to about 5 to 10 °C. pH of the reaction mass was adjusted to about 9 to 9.5 using 10% aqueous acetic acid solution and maintained under stirring for about 15 minutes. The reaction mass was further cooled to 0 to 5 ⁰C and maintained for 60 minutes. Another 60 liters of water was added to the reaction mass and maintained at the same temperature for about 4 hours. The reaction mass was filtered and the filtered solid was washed with chilled water (20 liters). The material was spin dried for about 2 hours and then further dried at about 50 ⁰C for 8 hours. The dry solid was taken into another reactor and 39 liters of tetrahydrofuran was added to it, and heated to 40 to 45 ⁰C. The reaction mass was checked for clear dissolution and then filtered. The filtrate was cooled to 30 to 35 ⁰C and 78 liters of water was added to it slowly. The reaction mass was maintained at the same temperature for about 30 minutes and then further cooled to 0-5 ⁰C. The reaction mass was maintained at 0 to 5 ⁰C for about 3 hours and then filtered. The filtered solid was washed with a mixture of 2.2 liters of tetrahydrofuran and 4.3 liters of water. The wet material was suck dried for about 60 minutes and then ethyl acetate (20 liters) was added to it. The mixture was heated to about 50 ⁰C and maintained for about 60 minutes. The reaction mass was the cooled to 0 to 5°C and then the separated solid was filtered, and washed with chilled ethyl acetate (6.5 liters). The wet material was taken into another reactor and ethyl acetate (20 liters) was added to it and stirred at 0 to 5 ⁰C for 2 to 3 hours. The reaction mass was then filtered and the filtered solid was washed with chilled ethyl acetate (6.5 liters). The wet material was spin dried for about 2 hours and then dried at about 50 ⁰C under a vacuum of about 650 mm/Hg for about 8 hours to yield 3.68 kg of the title compound (% yield 35.04%). Purity by HPLC: 99.7%.

EXAMPLE 6: PREPARATION OF LANSOPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE IN THE PRESENCE OF 1.0 EQUIVALENT OF SODIUM HYDROXIDE:

2-[[{4-(2,2,2-trifluoroethoxy)-3-methyl pyridine-2-yl}methyl]thio]-1 H-benzimidazole (5 kg) and acetonitrile (100ml) were taken into a round bottom flask and stirred for about 10 minutes. A solution of sodium hydroxide (0.58 g) in water (2.3 ml) was prepared and 11.7 % aqueous sodium hypochlorite solution (9.9 ml) was added to it. The above solution was added to the reaction mass at 25 to 35 ⁰C and maintained for about 30 minutes at the same temperature. Reaction completion was checked using thin layer chromatography. After the reaction was complete, pH of the reaction mass was adjusted to 6.5 and then water (300 ml) was added to it and stirred for about 1 hour. The separated solid was filtered and washed with water. The wet solid was dried at about 45 ⁰C for about 3 hour to yield 3.9 kg (% yield: 75%) of the title compound. Purity By HPLC: 98%. % of sulfide impurity: 0.033. % of Sulfone impurity: 0.219%. EXAMPLE 7: PREPARATION OF 2-[4-(3-METHOXYPROPOXY)-S-METHYL-PYRIDIN- 2-YLMETHYLSULFANYL]-1 H-BENZIMIDAZ0LE (RABEPRAZOLE SULFIDE) (FORMULA Hb)-USING 2.5 EQUIVALENTS OF SODIUM HYDROXIDE:

A solution of sodium hydroxide (113 g) in water (1200 ml) was taken into a round bottom flask and 2-mercaptobenzimidazole (170 g) was added to it. Acetone (600 ml) was added to it followed by the addition of a solution of 2-chloromethyl-4-(3- methoxypropoxy)-3-methyl-pyridine (300 g) in water (600 ml) at 25 to 35 ⁰C. The reaction mass was maintained at 25 to 35 ⁰C for about 2 hours and then reaction completion was checked using thin layer chromatography. After the reaction was completed, water (1200 ml) was added to the reaction mass and stirred for about 2 hours. The separated solid was filtered and washed with a mixture water (of 300 ml) and acetone (150 ml). The wet material was taken into a solution of sodium hydroxide (30 g) in water (3000 ml) and stirred for about 60 minutes. The reaction mass was filtered and the solid was washed with water (3000 ml). The wet material was dried at 55 to 60 ⁰C for about 4 hours. The dry material was taken into another round bottom flask and ethyl acetate (600 ml) was added to it. The mixture was heated to reflux for getting clear dissolution and maintained for about 1 hour. Then the solution was cooled to 25 to 35 ⁰C and maintained for about 2 hours. The separated solid was filtered and washed with ethyl acetate (300 ml). The wet material was dried at 55 to 60 ⁰C for about 5 hours to yield 300 g of the title compound (% yield: 77.5%).

EXAMPLE 8: PREPARATION OF RABEPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE AND 2.25 EQUIVALENTS OF SODIUM HYDROXIDE:

RAB-1 (20Og) and acetonitrile (600 ml) was taken into a round bottom flask and cooled to 0 to 5 ⁰C. A mixture of a solution of 52.47 g of sodium hydroxide in 240 ml of water and 11.2% aqueous sodium hypochlorite solution (400 ml) and was added to it at the same temperature, and maintained for about 10 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, a solution of sodium thiosulfate (80 g) in water (400 ml) was added to it, and stirred for about 10 minutes. Another water (1000 ml) was added to the reaction mass and the reaction mass was allowed to reach 30 ⁰C. Carbon (20 g) was added to it and stirred for about 15 minutes. Then the reaction mass was filtered and the filtered bed was washed with water (200 ml). The filtrate was washed with toluene (400 ml) in two equal lots and then dichloromethane (400 ml) was added to it. pH of the reaction mass was adjusted to about 8.3 and the organic layer was separated. The aqueous layer was extracted into dichloromethane (60 ml). The combined organic layer was added to methyl tertiary butyl ether (1320 ml) and cooled to about 5 ⁰C. 4 g of seeding material was added to the reaction mass and stirred at about 5 ⁰C for about 3 hours. The separated solid was filtered and washed with methyl tertiary butyl ether (200 ml). The wet material was dried at about 45 to 50 ⁰C for about 4 hours to yield 140.7 g of the title compound (% yield:

67.2).

Purity by HPLC: 99.7.

Impurity 1 (Rabeprazole sulfide): 0.07%.

Impurity 2 (Rabeprazole sulfone): 0.04%.

EXAMPLE 9: PREPARATION OF RABEPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE AND 2.0 EQUIVALENTS OF SODIUM HYDROXIDE:

RAB-1 (25 g) and acetonitrile (75 ml) were taken into a round bottom flask and cooled to 0 to 5 ⁰C. A mixture of a solution of 5.8 g of sodium hydroxide in 30 ml of water and 11.2% aqueous sodium hypochlorite solution (50 ml) and was added to it at the same temperature, and maintained for about 20 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, a solution of sodium thiosulfate (10 g) in water (50 ml) was added to it, and stirred for about 10 minutes. Another lot of water (125 ml) was added to the reaction mass and the reaction mass was allowed to reach 30 ⁰C. Carbon (0.25 g) was added to it and stirred for about 15 minutes. Then the reaction mass was filtered and the filtered bed was washed with water (25 ml). The filtrate was washed with toluene (50 ml) in two equal lots and then dichloromethane (50 ml) was added to it. pH of the reaction mass was adjusted to about 8.4 with acetic acid and the organic layer was separated. The aqueous layer was extracted into dichloromethane (7.5 ml). The combined organic layer was added to methyl tertiary butyl ether (165 ml) and cooled to about 5 ⁰C. 0.5 g of seeding material was added to the reaction mass and stirred at about 5 ⁰C for about 3 hours. The separated solid was filtered and washed with methyl tertiary butyl ether (25 ml). The wet material was dried at about 45 to 50 ⁰C for about 4 hours to yield 17.6 g of the title compound (% yield: 67.4).

Purity By HPLC: 99.6%

Impurity 1 (Rabeprazole sulfide): Less than 0.002%.

Impurity 2 (Rabeprazole sulfone): 0.02%.

EXAMPLE 10: PREPARATION OF RABEPRAZOLE SODIUM:

Sodium hydroxide flakes (11.7 g) and methanol (200 ml) were taken into a round bottom flask and stirred for about 10 minutes. Rabeprazole sulfide (100 g) was added to it followed by addition of carbon, and then stirred for about 30 minutes. The reaction mass was filtered and the filtered bed was washed with methanol (200 ml). The filtrate was distilled off completely at 50 ⁰C and n-butanol (50 ml) was added to it followed by addition of methyl tertiary butyl ether (400 ml). The reaction mass was stirred for about 15 minutes and then another methyl tertiary butyl ether (600 ml) was added and stirred for 10 minutes. Pure rabeprazole sodium (2 g) was added as seed and stirred at 25 to 35 ⁰C for about 15 hours. The reaction mass was then cooled to 0 to 5 ⁰C and stirred for another 1 hour. The separated solid was filtered and washed with methyl tertiary butyl ether (200 ml). The wet material was dried at 50 to 55 ⁰C for about 2 hours followed by sieving followed by drying at 80 to 90 ⁰C for about 5 hours to yield 96 g of the title compound. Purity By HPLC: 99.7% Impurity 1 (Rabeprazole sulfone): 0.05%.

Claims

CLAIMS:

1 A process for preparing 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives having Formula I:

^R4

Formula I wherein Ri represents a hydrogen atom, a methoxy group, or a difluoromethoxy group, R₂ represents a methyl group, or a methoxy group, R₃ represents a 3-methoxypropoxy group, a methoxy group, or a 2,2,2-trifluoroethoxy group, and R₄ represents a hydrogen atom or a methyl group, which process comprises: a) reacting a sulfide intermediate of Formula Il

^R<

Formula Il with about 0.8 to about 1.25 equivalents of an oxidizing agent in the presence of less than or about 2.25 equivalents of a base.

2. The process according to claim 1 , wherein said oxidizing agent is aqueous sodium hypohalite.

3. The process according to claim 2, wherein the hypohalite is sodium hypochlorite,.

4. The process according to claim 2, wherein the percentage of hypochlorite in the solution ranges from about 5 to about 50%.

5. The process according to claim 1 , wherein said base is an alkali metal hydroxide.

6. The process according to claim 5, wherein the base is sodium hydroxide.

7. The process according to claim 1 , wherein R-i represents hydrogen, R₂ represents methyl, R₃ represents trifluoroethoxy, and R₄ represents hydrogen.

8. The process according to claim 1 , wherein Ri represents difluromethoxy, R₂ represents methoxy, R₃ represents methoxy, and R₄ represents hydrogen.

9. The process according to claim 1 , wherein Ri represents hydrogen, R₂ represents methyl, R₃ represents methoxypropoxy, and R₄ represents hydrogen.

10. The process according to claim 1 , wherein Ri represents methoxy, R₂ represents methyl, R₃ represents methoxy, and R₄ represents methyl.

11. A compound which is Lansoprazole prepared according to claim 7, which is substantially free of its sulfide and sulfone impurities.

12. A compound which is pantoprazole prepared according to claim 8, which is substantially free of its sulfide and sulfone impurities.

13. A compound which is Rabeprazole prepared according to claim 9, which is substantially free of its sulfide and sulfone impurities.

14. A compound which is Omeprazole prepared according to claim 10, which is substantially free of its sulfide and sulfone impurities.