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Preparation of optically enriched 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole

IP.com Disclosure Number: IPCOM000126642D
Publication Date: 2005-Jul-25

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Preparation of optically enriched 5-Methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole

    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.

Optically enriched 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole may be obtained by kinetic resolution of racemic 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H- benzimidazole. The processcomprises the steps of: combining at an ambient temperature, an organometalic complex, a chiral ligand and racemic 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole with a halogenated hydrocarbon solvent, to obtain a solution. The obtained solution is then combined with a mixture of a solution containing of an oxidizing agent, and a halogenated hydrocarbon solvent, and is maintained for at least one hour.

Optically enriched 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole may be is recovered from this solution by any methods known in the art, such as evaporating the solvents.

The recovered optically enriched 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole is obtained in enantiomeric excess of at least about 30%, by chiral HPLC.

    The organometallic complex may preferably be, a transition metal complex, and more preferably, Ti(i-PrO) or VO(acac)2. The complex may be applied, preferably in a catalytic amount. Specifically, the complex may be applied in an

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mount of about 0.5 to 1 equivalents per mole equivalent, of racemic 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole.

  The chiral ligand may preferably be D or L-diethyl tartrate or (S)-(-)-2-(3,5- Di-t-butylsalicylideneamino)-3,3-dimethyl-1-butanol.

The halogenated hydrocarbon solvent may preferably be dichloromethane.

    Optionally, the mixture of the organometallic complex, chiral ligand and halogenated hydrocarbon may be maintained for a about one hour before the addition of racemic 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H- benzimidazole.

    Preferably, the oxidizing agent may be a solution of about 80% cumene hydroperoxide in cumyl alcohol.

Optionally, the solution obtained after combining the organometallic complex, chiral ligand and racemic 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]sulfinyl]-1H-benzimidazole with the halogenated hydroca...