Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• This application relates to a process for the preparation of 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives and their pharmaceutically acceptable salts.
• 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
• Ri represents a hydrogen atom, a methoxy group, or a difluoromethoxy group
• R 2 represents a methyl group, or a methoxy group
• R 3 represents a 3-methoxypropoxy group, a methoxy group, or a 2,2,2-trifluoroethoxy group
• R 4 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
• 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.
• Ri represents a hydrogen atom, a methoxy group, or a difluoromethoxy group
• R 2 represents a methyl group, or a methoxy group
• R3 represents a 3-methoxypropoxy group, a methoxy group, or a 2,2,2-trifluoroethoxy group
• R 4 represents a hydrogen atom or a methyl group
• 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.
• 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.
• alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, and the like
• ketones such as acetone, ethyl methyl ketone, methyl
• 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.
• 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 0 C to about 50 0 C 1 and more particularly from about 10 0 C to about 30 0 C.
• Suitable bases 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.
• 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.
• HPLC high performance liquid chromatography
• 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.
• 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 0 C to about 50 0 C, more particularly from about 10 0 C to about 30 0 C.
• Suitable bases 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%.
• 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.
• 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 0 C to about 50 0 C 1 or from about 10 0 C to about 30 0 C.
• Suitable bases 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%.
• a process for the preparation of 2-(2- pyridylmethyl) sulfinyl-1 H-benzimidazole derivatives of the Formula I 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 0 C to about 50 °C, or from about 10 0 C to about 30 0 C.
• 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 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.
• halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as toluene, xylene, n-hexane, n-heptane
• 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.
• HPLC high performance liquid chromatography
• 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.
• Suitable temperatures which can be used for conducting the reaction range from about -10 0 C to about 50 0 C, or from about 10 0 C to about 30 0 C.
• 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 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.
• 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.
• 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.
• 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.
• 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.
• esters such as ethyl acetate, propyl acetate and the like
• halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as tol
• 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.
• HPLC high performance liquid chromatography
• 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 0 C to about 50 0 C, or from about 10 0 C to about 30 0 C.
• 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 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.
• lansoprazole 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 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 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
• 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 0 C to about 35 0 C.
• 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.
• HPLC high performance liquid chromatography
• 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 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 temperatures that can be used for conducting the reaction range from about -10 0 C to about 50 0 C, or from about 10 0 C to about 30 0 C.
• 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.
• 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.
• 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.
• 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.
• 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 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.
• esters such as ethyl acetate, propyl acetate and the like
• halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like, hydrocarbons such as tol
• 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.
• HPLC high performance liquid chromatography
• 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.
• 2-(2-pyridylmethyl) sulfinyl-1 H-benzimidazole is pantoprazole
• the pharmaceutically acceptable base is sodium hydroxide
• 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.
• 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 0 C 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.
• 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 0 C to about 25 0 C, 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.
• 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 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.
• 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.
• 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.
• compositions 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.
• 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.
• compositions 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
• 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.
• 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:
• EXAMPLE 2 PREPARATION OF PANTOPRAZOLE USING 1.0 EQUIVALENT OF SODIUM HYPOCHLORITE IN THE PRESENCE OF 1.0 EQUIVALENT OF SODIUM HYDROXIDE
• pantoprazole sulfide 50 g 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 0 C.
• the resultant reaction mixture was stirred for 30-45 minutes at 25-30 0 C followed by quenching the reaction mass by addition of 1 liter of water and stirring for about 30 minutes at 25-30 0 C.
• the resultant reaction mixture was filtered and the filtrate was added into the fresh round bottom flask and cooled to 0-5 0 C.
• 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.
• 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 0 C, 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 0 C for 1 hour and then centrifuged.
• the filtered solid was washed with water (60 liters), and the wet material was dried at about 45 0 C 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 0 C.
• 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 0 C.
• 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 0 C 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 0 C under a vacuum of 650 mm/Hg.
• the obtained residue was cooled to 25 to 35 0 C 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 0 C and pure pantoprazole sodium sesquihydrate (0.1 1 kg) was added as seeding material.
• the reaction mass was further maintained at 25 to 35 0 C for about 5 hours, and then further cooled to about 0 to 5 0 C.
• the reaction mass was stirred at 0 to 5 0 C for about 3 hours and then filtered.
• EXAMPLE 5 PREPARATION OF LANSOPRAZOLE USING 1.2 EQUIVALENTS OF SODIUM HYPOCHLORITE IN THE PRESENCE OF 1.2 EQUIVALENTS OF SODIUM HYDROXIDE:
• the reaction mass was checked for clear dissolution and then filtered.
• the filtrate was cooled to 30 to 35 0 C 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 0 C.
• the reaction mass was maintained at 0 to 5 0 C 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 0 C 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 0 C 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 0 C 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:
• 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:
• 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 0 C 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.
• the solution was cooled to 25 to 35 0 C 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 0 C 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:
• 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 0 C.
• the separated solid was filtered and washed with methyl tertiary butyl ether (25 ml).
• the wet material was dried at about 45 to 50 0 C for about 4 hours to yield 17.6 g of the title compound (% yield: 67.4).
• Impurity 1 (Rabeprazole sulfide): Less than 0.002%.
• Impurity 2 (Rabeprazole sulfone): 0.02%.

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