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Preparation method for key intermediate rabeprazole thioether

A technology of rabeprazole sulfide compound and rabeprazole hydroxy compound, which is applied in the field of medicinal chemistry and can solve the problems of low yield of sulfide compound, complicated preparation process, equipment corrosion and the like

Inactive Publication Date: 2017-05-17
SHOUGUANG FUKANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The above-mentioned reaction sulfide yield is low, the preparation process is complicated, and because the chlorination reaction uses strong corrosive chlorination reagents such as thionyl chloride, phosphorus trichloride and phosphorus oxychloride, and sodium hydroxide, hydroxide Strong alkaline reagents such as potassium and barium hydroxide, causing serious corrosion to equipment

Method used

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  • Preparation method for key intermediate rabeprazole thioether
  • Preparation method for key intermediate rabeprazole thioether
  • Preparation method for key intermediate rabeprazole thioether

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Experimental program
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preparation Embodiment 1

[0021] Take 100g of rabeprazole hydroxyl (473.35mmol) and add it into a 2L three-necked flask, then add 1L of tetrahydrofuran, 71.10g of mercaptobenzimidazole (473.35mmol), and 136.58g of triphenylphosphine (520.69mmol). Stirring was turned on and the temperature was controlled at 0-10 °C. Then 90.678 g (520.69 mmol) of diethyl azodicarboxylate were added dropwise. After the dropwise addition, keep the temperature for 5h-10h, and monitor the completion of the reaction by pointing the plate. After the reaction, tetrahydrofuran was evaporated to dryness, and then recrystallized using methanol to obtain 130.0 g of rabeprazole thioether, with a yield of 80% and a purity of 98.3% by HPLC. 1H-NMR (CDCl3, 600MHz) δ: 8.36~8.37(d, J=6.0Hz, 1H, NH), 7.56(s, 2H), 7.19~7.20(t, 2H), 6.79~6.80(d, J= 6.0Hz, 1H), 4.40(s, 2H), 4.14~4.16(t, 2H), 3.58~3.60(t, 2H), 3.38(s, 3H), 2.28(s, 3H), 2.11~2.13(t ,2H). EI-MS m / z: 343.9 [M+1]. See attached for specific data map figure 1 with 4 .

preparation Embodiment 2

[0023] Take 50g of rabeprazole hydroxyl (236.68mol) and add it to a 1L three-necked flask, then add 500ml of 1,4-dioxane, 35.55g of mercaptobenzimidazole (236.68mol), 68.29g of triphenylphosphine (260.35mmol) . Stirring was turned on and the temperature was controlled at 0-10 °C. Then 52.59 g (260.35 mmol) of diisopropyl azodicarboxylate were added dropwise. After the dropwise addition, keep the temperature for 5h-10h, and monitor the completion of the reaction by pointing the plate. After the reaction, tetrahydrofuran was evaporated to dryness, and then 56.83 g of rabeprazole sulfide was recrystallized from methanol, with a yield of 70% and a purity of 98.5% by HPLC.

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Abstract

The invention discloses a preparation method for rabeprazole thioether 2-[[[4-(3- methoxypropoxy)-3-methylpyridin-2-yl] methyl] sulfo]-1H-benzimidazole. By using Mitsunobu reaction, the rabeprazole thioether is prepared from rabeprazole oxhydryl in one-step synthesis way without chlorination reaction. In the reaction process, the high-corrosive chloride agent, such as, thionyl chloride, is not used, so that the violent corrosion of the reaction to the device is obviously reduced, and meanwhile, the reaction yield is obviously increased due to the shortened reaction step. According to the invention, the process is simple, the reaction condition is mild, the corrosion to the device is small, the yield is higher (70%-80%) and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a key intermediate sulfide of rabeprazole. Background technique [0002] The synthetic route of rabeprazole in the prior art mainly uses 2,3-dimethyl-4-chloropyridine as the starting material through the following synthetic route. [0003] [0004] The preparation process of rabeprazole sulfide is generally to use hydroxyl compound to react with chlorination reagent to generate chloride, and then react chloride with mercaptobenzimidazole under alkaline conditions to generate thioether. Chlorination reagents can be selected from thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and sulfuryl chloride. Thionyl chloride is the preferred chlorination reagent in the chlorination reaction. The temperature range for this reaction is -5-30°C. The reaction between chloride and mercaptobenzimidazole needs to be carried...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 魏代宝宋伟国高东圣董良军甲宗青王连进王伟杨春程王耀朋刘春玲
Owner SHOUGUANG FUKANG PHARMA