Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for their Preparation

Inactive Publication Date: 2007-07-12
UNGE SVERKER VON +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to new compounds, their preparation and their use as intermediates in the synthesis of the S- and R-enantiomer of omeprazole and pharmaceutically acceptable salts thereof. These compounds are highly crystalline sulphoxides which are stable enough to be directly recrystallised and can be used as intermediates in the synthesis of the final products without the need for an alkaline medium. The purification process involves a reduction in the amount of impurities, resulting in a more pure final product. The new compounds have improved optical and chemical purity compared to the non-crystalline compounds described in previous patents."

Problems solved by technology

Single enantiomers of omeprazole in neutral form are difficult to obtain in crystalline state and thus these compounds are most frequently obtained as non crystalline products.

Method used

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  • Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for their Preparation
  • Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for their Preparation
  • Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for their Preparation

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of (S)-2-[[(4-chloro-3,5-dimethy-2-pyridinyl)methyl]sulfinyl]5-methoxy-1H-benzimidazole

[0029] 1.2 g (3.6 mmol) of 2-{[(4-chloro-3,5-dimethyl-2-pyridinyl)methyl]thio}-5-methoxy-1H-benzimidazole was mixed with toluene (40 mL). The mixture was concentrated until half to the volume was left. Water (38 mg, 2.1 mmol), (S,S)-diethyl tartrate (1.85 g, 9.0 mmol) and titanium tetraisopropoxide (1.0 g, 3.6 mmol) were added in the given order while stirring. The mixture was then stirred at 50° C. for an hour and then N,N-diisopropylethylamine (0.46 g, 3.6 mmol) was added at room temperature. After 15 minutes cumene hydroperoxide (80% in cumene, 0.69 g, 3.6 mmol) was added dropwise is and stirring was then continued for 2 h at room temperature. The optical purity of crude sulfoxide turned out to be 75% ee as determined by chiral HPLC analysis of the solution. The mixture was washed with water and then evaporated. The product was purified by chromatography on silica gel using methanol / ...

example 2

Synthesis of (S)-2-[[(4-nitro-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]5-methoxy-1H-benzimidazole

[0031] In an analogous experiment as in Example 1—starting from 1.2 g of (S)-2-[[(4-nitro-3,5-dimethyl-2-pyridinyl)methyl]thio]5-methoxy-1H-benzimidazole—1.0 g of the title compound as a crystalline product was obtained. The enantiomeric excess of this crude product was determined to be 48% by chiral HPLC analysis.

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Abstract

The present invention relates to an improved method for the synthesis of the (S)- or (R)-enantiomer of omeprazole, characterized in that 2-[[(4-X-3,5-dimethylpyridin-2-yl)methyl]thio]-5-methoxy-1H-benzimidazole or 2-[[(4-X-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]thio]-5-methoxy-1H-benzimidazole, wherein X is a leaving group, is oxidized into the corresponding sulphoxide which is obtained as a crystalline compound. Recrystallisation of the thus obtained sulphoxide results in a compound of enhanced chemical and optical purity, which is subsequently transformed into the (S)- or (R)-enantiomer of omeprazole.

Description

FIELD OF THE INVENTION [0001] The present invention is directed to new compounds of high optical purity, a process for their preparation and their use as intermediates in the synthesis of the S- or R-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole. BACKGROUND OF THE INVENTION [0002] The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole, having the generic name omeprazole, and therapeutically acceptable alkaline salts thereof are described in EP 5129 and EP 124 495, respectively. Omeprazole and its alkaline salts are effective gastric acid secretion inhibitors, and are useful as antiulcer agents. The compounds, being sulphoxides, have an asymmetric center in the sulphur atom, i.e. exist as two optical isomers (enantiomers). It has been shown that the lo magnesium salt of the S-enantiomer of omeprazole has better pharmacokinetic and metabolic properties compared to omeprazole, and this is de...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/4439C07D403/02A61P1/04C07DC07D401/12
CPCC07D401/12A61P1/04
InventorUNGE, SVERKER VONFREGLER, CHRISTINA
OwnerUNGE SVERKER VON