Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole

A technology of pantoprazole and methoxyethoxy, applied in the fields of active ingredients of heterocyclic compounds, organic chemistry, digestive system, etc.

Inactive Publication Date: 2006-09-27
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although sodium perborate is less expensive than MCPBA and less harmful to the environment, its advantages in this regard are not as obvious as sodium hypochlorite

Method used

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  • Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole
  • Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole
  • Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] A flask equipped with a stirrer was charged with ethyl acetate (140ml). Under stirring, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]thio]-1H-benzimidazole VI (5g, 13.6mmol) into the flask, and then 18.8% NaOH aqueous solution (11.5ml, d=1.16g ml -1 , 4.9eq.). The flask reactor was cooled to -10°C, and 9.7% NaOCl (9.7ml, d=1.16g ml) was added dropwise within 15 minutes -1 , 1.04eq.). The resulting biphasic mixture was stirred at room temperature for 3 hours. The two phases were then separated, and 27% sodium metabisulfite (Na 2 S 2 o 5 ) aqueous solution (7ml) was added to the aqueous phase to quench unreacted oxidant. The organic phase was washed with water and the aqueous phase was washed twice with ethyl acetate. The combined organic phases were washed with sodium sulfate (Na 2 SO 4 ) was dried and evaporated under vacuum at 20 mmHg. The resulting oil was triturated with methyl tert-butyl ether and filtered to afford pantoprazole (3.7 g, 71% yie...

Embodiment 2

[0122] A flask equipped with a stirrer was charged with ethyl acetate (140ml). With stirring, compound VI (7 g) was added followed by 47% aqueous NaOH (4.6 g, 2.8 eq.). The flask was cooled to 0°C, and 9.4% active NaOCl aqueous solution (16.5ml, d=1.16g ml) was added dropwise within 30 minutes -1 , 1.27eq.). The resulting biphasic mixture was stirred at room temperature for 1.5 hours. Then 27% Na 2 S 2 o 5 Aqueous solution (8ml) was added to the mixture. After a few minutes of stirring, the two phases separated. The organic phase was washed with water and the aqueous phase was washed twice with ethyl acetate. The organic phases were combined and concentrated to give 15 g of an oily residue. The oily residue was then taken up in a 1:2 ethyl acetate:hexane mixture (15 mL) and allowed to precipitate. The precipitate was then filtered and washed to obtain pantoprazole (6.7 g, 92.3%), which contained 0.19% sulfone and 0.08% compound VI within the detection limit of UV.

Embodiment 3

[0124] A flask equipped with a stirrer was charged with ethyl acetate (50ml). With stirring, compound VI (10 g) was added followed by 47% NaOH (8.72 g, 3.8 eq.). The flask was cooled to 0°C and 11.1% active aqueous NaOCl (27.4 g, 1.5 eq.) was added dropwise over 20 minutes. The resulting biphasic mixture was stirred at room temperature for 1.5 hours. Then add 7% Na 2 S 2 o 5Aqueous solution (50ml). After a few minutes of stirring, the two phases separated. The organic phase was washed with water and the aqueous phase was washed twice with ethyl acetate. The combined organic phases were concentrated to give 24 g of an oily residue. The oily residue was then taken up with toluene (15ml) and allowed to precipitate. The precipitate was then filtered and washed to obtain pantoprazole (7.82 g, 75.2%), which contained 0.05% sulfone and contained no compound VI within the detection limit of UV.

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Abstract

The present invention provides a process comprising admixing a thioether with about 1.05 to about 1.6 molar equivalents of an active chlorine-containing oxidant, preferably sodium hypochlorite, and about 2.5 to about 5.0 molar equivalents of an alkali metal base; and recovering a sulfoxide that is preferably pantoprazole, lansoprazole, omeprazole, or rabeprazole. The process may further comprise contacting the sulfoxide with a source of sodium ions, preferably sodium hydroxide, to produce the sodium salt of the sulfoxide. The invention also relates to novel chlorinated derivatives of pantoprazole including 5(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)-chloromethyl]sulfinyl]-1H- benzimidazole and 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)chlorohydroxymethyl] sulfinyl]-1H-benzimidazole and processes for making them. The invention also relates to processes of quantifying and identifying a compound other than pantoprazole in a mixture of pantoprazole and at least one other compound.

Description

[0001] priority [0002] This application claims the benefit of US Provisional Application Serial No. 60 / 477,045, filed June 10, 2003, and US Provisional Application Serial No. 60 / 525,851, filed December 1, 2003, both of which are incorporated herein by reference. field of invention [0003] The present invention relates to a method for preparing 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles by oxidizing 2-[(pyridyl)methyl]thio-substituted benzimidazoles, and to certain panimidazoles Chlorinated derivatives of toprazole. Background of the invention [0004] It is known that 2-[(pyridyl)methyl]sulfinyl-substituted benzimidazoles with certain molecular structures classified into the following formula (I) can exert pharmacological effects in humans to inhibit gastric acid secretion: [0005] [0006] where R 1 is hydrogen, halogen, alkyl, alkoxy (mainly fluorine-substituted alkoxy), alkanoyl or ethoxyf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/44A61P1/04C07D235/00C07D213/00
Inventor A·利伯曼C·辛格Y·赖兹V·布劳德N·芬克尔斯泰因K·陈G·皮拉斯基
Owner TEVA PHARMA IND LTD
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