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Preparation method of rabeprazole and sodium salts thereof

A technology of rabeprazole and benzimidazole, which is applied in the field of preparation of rabeprazole and rabeprazole sodium, can solve the problems of many by-products, sources of oxidants, and low yield, and achieve moderate cost and post-treatment Simple operation and high yield

Active Publication Date: 2013-04-17
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to overcome the problems such as low yield, many by-products, and sources of oxidant in the synthetic process of rabeprazole sodium above, the present invention adopts a kind of oxidative agent with milder oxidative properties—hexavalent chromium in the synthetic process of rabeprazole The coordination compound of salt and pyridine can accurately control the oxidation of thioether to generate sulfoxide, basically no peroxidation and other side reactions occur, and the post-treatment is simple, which improves the purity and yield of the product. Moreover, the oxidants used are available in the market for sale, suitable for industrial production

Method used

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  • Preparation method of rabeprazole and sodium salts thereof
  • Preparation method of rabeprazole and sodium salts thereof
  • Preparation method of rabeprazole and sodium salts thereof

Examples

Experimental program
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Embodiment 1

[0029] Add 250 g of dried methylene chloride to a 1L three-necked reaction flask, and then add 100 g of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]-methyl ]Sulfuryl]-1H-benzimidazole, stir to dissolve, slowly add 35g of oxidant PCC at 5-10°C, after addition, keep the temperature between 20-25°C for 2h, add 300ml of water after the reaction, mix well, and use 1N Adjust pH=9 with sodium hydroxide solution, separate layers, extract the aqueous layer with 100ml of dichloromethane, combine the dichloromethane layers, wash the dichloromethane layer with 200ml×3 saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure To dryness, 250 ml of acetone was added to the residue for recrystallization, filtered, the filter cake was washed with a small amount of acetone, and dried under reduced pressure to obtain 101 g of white solid rabeprazole.

[0030] Add the obtained rabeprazole into a 1000ml reaction flask, add 400ml of ethanol, adjust the pH=13 with ...

Embodiment 2

[0032] Add 300 g of dried chloroform to a 1L three-necked reaction flask, and then add 100 g of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]-methyl] Sulfuryl]-1H-benzimidazole, stir to dissolve, slowly add 60g of oxidant PDC at 5-10°C, after the addition, keep the temperature between 10-20°C for 2.5h, after the reaction, add 300ml of water and mix well, use 1N Adjust pH=9.5 with sodium hydroxide solution, separate the layers, extract the aqueous layer with 100ml chloroform, combine the chloroform layers, wash the chloroform layer with 200ml×3 saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure To dryness, 250 ml of ethyl acetate was added to the residue for recrystallization, filtered, the filter cake was washed with a small amount of ethyl acetate, and dried under reduced pressure to obtain 97 g of white solid rabeprazole.

[0033] Add the obtained rabeprazole into a 1000ml reaction flask, add 400ml of methanol, adjust the pH=12.5 with ...

Embodiment 3

[0035] Add 250 g of dried methylene chloride to a 1L three-necked reaction flask, and then add 100 g of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]-methyl] Sulfuryl]-1H-benzimidazole, stir and dissolve, slowly add 70g of oxidant chromium trioxide pyridine at 5-10°C, after the addition is complete, slowly raise the temperature to 40-45°C for 3.5h, add water 300ml after the reaction Mix well, adjust the pH to 9.5 with 1N sodium hydroxide solution, separate the layers, extract the aqueous layer with 100ml of dichloromethane, combine the dichloromethane layers, wash the dichloromethane layer with 200ml×3 saturated brine, and anhydrous sulfuric acid Dry over sodium, concentrate to dryness under reduced pressure, add 350 ml of acetone to the residue for recrystallization, filter, wash the filter cake with a small amount of acetone, and dry to obtain 92 g of white solid rabeprazole.

[0036] Add the obtained rabeprazole into a 1000ml reaction flask, add 300ml of ethanol, adjust the...

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Abstract

The invention discloses a preparation method of rabeprazole and sodium salts thereof; 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl]-methyl]thio]-1H-benzimidazole is used as a substrate; a coordination compound of hexavalent chromium salt and pyridine is used as an oxidant; the thioether is oxidized into sulfoxide under accurate control to obtain rabeprazole, and rabeprazole sodium is prepared from rabeprazole and sodium hydroxide through salification. The process of the invention is simple; the oxidant raw material is easily available; little other impurities are introduced; the product has high purity; and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of rabeprazole and rabeprazole sodium, belonging to the technical field of medicine and chemical industry. technical background [0002] Rabeprazole sodium [chemical name 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]-methyl]sulfinyl]-1H-benzimidazole Sodium salt] is a new generation of proton pump inhibitors, developed by Japan's Eisai company, as an anti-ulcer drug, against choline and histamine H 2 No receptor antagonistic effect. Its molecular formula is: C 18 h 20 N 3 o 3 NaS, the structural formula is as follows: [0003] [0004] There are a lot of bibliographical reports on the synthesis of rabeprazole sodium, but usually all adopt 2,3-dimethyl-4-chloropyridine as the starting raw material, synthesized by the following route: [0005] [0006] In the above synthetic route, from the starting material to the intermediate 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]-methyl]sulfanyl]-1H -T...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 柏子辉徐虹
Owner NEW FOUNDER HLDG DEV LLC
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