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Method for preparing 2- (2-pyridylmethylsulphinyl) benzimidazoles

a technology of benzimidazoles and pyridylmethylsulphinyl, which is applied in the field of preparation of anti-ulcer agents, can solve the problems of poor quality control of methods, substantial mass production difficulties, and high cost of mcpba, and achieve mild reaction conditions and less toxic effects

Inactive Publication Date: 2006-06-15
IND TECH RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018] The present invention adopts an organic composite catalyst, e.g. molybdenyl acetyl acetone (also named as acetylacetonate of molybdenium) (hereinafter abbreviated as Mo(acac)2), together with an oxidant, for the oxidation reaction of the precursors of benzimidazole compounds, such as Omeprazole, Lansoprazole, and Pantoprazole. According to the present invention, the reaction conditions are mild without severe temperature conditions. Furthermore, a Mo-series catalyst is less toxic than a vanadium catalyst. Most importantly, the reaction produces a rather small amount of the by-products I and II (1-2%). Accordingly, a preparation method according to the present invention is far superior in comparison to the conventional preparation methods. Thus, the method for preparing a thio-containing antiulcer agent, such as Omeprazole, Lansoprazole and Pantoprazole, according to the present invention is improved over the conventional methods and applicable for mass production.

Problems solved by technology

Therefore, the method is rather difficult in quality control.
However, when MCPBA is used as an oxidant, the reaction temperature is −20° C.˜−60° C., and MCPBA is expensive.
Under consideration of the low-temperature reaction condition and the production cost, such a method has substantial difficulties in mass production.
Thus, the desired product, after crystallization purification of the reaction product mixture, are rather difficult to be separated from the by-products I and II.
If further elaborate purifications are performed, the yield is liable to drop dramatically.
Thus, such a process is not industrially feasible.

Method used

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  • Method for preparing 2- (2-pyridylmethylsulphinyl) benzimidazoles

Examples

Experimental program
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Effect test

example 1

[0020] 2.68 g of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine.HCl, 1.376 g of 2-mercaptobenzimidazole, and 0.134 g of benzyl triethyl ammonium chloride as an interphase transfer catalyst were mixed in 24 ml of dichloromethane. 0.9534 g of NaOH (40%) / 12 ml water mixture solution was dripped into the above mixture while stirring. The temperature of the resulting solution was raised to 40° C. for about 2 hours. Then, dichloromethane was removed from the mixture under a reduced pressure. The solid obtained was stirred with 50 ml of water, and filtered to obtain 3.28 g of solid Lansoprazole precursor: 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole. At room temperature, 3.28 g of the above precursor, 0.1625 g of polyethylene glycol-400 as an interphase transfer catalyst, and 0.3936 g of Mo(acac)2 as an oxidation catalyst were mixed in 45 ml of isopropanol (abbreviated as IPA). To the resulting mixture 3.06 g of 35% H2O2 aqueous solution was adde...

example 2

[0021] At room temperature, 1.307 g of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole, 0.059 g of tetrabutyl ammonium bromide as an interphase transfer catalyst, and 0.157 g of Mo(acac)2 oxidation catalyst were mixed in 15 ml of IPA. Next, 1.36 g of TBHP (70% aqueous solution) was added into the mixture in about 5-10 minutes. The reaction was carried out for about 30 hours, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 37% (HPLC purity >96%).

example 3

[0022] 3 g of Omeprazole precursor: 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-5-methoxy-1H-benzimidazole, 0.09 g of Mo(acac)2 oxidation catalyst were dissolved in 20 ml of methanol by stirring. The temperature of the resulting solution was reduced to 0-5° C., followed by adding 1.17 g of 35% H2O2 aqueous solution. The reaction was carried out for about two hours, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Omeprazole with a yield of about 91-92% (HPLC purity >98%).

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Abstract

The present invention provides a method for preparing an antiulcer agent, 2-(2-pyridylmethylsulphinyl)benzimidazoles, such as Omeprazole, Lansoprazole and Pantoprazole, which includes oxidizing an intermediate having a linkage of methylthio group (—CH2S—) to methylsulfinyl (—CH2S(O)—) in the presence of an oxidation catalyst of acetyl acetonate of molybdenium (II) [(CH3C(O)CH2C(O)CH2)2Mo].

Description

FIELD OF THE INVENTION [0001] The present invention provides a method for preparing an antiulcer agent, 2-(2-pyridylmethylsulphinyl)benzimidazoles, such as Omeprazole, Lansoprazole and Pantoprazole, and particularly to a catalyst for the oxidation reaction in the preparation method. BACKGROUND OF THE INVENTION [0002] Many patents have disclosed a series of 2-(2-pyridylmethylsulphinyl)benzimidazoles as excellent agents for inhibiting the secretion of gastric acid, for example 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole (generic name: Omeprazole), 2-[[3-methy-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]-1H-benzimidazole (generic name: Lansoprazole), and 5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl-methylsulfinyl)-1H-benzimidazole] (generic name: Pantoprazole). One common technical feature for the preparation of these benzimidazole compounds includes that individual precursors 1, 2, or 3 need to undergo similar oxidation reactions to form sul...

Claims

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Application Information

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IPC IPC(8): C07D403/02
CPCC07D401/12
Inventor CHEN, CHIH-HUNG
Owner IND TECH RES INST
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