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WO2014091450A1 - Procédé pour la préparation de rabéprazole - Google Patents

Procédé pour la préparation de rabéprazole Download PDF

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Publication number
WO2014091450A1
WO2014091450A1 PCT/IB2013/060883 IB2013060883W WO2014091450A1 WO 2014091450 A1 WO2014091450 A1 WO 2014091450A1 IB 2013060883 W IB2013060883 W IB 2013060883W WO 2014091450 A1 WO2014091450 A1 WO 2014091450A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
salt
rabeprazole
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2013/060883
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English (en)
Inventor
Ashwini Kumar Kapoor
Pranab Chatterjee
Asok Nath
Mohan Prasad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2014091450A1 publication Critical patent/WO2014091450A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

Definitions

  • the present invention provides a compound of Formula III, process of its preparation and its use as a reference marker or as a reference standard.
  • the present invention further provides a process for the preparation of rabeprazole, a salt or a solvate thereof.
  • the invention also provides a chromatographic method for testing the purity of rabeprazole, a salt or a solvate thereof.
  • Rabeprazole sodium is marketed in the United States under the brand name Aciphex ® and is indicated for the treatment in healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD).
  • GEF ulcerative gastroesophageal reflux disease
  • Rabeprazole sodium of Formula I is chemically described as sodium salt of 2-( ⁇ [4-(3- methoxypropoxy)-3-methylpyridin-2-yl]methyl ⁇ sulfinyl)-lH-benzimidazole of Formula II.
  • the present inventors have found that the existing processes for the preparation of rabeprazole result in the formation of impurities including genotoxic impurities.
  • the present invention provides a process for the control of the impurities in the final active pharmaceutical ingredient and dosage form.
  • the present invention provides a compound of Formula III, process of its preparation and its use as a reference marker or as a reference standard.
  • the present invention further provides a process for the preparation of rabeprazole, a salt or a solvate thereof.
  • the invention also provides a chromatographic method for testing the purity of rabeprazole, a salt or a solvate thereof.
  • a first aspect of the present invention provides a compound of Formula III.
  • the compound of Formula III is found to be genotoxic in nature. This was confirmed by using various techniques like DEREK (Deductive Estimation of Risk from Existing Knowledge) analysis and Ames biological assays.
  • a second aspect of the present invention provides a process for the preparation of rabeprazole, a salt or a solvate thereof, substantially free from a compound of Formula III, wherein the process comprises:
  • a third aspect of the present invention provides a process for the preparation of rabeprazole, a salt or a solvate thereof, substantially free from a compound of Formula III, wherein the process comprises:
  • the compound of Formula IV or a salt thereof may be prepared by any method known in the literature, for example U.S. Patent No. 5,045,552.
  • the chlorinating agent may be selected from the group consisting of thionyl chloride, phosphorous trichloride, phosphorous oxy chloride, phosphorous pentachloride and sulfuryl chloride.
  • a preferred chlorinating agent is thionyl chloride.
  • the temperature for the chlorination of the compound of Formula IV or a salt thereof is less than about 0°C.
  • the temperature for chlorination is, for example, from about -5°C to about -30°C, for example, from about -10°C to about -20°C.
  • the chlorination of the compound of Formula IV or a salt thereof is carried out optionally in the presence of a base.
  • the base may be selected from the group consisting of inorganic bases and organic bases.
  • the inorganic bases may be selected from the group consisting of hydroxides, carbonates and bicarbonates.
  • Hydroxides may be, for example, sodium hydroxide, potassium hydroxide or barium hydroxide.
  • Carbonates may be, for example, sodium carbonate, potassium carbonate or barium carbonate.
  • Bicarbonates may be, for example, sodium bicarbonate, magnesium bicarbonate or potassium bicarbonate.
  • the organic bases may be, for example, triethyl amine, ethyl amine, ammonia or diisopropyl ethyl amine.
  • a preferred base is sodium carbonate.
  • the compound of Formula IV or a salt thereof may be reacted with the chlorinating agent in the presence of a solvent.
  • the solvent may be selected from the group consisting of water, alcohols, halogenated hydrocarbons, esters, nitriles, and a mixture thereof.
  • Alcohols may be, for example, methanol, ethanol or methylated ethanol.
  • Halogenated hydrocarbons may be, for example, dichloromethane.
  • Esters may be, for example, ethyl acetate, or diisopropyl ethyl acetate.
  • Nitriles may be, for example, acetonitrile.
  • Preferred solvents include dichloromethane, methylated ethanol, or mixtures thereof.
  • the salt of the compound of Formula V may be, for example hydrochloride salt.
  • the compound of Formula IV or its salt may be chlorinated to prepare the compound of Formula V or its salt for about 3 hours to 8 hours, for example for about 4 hours to about 6 hours.
  • the compound of Formula V or its salt may optionally be isolated from the reaction mixture.
  • isolated includes filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • the compound of Formula V or a salt is reacted with the compound of Formula VI in a solvent and optionally in the presence of base.
  • the base may be selected from the group consisting of inorganic bases and organic bases.
  • the inorganic bases may be selected from the group consisting of hydroxides, carbonates and bicarbonates.
  • Hydroxides may be, for example, sodium hydroxide, potassium hydroxide or barium hydroxide.
  • Carbonates may be, for example, sodium carbonate, potassium carbonate or barium carbonate.
  • Bicarbonates may be, for example, sodium bicarbonate, magnesium bicarbonate or potassium bicarbonate.
  • the organic bases may be, for example, triethyl amine, ethyl amine, ammonia or diisopropyl ethyl amine.
  • a preferred base is sodium hydroxide.
  • the solvent for the reaction of the compound of Formula V or a salt and the compound of Formula VI may be selected from the group consisting of water, alcohols, halogenated hydrocarbons, esters, nitriles, and mixtures thereof.
  • Alcohols may be, for example, methanol, ethanol, or methylated ethanol.
  • Halogenated hydrocarbons may be, for example,
  • Ester solvents may be, for example, ethyl acetate or diisopropyl ethyl acetate.
  • Nitriles may be, for example, acetonitrile.
  • Preferred solvents include water, methylated ethanol or mixtures thereof.
  • the reaction of the compound of Formula V or a salt and the compound of Formula VI may be carried out at about 15°C to about 55°C, for example, at about 25°C to about 45°C.
  • the reaction of the compound of Formula V or a salt and the compound of Formula VI may be carried in about 1 hour to about 4 hours, for example, in about 2 hours to about 3 hours.
  • V and the compound of Formula VI may optionally be isolated from the reaction mixture.
  • isolated includes filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • the compound of the Formula VII may be converted to rabeprazole of the compound of Formula II in the presence of an oxidizing agent, a base and a solvent.
  • the oxidizing agent may be selected from the group consisting of sodium hypochlorite, hydrogen peroxide, m- chlroperoxybenzoic acid, and cumene hydroperoxide.
  • Preferred oxidizing agent is sodium hypochlorite.
  • Sodium hypochlorite may used in any strength, for example from about 2% to about 15%, for example from about 6% to about 9%.
  • the compound of Formula VII may be converted to the compound of Formula II in the presence of sodium thiosulphate.
  • the base used for the conversion of the compound of Formula VII may be selected from the group consisting of inorganic bases, and organic bases.
  • the inorganic bases may be selected from the group consisting of hydroxides, carbonates and bicarbonates.
  • Hydroxides may be, for example, sodium hydroxide, potassium hydroxide or barium hydroxide.
  • Carbonates may be, for example, sodium carbonate, potassium carbonate or barium carbonate.
  • Bicarbonates may be, for example, sodium bicarbonate, magnesium bicarbonate or potassium bicarbonate.
  • the organic bases may be, for example, triethyl amine, ethyl amine, ammonia or diisopropyl ethyl amine.
  • a preferred base is sodium hydroxide.
  • the solvent used for the conversion of the compound of Formula VII to rabeprazole of the compound of Formula II may be selected from the group consisting of water, glacial acetic acid, alcohols, halogenated hydrocarbons, ketones, esters, nitriles, and a mixture thereof.
  • Alcohols may be, for example, methanol, ethanol or methylated ethanol.
  • Halogenated hydrocarbons may be, for example, dichloromethane.
  • Ester solvents may be, for example, ethyl acetate, or diisopropyl ethyl acetate.
  • Nitriles may be, for example, acetonitrile.
  • Ethers may be, for example, diisopropyl ether.
  • Ketones may be, for example, acetone.
  • Preferred solvents include water, glacial acetic acid, acetonitrile, ethyl acetate and diisopropyl ether.
  • the conversion of the compound of Formula VII to rabeprazole of the compound of Formula II may be carried out in the presence of a seed of rabeprazole.
  • the seed of rabeprazole may be prepared by the process disclosed in U.S. Patent No. 5,045,552.
  • the conversion of the compound of Formula VII to rabeprazole of the compound of Formula II may be carried out at about -20°C to about 60°C, for example, at about -10°C to about 50°C.
  • the conversion of the compound of Formula VII to rabeprazole of the compound of Formula II may be carried in about 4 hours to about 8 hours, for example, in about 6 hours to 7 hours.
  • Rabeprazole of the compound of Formula II may optionally be isolated.
  • isolated includes filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • Rabeprazole of the compound of Formula II may optionally be purified using a solvent selected from the group consisting of water, glacial acetic acid, alcohols, halogenated hydrocarbons, ketones, esters, nitriles, and mixtures thereof.
  • Alcohols may be, for example, methanol, ethanol or methylated ethanol.
  • Halogenated hydrocarbons may be, for example, dichloromethane.
  • Esters may be, for example, ethyl acetate, or diisopropyl ethyl acetate.
  • Nitriles may be, for example, acetonitrile.
  • Ethers may be, for example, diisopropyl ether.
  • Ketones may be, for example, acetone.
  • Preferred solvents include acetone and diisopropyl ether.
  • Rabeprazole of the compound of Formula II may optionally be converted to its salt or a solvate thereof.
  • the salt of the rabeprazole may be, for example, sodium salt.
  • the solvate of the compound of Formula II may be, for example, acetone solvate or alcohol solvate. Alcohol solvate may include ethanol solvate or methanol solvate.
  • Rabeprazole of the compound of Formula II may be converted to the sodium salt of the Formula I using a base and a solvent.
  • the base may be selected form sodium hydroxide and sodium carbonate.
  • the solvent used for the preparation of rabeprazole sodium of Formula I may be selected from the group consisting of water, alcohols, halogenated hydrocarbons, ketones, esters, nitriles, and a mixtures thereof.
  • Alcohols may be, for example, methanol, ethanol or methylated ethanol.
  • Halogenated hydrocarbons may be, for example, dichloromethane.
  • Esters may be, for example, ethyl acetate or diisopropyl ethyl acetate.
  • Nitriles may be, for example, acetonitrile.
  • Ethers may be, for example, diisopropyl ether.
  • Ketones may be, for example, acetone.
  • a preferred solvent is ethanol.
  • Rabeprazole sodium of the compound of Formula I may be isolated and characterized.
  • isolated includes filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • Rabeprazole sodium of the compound of Formula I may be amorphous in nature.
  • a fourth aspect of the present invention provides use of a compound of Formula III as a reference marker or a reference standard to analyze the purity of rabeprazole, a salt or solvate thereof.
  • An embodiment of the present invention provides use of the compound of Formula III as a reference marker or a reference standard to analyze the purity of rabeprazole, a salt or solvates thereof wherein the sample comprises any of the following:
  • composition comprising active pharmaceutical ingredient or its sodium salt
  • a pharmaceutical composition comprising solvates or a salt of rabeprazole.
  • a fifth aspect of the present invention provides a chromatographic method for testing the purity of rabeprazole, a salt or solvates thereof, wherein the method comprises:
  • the chromatographic method may be, for example, HPLC (high-performance liquid chromatography), LC-MS (liquid chromatography-mass spectrometry), or TLC (thin layer chromatography) .
  • the determination of the presence of the compound of Formula III in the sample solution is effected by comparing the retention [(retention time in HPLC (high-performance liquid chromatography) or LC-MS (liquid chromatography-mass spectrometry), or retention factor in TLC (thin layer chromatography)] of the different components of the sample solution separated by the chromatographic method with the retention of the compound of Formula III under the same chromatographic conditions (i.e. same stationary phase, mobile phase, temperature, pressure).
  • a preferred chromatographic method is a liquid chromatographic method, such as a LC-MS method.
  • comparing the retention is to be understood as determining whether two retention values are substantially the same, for example, the first value being the retention of one of the different components of the sample solution separated by the chromatographic technique and the second value being the retention of the compound of Formula III under the same chromatographic conditions.
  • substantially the same means that the retention values differ in less than 10%, preferably less than 5%, even more preferably less than 1%, still more preferably less than 0.5%, the most preferably less than 0.1%.
  • a sixth aspect of the present invention provides a method for the purification of rabeprazole, salt or solvate thereof suitable for pharmaceutical use, comprising the steps of: a) preparing rabeprazole, salt or solvate thereof;
  • step c) subjecting rabeprazole, salt or solvate thereof to purification, wherein step c) may also be carried out before step b).
  • a seventh aspect of the present invention provides rabeprazole, a salt or solvate thereof substantially free from the compound of Formula III.
  • substantially free includes less than 10%, preferably less than 5%, even more preferably less than 1%, still more preferably less than 0.5%, the most preferably less than 0.1% of the compound of Formula III.
  • substantially free may include rabeprazole completely free from a compound of Formula III.
  • reference marker refers to a compound that may be used in qualitative analysis to identify components of a mixture based on their position, e.g. in a HPLC chromatogram, LC-MS chromatogram or on a Thin Layer Chromatography (TLC) plate, and/or in quantitative analysis to determine the concentration of said compound in a mixture by reference to the concentration of a solution comprising a known amount of said compound.
  • step (c) refers to conventional purification techniques, such as chromatography, distillation and crystallization.
  • reference standard as used in the context of the present invention, has an equivalent meaning to "reference marker”.
  • An eighth aspect of the present invention provides a process for the preparation of a compound of Formula III
  • the compound of Formula VIII may be prepared as described herein in step a) of Example 6.
  • reaction of the compound of Formula VIII with the compound of Formula VI is carried out in a solvent optionally in the presence of a base.
  • the base may be selected from the group consisting of inorganic bases and organic bases.
  • the inorganic bases may be selected from the group consisting of hydroxides, carbonates and bicarbonates.
  • Hydroxides may be, for example, sodium hydroxide, potassium hydroxide or barium hydroxide.
  • Carbonates may be, for example, sodium carbonate, potassium carbonate or barium carbonate.
  • Bicarbonates may be, for example, sodium bicarbonate, magnesium bicarbonate or potassium bicarbonate.
  • the organic bases may be, for example, triethyl amine, ethyl amine, ammonia or diisopropyl ethyl amine.
  • a preferred base is sodium hydroxide.
  • the solvent may be selected from the group consisting of water, alcohols, halogenated hydrocarbons, esters, nitriles, and mixtures thereof.
  • Alcohols may be, for example, methanol, ethanol or methylated ethanol.
  • Halogenated hydrocarbons may be, for example,
  • esters may be, for example, ethyl acetate, diisopropyl ethyl acetate.
  • Nitriles may be, for example, acetonitrile.
  • Preferred solvents include water, methylated methanol or mixtures thereof.
  • the reaction of the compound of Formula VIII with the compound of Formula VI may be carried out at about 10°C to about 50°C, for example, at about 20°C to about 40°C.
  • the reaction of the compound of Formula VIII with the compound of Formula VI may be carried in about 1 hours to about 6 hours, for example in about 2 hours to about 4 hours.
  • the compound of Formula IX obtained by the reaction of the compound of Formula VIII and the compound of Formula VI may optionally be isolated from the reaction mixture.
  • isolated includes filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • the compound of Formula IX is converted to the compound of Formula III in the presence of an oxidizing agent, a base and a solvent.
  • the oxidizing agent may be selected from the group consisting of sodium hypochlorite, hydrogen peroxide, m-chlroperoxybenzoic acid, and cumene hydroperoxide.
  • a preferred oxidizing agent is sodium hypochlorite.
  • Sodium hypochlorite may be used in any strength, for example, from about 2% to about 15 %, for example, from about 6% to about 9 %.
  • the compound of Formula IX is converted to the compound of Formula III in the presence of sodium thiosulphate.
  • the base may be selected from the group consisting of inorganic bases and organic bases.
  • the inorganic bases may be selected from the group consisting of hydroxides, carbonates and bicarbonates.
  • Hydroxides may be, for example, sodium hydroxide, potassium hydroxide or barium hydroxide.
  • Carbonates may be, for example, sodium carbonate, potassium carbonate or barium carbonate.
  • Bicarbonates may be, for example, sodium bicarbonate, magnesium bicarbonate or potassium bicarbonate.
  • the organic bases may be, for example, triethyl amine, ethyl amine, ammonia or diisopropyl ethyl amine.
  • Preferred base is sodium hydroxide.
  • the solvent used for the conversion of the compound of Formula IX to the compound of Formula III may be selected from the group consisting of water, acetic acid, alcohols, halogenated hydrocarbons, ketones, esters, nitriles, and mixtures thereof.
  • the acetic acid solution may be aqueous or glacial acetic acid.
  • Alcohols may be, for example, methanol, ethanol or methylated ethanol.
  • Halogenated hydrocarbons may be, for example, dichloromethane.
  • Esters may be, for example, ethyl acetate, diisopropyl ethyl acetate.
  • Nitriles may be, for example, acetonitrile.
  • Ethers may be, for example, diisopropyl ether.
  • Ketones may be, for example, acetone.
  • Preferred solvents include water, acetic acid, acetonitrile, ethyl acetate or a mixture thereof.
  • the base may be selected from the group consisting of inorganic bases, and organic bases.
  • the inorganic bases may be selected from the group consisting of hydroxides, carbonates and bicarbonates.
  • Hydroxides may be, for example, sodium hydroxide, potassium hydroxide or barium hydroxide.
  • Carbonates may be, for example, sodium carbonate, potassium carbonate or barium carbonate.
  • Bicarbonates may be, for example, sodium bicarbonate, magnesium bicarbonate or potassium bicarbonate.
  • the organic bases may be, for example, triethyl amine, ethyl amine, ammonia or diisopropyl ethyl amine.
  • a preferred base is sodium hydroxide.
  • the conversion of the compound of Formula IX to the compound of Formula III may be carried out at about -20°C to about 60°C, for example, at about -10°C to about 50°C.
  • the conversion of the compound of Formula VIII to the compound of Formula III may be carried in about 4 hours to about 8 hours, for example in about 6 hours to about 7 hours.
  • the compound of Formula III may optionally be isolated.
  • isolated includes filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • the pH was adjusted to 7.0 to 7.5 with the aqueous sodium carbonate solution (prepared by dissolving 120 g of sodium carbonate in 500 mL of de-ionized water at 20°C to 25°C) at -10°C to -5°C.
  • the temperature of the reaction mixture was raised to 0°C to 5°C.
  • the mixture was allowed to settle for 10 minutes to 20 minutes and the layers obtained were separated.
  • the organic layer was concentrated at 15°C to 30°C at 50 mm to 100 mm Hg of pressure.
  • the residue obtained was dissolved in denatured spirit (100 mL).
  • the mixture was concentrated at 15°C to 30°C at 20 mm to 30 mm Hg of pressure.
  • the residue obtained was used in the next step.
  • Example 1 Sodium hydroxide (24.3 g) was added to de-ionized water (500 mL) and the mixture was stirred. The mixture was cooled to 25°C to 30°C.
  • Denatured spirit (100 mL) and 2- mercaptobenzimidazole (Formula VI) (63.7 g) were added to the reaction mixture and it was stirred at 25°C to dissolve the solid material.
  • the product obtained in Example 1 was dissolved in 100 mL of methylated ethanol and added to the reaction mixture at 25°C to 30°C for 20 minutes to 30 minutes. The reaction mixture was stirred at 25°C to 30°C for 30 minutes to 60 minutes.
  • De-ionized water (500 mL) was added at 25° C to 30°C for 30 minutes to 45 minutes.
  • the mixture was stirred at 25°C to 30°C for 60 minutes to 70 minutes.
  • the solid obtained was filtered and washed with de-ionized water (2 X 500 mL).
  • the wet solid obtained was dried at 50°C to 55°C till the moisture content was not more than 0.5% w/w in an oven to obtain the title compound.
  • Sodium hypochlorite (1.05 mole equivalent) was added to the reaction mixture at -8°C to -2°C for 30 minutes to 50 minutes.
  • Sodium thiosulphate solution (prepared by dissolving 12.5 g sodium thiosulphate in 125 mL de-ionized water) was added to the reaction mixture at -8°C to +5°C.
  • the pH of the mixture was adjusted to 8.7 to 9.1 with aqueous acetic acid solution (80 mL; prepared by dissolving 40 mL glacial acetic acid with 40 mL de-ionized water) at 0°C to 5°C.
  • Ethyl acetate (625 mL) was added to the mixture and the temperature was increased to 10°C to 20°C. The mixture was allowed to settle for 10 minutes to 30 minutes and the layers obtained were separated. The organic layer was concentrated at 15°C to 30°C and 20 mm to 30 mm of Hg pressure.
  • the solid obtained was filtered and washed with pre-cooled (0°C to 5°C) acetone-diisopropyl ether (2 X 125 mL; prepared by dissolving 125 mL acetone in 125 mL diisopropyl ether).
  • the solid obtained was dried at 40°C to 45°C at 10 mm to 20 mm of Hg pressure till the loss on drying was not more than 1.0% w/w to obtain the title compound.
  • Rabeprazole (80 g) prepared in Example 3 was added to acetone (1280 mL). The mixture was heated to 30°C to 35°C. Activated carbon (8.0 g) was added to the reaction mixture and it was stirred at 30°C to 35°C for 25 minutes to 35 minutes. The reaction mixture obtained was filtered through celite. The celite was washed with acetone (2 X 180 mL). The mixture obtained was concentrated to 360 mL to 400 mL at 15°C to 30°C and 20 mm to 30 mm of Hg pressure. Diisopropyl ether (400 mL) was added to the reaction mixture at 15°C to 30°C for 30 minutes to 45 minutes.
  • the reaction mixture was cooled to 10°C to 15°C and stirred for 50 minutes to 70 minutes.
  • the solid obtained was filtered and washed with pre-cooled (10°C to 15°C) acetone- diisopropyl ether (2 X 80 mL; prepared by dissolving 80 mL acetone in 80 mL diisopropyl ether).
  • the solid obtained was dried at 40°C to 45°C at 10 mm to 20 mm of Hg till the loss on drying was not more than 0.5% w/w to obtain the title compound.
  • Rabeprazole (65 g) obtained in Example 4 was added to the reaction mixture and it was stirred at 20°C to 25°C.
  • Activated carbon (3.25 g) was added to the reaction mixture and the mixture was stirred at 20°C to 25°C for 30 minutes.
  • the mixture was filtered through celite and washed with ethanol (2 X 130 mL). The filtrates were combined and filtered.
  • the filter paper was washed with ethanol (65 mL) and spray dried under following conditions.
  • Inlet temperature 110°C to 120°C
  • Oxygen Level Not more than 3.0% The solid obtained was dried at 60°C to 65°C at 10 mm to 20 mm Hg till the ethanol content is not more than 5000 ppm and water content was not more than 4.5% w/w to obtain the title compound.
  • the solid obtained was dried at 35°C to 40°C for 2 hours to 3 hours to obtain the title compound.
  • the chromatographic separation was carried out in a Kromasil C18, 5 ⁇ , 4.6 mm x 150 mm column at 50°C.
  • the mobile phase was prepared by filtering and degassing an acetonitrile / buffer solution (70:30) v/v mixture.
  • the buffer solution was obtained by dissolving 0.77 g of ammonium acetate in 2000 mL water.
  • the pH of the solution was adjusted to 7.0 ⁇ 0.05 with 1% ammonia solution (prepared by dissolving 1 ml of 25 % ammonia solution in 99 mL water) and filtered through 0.45 ⁇ .
  • the chromatograph was equipped with a mass spectrometer detector and the flow rate was 1.5 mL per minute. 10 of the test samples were injected. The samples were prepared by dissolving 50 mg of sample in 100 mL of diluent and diluting 25 mL of solution to 100 mL with diluent. The diluent was prepared by dissolving water and methanol at the ratio of 50:50. The chromatogram was run for at least 15 minutes. The approximate retention time for the compound of Formula III was found to be 10.8 minutes.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule III, un procédé pour sa préparation et son utilisation comme marqueur de référence ou comme étalon. La présente invention concerne en outre un procédé pour la préparation de rabéprazole, d'un sel ou d'un solvate correspondants. L'invention concerne également un procédé chromatographique destiné à tester la pureté du rabéprazole, d'un sel ou d'un solvate correspondants.
PCT/IB2013/060883 2012-12-12 2013-12-12 Procédé pour la préparation de rabéprazole Ceased WO2014091450A1 (fr)

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IN3826DE2012 2012-12-12
IN3826/DEL/2012 2012-12-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085486A (zh) * 2015-09-09 2015-11-25 上海汇伦生命科技有限公司 一种右旋雷贝拉唑钠的精制方法
CN113582973A (zh) * 2021-09-28 2021-11-02 丽珠医药集团股份有限公司 一种硫醚的制备方法

Citations (10)

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EP0369208A1 (fr) * 1988-11-15 1990-05-23 Hafslund Nycomed Pharma Aktiengesellschaft Procédé de préparation de dérivés de la diméthyl-3,5 méthoxy-4 pyridine et produits intermédiaires à cette fin
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