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Preparation method of pantoprazole sodium

A technology of pantoprazole sodium and benzimidazole, which is applied in the field of medicine, can solve problems such as cumbersome process, cumbersome post-processing, and environmental impact, and achieve the effects of lowering reaction temperature, easy control of side reactions, and improving selectivity

Active Publication Date: 2015-01-07
桂林华信制药有限公司
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Problems solved by technology

[0008] CN102887886A discloses a preparation method of pantoprazole sodium, comprising the following steps: 1) taking 2-hydroxymethyl 3,4-dimethoxypyridine (II) as the starting material, under the action of chloride, Generate 2-chloromethyl 3,4-dimethoxypyridine hydrochloride (Ⅲ); 2) the obtained compound (Ⅲ) is mixed with 5-difluoromethoxy-2-mercapto-1H under basic conditions -Benzimidazole is condensed under the effect of inorganic base to generate 5-difluoromethoxy 2[(3,4-dimethoxy-2-pyridyl)methyl]thio-1H-benzimidazole (Ⅳ ); 3) the obtained compound (IV) is salified with sodium hydroxide, and then oxidized by sodium hypochlorite to generate 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl) methyl Base] sulfinyl-1H-benzimidazole sodium, i.e. pantoprazole sodium (I), simple to operate as described by the inventor, strong in safety, easy to control, but the impurities in the oxidation process cannot be effectively controlled
W0962798 is synthesized by chiral oxidation, but the post-treatment is cumbersome, and there is no clear purification method; CN102382103 provides detailed purification and salt-forming methods, but the acid-base adjustment is required during the purification process, which is cumbersome and used in the salt-forming process A large amount of organic solvents have an impact on the environment

Method used

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  • Preparation method of pantoprazole sodium
  • Preparation method of pantoprazole sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Add 1L of water, sodium hydroxide (45g, 1.13mol) and triethylbenzylammonium chloride (3g, 0.013mol) into a 2.5L three-necked flask, stir until clear, and add dichloromethane (0.85 L) and 5-difluoromethoxy-2-mercapto-1H-benzimidazole (99.8g, 0.466mol), stir well and drop into 2-chloromethyl 3,4-dimethoxypyridine hydrochloride (99g, 0.44mol) in water (0.6L) solution, dripped within 1.6h, reacted at 30-35°C for 4.5h, TLC [developing solvent: ethyl acetate: methanol = 9: 1] after the completion of the detection reaction, let stand to separate layer, the dichloromethane layer was separated and washed with 0.1mol / L sodium hydroxide solution, and then an aqueous solution of sodium tungstate (Na 2 WO 4 .2H 2 O16g, H2 (00.75L), 250ml of 30% hydrogen peroxide, adjust the pH value to 3.5 with weak acid, react at -6°C-0°C for 4.5h, detect by TLC (developing solvent: ethyl acetate:methanol=9:1), add saturated carbonic acid after the reaction is completed Adjust the pH value of th...

Embodiment 2

[0032] Add 0.95L of water, sodium hydroxide (45.2g, 1.13mol) and tetrabutylammonium bromide (4.83g, 0.015mol) into a 2.5L three-necked flask, stir until clear, cool to room temperature and add dichloromethane (0.85L) and 5-difluoromethoxy-2-mercapto-1H-benzimidazole (99.8g, 0.466mol), stir well and add 2-chloromethyl 3,4-dimethoxypyridinium dropwise Acetate (99g, 0.44mol) in 0.6L of water solution, dripped within 1.6h, reacted at 30-35°C for 4.5h, TLC [developing solvent: ethyl acetate: methanol = 9: 1] after the completion of the detection reaction, let it stand and separate layer, the dichloromethane layer was separated and washed with 0.1mol / L sodium hydroxide solution, and then an aqueous solution of sodium tungstate (Na 2 WO 4 .2H 2 O16.5g, H 2 (00.75L), 255ml of 30% hydrogen peroxide, adjust the pH value to 2.5 with weak acid, react at -5°C-0°C for 4.5h, detect by TLC (developing solvent: ethyl acetate:methanol=9:1), add saturated carbonic acid after the reaction is c...

Embodiment 3

[0035] Add 1L of water, sodium hydroxide (43g, 1.13mol) and tetrabutylammonium bisulfate (5.08g, 0.015mol) into a 2.5L three-necked flask, stir until clear, and add chloroform (0.84L) after cooling to room temperature And 5-difluoromethoxy-2-mercapto-1H-benzimidazole (100g, 0.466mol), after stirring well, drop into 2-chloromethyl 3,4-dimethoxypyridine hydrochloride (98.5g , 0.44mol) of water 0.6L solution, dripped within 1.6h, reacted at 30-35°C for 4.5h, TLC [developing solvent: ethyl acetate: methanol = 9:1] detection, after the completion of the reaction, let it stand for stratification, and separate The chloroform layer was washed with 0.1mol / L sodium hydroxide solution, and then an aqueous solution of potassium tungstate (Na 2 WO 4 .2H 2 O18g, H 2 (00.76L), 30% hydrogen peroxide 260ml, adjusted pH value to 3.5 with weak acid, reacted at -5°C-0°C for 4.5h, detected by TLC (developing solvent: ethyl acetate:methanol=9:1), after the reaction was completed, add saturated c...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a preparation method of pantoprazole sodium. Aiming at operation of condensation, oxidization and salification by adopting a one-pot process in the prior art, a phase transfer catalyst is added into the condensation process, so that the reaction speed and yield are increased. By virtue of catalytic oxidation of hydrogen peroxide in the presence of tungstate, the selectivity of the reaction is improved and the impurities are reduced. The method provided by the invention is simple to operate, the yield and the purity of the product are improved, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to a preparation method of pantoprazole sodium. Background technique [0002] Pantoprazole (pantoprazole sodium) chemical name: 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzo Sodium imidazole, the structural formula is: [0003] [0004] This product is a new generation of proton pump inhibitors (PPI) after omeprazole and lansoprazole, with better selectivity, strong and long-lasting acid suppression effect, adverse reactions and drug interactions In 1994, Germany’s BydGulden company was first successfully developed and launched in South Africa, and it has been approved for marketing in more than 20 countries such as the United States, Britain, and Germany. Proton pump inhibitors (PPI) have become an Mainstream drugs for the treatment of systemic diseases. [0005] Mathad VT, Govindan S, Kolla NK, et al.An improved And single-pot process for the pro...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 严白双
Owner 桂林华信制药有限公司
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