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Process for Preparing 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole by Optical Resolution

IP.com Disclosure Number: IPCOM000126473D
Publication Date: 2005-Jul-20
Document File: 4 page(s) / 91K

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Process for Preparing 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole by Optical Resolution

    5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H- benzimidazole is a proton pump inhibitor and useful for the treatment of heartburn and other symptoms associated with gastroesophageal reflux disease (GERD).

Since 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H- benzimidazole is an asymmetric sulfoxide it has a chiral center on the sulfur atom and therefore exists in two enantiomeric forms.

    Racemic 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole may be obtained, for example, according to the methods provided in EP patent. No. 005129.

    The sodium salt of the racemic 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole may be obtained, for example, according to the methods provided in US patent. No. 4,738,974.

The diastereomeric pair of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole-N-benzyl cinchoninium salt is prepared by a process comprising: combining an aqueous solution of racemic 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole salt of an alkali metal, preferably, sodium salt, with an aqueous slurry of N-benzylcinchoninium chloride in a halogenated hydrocarbon solvent, preferably dichloromethane, to obtain a suspension. The suspension is maintained preferably for one hour, until a clear solution is obtained. The desired product is recovered by any methods known in the art such as, separating the organic phase and evaporating the halogenated hydrocarbon solvent to dryness.

The diastereomeric pair of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole-N-benzyl cinchoninium salt may also be prepared by a process comprising: combining an aqueous solution of racemic 5- methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole

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salt of an alkali metal, preferably sodium salt, with an aqueous slurry of N- benzylcinchoninium chloride in an aromatic solvent, preferably toluene, to obtain a suspension. The suspension is maintained preferably at ambient temperature, for three days. The desired product is then recovered by any methods known in the art, such as filtering and drying.

The diastereomeric pair of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole-N-benzyl cinchoninium salt may be separated to give an enriched (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole-N-benzyl cinchoninium salt by a process of optical resolution comprising: dissolving the diastereomeric pair in a mixture of C1-

C4 alcohol and water, to obtain a solution. Preferably the C1-C4 alcohol is ethanol. The obtained solution is then maintained overnight at an ambient temperature, followed by adding water and maintaining, preferably for 4...