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Preparation method of benzimidazole compound

A technology of benzimidazoles and compounds, applied in the field of pharmaceutical chemical synthesis, can solve the problems of reducing the yield of benzimidazoles, increasing the cost of purification, and long process time, so as to reduce the production of impurities, improve the yield, and improve the process. simple effect

Inactive Publication Date: 2013-04-17
北京华禧联合科技发展有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] Therefore, because the omeprazole prepared by the above method has impurities, the yield of benzimidazoles is further reduced, generally about 40% as the yield, and the method also increases the final purification cost
In addition, at present, the process time is long and the yield is low when preparing benzimidazoles from omeprazole I by the HPLC method.

Method used

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  • Preparation method of benzimidazole compound
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  • Preparation method of benzimidazole compound

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preparation example Construction

[0034] The invention provides a kind of preparation method of benzimidazole compound, such as figure 1 As shown, the benzimidazole compound has the structural formula VIII, and the preparation method comprises the following steps: (1) oxidizing the compound A of the structural formula V into the compound C of the structural formula VI; (2) compound C and the compound D of the structural formula IV A condensation reaction occurs to obtain a compound E with a structural formula of VII; (3) oxidizing the sulfide group of the compound E to obtain a compound with a structural formula of VIII, that is, a benzimidazole compound; wherein, the structural formula V is Structural formula Ⅵ is Structural formula IV is Structural formula VII is Structural formula VIII is wherein Y is a halogen substituent. Preferably, the halogen substituent is chlorine.

[0035] By first oxidizing the pyridyl group in compound A (2-chloromethyl-3,5-dimethyl-4-methoxypyridine), the compound C obt...

Embodiment 1

[0041]1) Preparation of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine nitrogen oxide

[0042] Take 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (2.2g, 0.01mol) and add to sodium carbonate (1.3g, 0.012mol) aqueous solution and dichloromethane (2.0g ), then add m-chloroperoxybenzoic acid (1.9g, 0.011mol), stir at room temperature for 2h, separate liquids, extract the water layer, combine the organic phases, dry, filter, and spin the solvent to obtain 2-chloroform 2.0 g of the crude product of 3,5-dimethyl-4-methoxypyridine nitroxide.

[0043] 2) Preparation of 5-methoxy-2-(4-methoxy-3,5-dimethylpyridine nitrogen oxide-2-yl)methylthio-1H-benzimidazole

[0044] 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine nitroxide (2.0g, 0.01mol) and 5-methoxy-2-mercapto-1H-benzimidazole (1.8g0 .01mol) was dissolved in methanol, 5ml of sodium hydroxide (0.44g, 0.011mol) aqueous solution was added, stirred at room temperature for 4h, concentrated, the aqueous solution was extract...

Embodiment 2

[0048] 1) Preparation of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine nitrogen oxide

[0049] The 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (0.022mol) was added to the mixed solution formed by 2.6g of sodium hydroxide solution and 4.3g of dichloromethane , then add hydrogen peroxide (0.02mol), stir for 3h, separate the layers, extract the water layer, combine the organic phases, dry, filter, and spin the solvent to obtain 2-chloromethyl-3,5-dimethyl-4-methoxy 4.0 g of crude pyridine nitrogen oxide.

[0050] 2) Preparation of 5-methoxy-2-(4-methoxy-3,5-dimethylpyridine nitrogen oxide-2-yl)methylthio-1H-benzimidazole

[0051] 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine nitroxide (4.0g, 0.02mol) and 5-methoxy-2-mercapto-1H-benzimidazole (10.8g , 0.06mol) was dissolved in 40ml of methanol, added 5ml of sodium hydroxide aqueous solution (containing 0.86g of sodium hydroxide solid), stirred at room temperature for 6h, concentrated, extracted the aqueous soluti...

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Abstract

The invention discloses a preparation method of a benzimidazole compound. The preparation method comprises the following steps: (1) oxidizing a compound A with the structural formula V into a compound C with the structural formula VI; (2) enabling the compound C and a compound C with the structural formula IV to carry out the condensation reaction to obtain a compound E with the structural formula VII; and (3) oxidizing the thioether group of the compound E to obtain the benzimidazole compound with the structural formula VIII, wherein the structural formula V, the structural formula VI, the structural formula IV, the structural formula VII and the structural formula VIII are shown in the specification, and Y refers to a halogen substitient group. Through the adoption of the preparation method, the problem that sulfinyl is further oxidized into sulfonyl is avoided, the impurity generation is reduced, and the yield of the benzimidazole compound with the structural formula VIII is improved. In addition, the preparation method has the advantages that not only the raw materials are easily obtained, the process is simple, the reaction condition is mild, and the efficiency is higher, but also the next-step operation can be carried out without the need of an intermediate purification step.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of benzimidazole compounds. Background technique [0002] Esomeprazole magnesium enteric-coated tablets, trade name Nexium, is a new generation of proton pump inhibitors for the treatment of erosive esophagitis, gastroesophageal reflux disease, NSAID-related gastric ulcer and Helicobacter pylori Duodenal ulcer. The chemical name is bis(5-methoxy-2-(S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)-sulfinyl)-1H-benzene and imidazol-1-yl) magnesium salt, its structure is as follows: [0003] [0004] Wherein esomeprazole is a single S isomer of omeprazole, wherein I is omeprazole, and II is esomeprazole, and the structure is as follows: [0005] [0006] Wherein, the synthesis of omeprazole is mainly divided into two categories: [0007] 1. Condensation direct preparation [0008] This type of synthesis method is directly prepar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 毕华张凯
Owner 北京华禧联合科技发展有限公司