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

Definitions

• the present invention relates to a process for obtaining pure rabeprazole sodium.
• Xhe present invention also relates to a novel process for the preparation rabeprazole sodium amorphous form, and to a pharmaceutical composition comprising it.
• Rabeprazole sodium is an inhibitor of the gastric proton pump. It suppress gastric acid secretion by inhibiting the gastric H + , K + ATPase at the secretory surface of the gastric parital cell and blocks the final step of gastric acid secretion.
• Rabeprazole sodium is a sulfoxide compound have been prepared by oxidizing thioether compound with an oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, sodium hypochlorite, sodium hypobromite etc., as described in JP-A1-6270 (EP 268956), US 5045552). Rabeprazole represented by following structure:
• Japanese patent application JP2001039975 indicates that the product obtained by example 33 of U.S. patent No. 5045552 with a melting point of 140- 141 0 C corresponds to amorphous rabeprazole sodium.
• the X- ray powder diffraction pattern of the amorphous rabeprazole sodium is shown.
• U.S. patent No. 6180652 concerns process for the purification of rabeprazole and its pharmaceutically acceptable salts for its sulfone impurity, via: acetone complex of the rabeprazole or its pharmaceutically acceptable salts.
• rabeprazole sodium in amorphous form is obtained by lyophilizing an aqueous solution of rabeprazole sodium acetone complex.
• lyophilization is a technique which is not suitable for production at industrial scale because this process presents serious limitations on cost, time, equipment capability and environmental protection.
• WO 2004/085424 A1 refers to the conversion of the rabeprazole sodium acetone complex into amorphous rabeprazole sodium by heating at elevated temperatures, preferably between 100 and 110 0 C. It is well known that exposing rabeprazole-type compounds to high temperatures increases the risk of decomposition to form impurities and as such, heat treatment of rabeprazole sodium acetone complex into amorphous rabeprazole sodium is not adequate for the production of a rabeprazole which is suitable for pharmaceutical use.
• a process for preparing amorphous rabeprazole sodium comprises: a) Mixing a solution of rabeprazole sodium in a chlorinated solvent with cyclohexane, b) stirring the contents obtained in step (a) at 0-50 0 C for at least 15 minutes, and c) isolating amorphous rabeprazole sodium from the contents obtained in step (b).
• the solution of rabeprazole sodium in the chlorinated solvent may be obtained for example, by dissolving rabeprazole sodium in the chlorinated solvent or as a part of reaction mass obtained by reaction of rabeprazole with a base such as sodium hydroxide.
• the chlorinated solvent used in step (a) may preferably be methylene chloride, ethylene chloride or chloroform; or a mixture thereof.
• the more preferred chlorinated solvent is methylene chloride.
• the stirring in step (b) may preferably carried out at 20-35 0 C for 15 to 75 minutes, more preferably at 15 to
• Preparation of the amorphous rabeprazole sodium may occur during step (b).
• the precipitated solid may be isolated from the contents by methods such as filtration or ce ⁇ trifugation. If required the isolation of the amorphous rabeprazole sodium may be performed by the methods known in the art such as by cooling, using an antisolvent, by partial evaporation or a combination thereof followed by filtration or a centrifugation.
• the bottom organic layer was separated twice by treating with methylene chloride (2 x 250 L), stirred and allowed to settle for 15 minutes.
• Water (1300 L) and sodium hydroxide flakes (50 Kg) were added to the reactor, cooled to 20 - 25 0 C and then added the methylene chloride layer to the reactor.
• Sodium chloride (50 Kg) was added to the reaction mixture, stirred for 20 minutes and allowed to settle for 20 minutes.
• the bottom organic layer was separated.
• the pH of the aqueous layer was adjusted to 9.2 - 9.4 with ammonium acetate solution (ammonium acetate: 52 Kg + water: 200 L) and acetic acid solution (acetic acid: 65 L + water: 200 L).
• the bottom organic layer was separated twice by treating with methylene chloride (2 x 650 L), stirred and allowed to settle for 15 minutes.
• the organic layer was given carbon treatment, filtered and washed the filtrate with methylene chloride (50 L). Dried the total organic layers with sodium sulfate (20 Kg) and 2-Amino ethanol (1.8 L) was added. The organic layer was concentrated until the mass temperature reached to 40 - 45 0 C.
• Acetonitrile (50 L) was added to the reaction mass and acetonitrile was distilled off from the reaction mass until the mass temperature reached to 40 - 45 0 C.
• Acetonitrile (600 L) was added to the reaction mass, stirred for 2 hours at room temperature and cooled to 0 - 5 0 C.
• the total organic layer was washed with sodiumchloride solution (sodium chloride: 36 Kg, DM water: 140 L), given carbon treatment, filtered, washed the filtrate with methylenechloride (50 L) and 2-amino ethanol (0.54 L) was added.
• the organic layer was concentrated until the mass temperature reached to 35 - 40 0 C.
• Acetonitrile (90 L) was added to the reaction mass and acetonitrile was distilled off from the reaction mass until the mass temperature reached to 35 - 40 0 C.
• Acetonitrile (270 L) was added to the reaction mass, cooled to 25 - 35 0 C, stirred for 1 hour 30 minutes, cooled to 0 - 5 0 C and stirred for 1 hour.
• Rabeprazole was added to the solution and stirred at 25 - 35 0 C for 1 hour. Methanol was distilled off from the reaction mass, dichloromethane (150 L) was added to the residual mass and the contents were stirred to obtain solution. The solution was added to cyclohexane (1080 L). The contents were stirred at 25 - 35 0 C for 30 minutes, centrifuged the material and washed at 60 - 65 0 C to obtain 69 Kg of amorphous rabeprazole sodium.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2008
  • 2008-07-07 EP EP08808137A patent/EP2294064A4/de not_active Withdrawn
  • 2008-07-07 WO PCT/IN2008/000433 patent/WO2010004571A2/en not_active Ceased

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