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New method for synthesizing esomeprazole through asymmetrically catalytic oxidation

A technology of esomeprazole and synthetic method, which is applied in the field of medicine, can solve the problems of large-scale use limitation, expensive resolution agent, waste of omeprazole, etc., and achieve high raw material utilization rate, convenient operation, and stability Good results

Active Publication Date: 2012-12-05
SHOUGUANG FUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Splitting omeprazole with this type of splitting method will waste half of the omeprazole, causing environmental pollution and economic losses, and the price of optically active resolving agent is also expensive, so this splitting method is widely used in industry. The large-scale use of

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (Esso Meprazole) preparation

[0023] 15 grams (45mmol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole was added to 75 Add 29.7 g (90 mmol) of (S,S)-6,6′-dihydroxy-2,2′-biphenyldicarboxylic acid diethyl ester at 55°C and Tetraisopropoxymolybdenum 19.8g (60mmol), add 4 drops of purified water at the same time, stir for 2 hours, then lower the temperature, 35-40°C, drop 3.46g (45mmol) of isopropyl hydrogen peroxide into the After the reaction solution was completed, it was incubated at 35-40° C. for 2 hours, and the end point of the reaction was determined by TLC. After the reaction was completed, 90 ml of 15% ammonia water was added for extraction, layered and settled, the aqueous layer was adjusted to pH=8-9 with concentrated acetic acid, extracted with ethyl acetate, and then concentrated to obtain 13.37 g of esomeprazole, with a yield of 85% and an...

Embodiment 2

[0025] (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (Esso Meprazole) preparation

[0026] 15 grams (45mmol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole was added to 75 Add 22.3 g (67.5 mmol) of (S,S)-6,6′-dihydroxy-2,2′-biphenyldicarboxylate to 55°C after heating to 65°C in 1 ml of ethyl acetate Add 11.2 grams (33.7 mmol) of tetraisopropoxy molybdenum, add 4 drops of purified water at the same time, stir for 1 hour, then lower the temperature, 35-40 ° C, use 3-4 hours to dissolve 3.81 grams (49.5 mmol) of isopropyl hydroperoxide ) into the reaction solution, after completion, keep warm at 35-40°C for 2 hours, and determine the end point of the reaction by TLC. After the reaction was completed, 90 ml of 15% ammonia water was added for extraction, layered and settled, the aqueous layer was adjusted to pH=8-9 with concentrated acetic acid, extracted with ethyl acetate, and then concentrated to obta...

Embodiment 3

[0028] (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole sodium salt ( esomeprazole sodium) preparation

[0029] Put 15 grams (45mmol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole into 500 Add 75ml of ethyl acetate to a three-necked flask, raise the temperature to 65°C, after dissolving, add (S,S)-6,6′-dihydroxy-2,2′-biphenyldicarboxylic acid diethyl at 55°C 29.7 g (90 mmol) of ester and 19.8 g (60 mmol) of tetraisopropoxy molybdenum, add 4 drops of purified water at the same time, stir for 1 hour, then cool down, 35-40 ° C, use 3-4 hours to dissolve isopropyl hydroperoxide 3.46 g (45 mmol) was added dropwise into the reaction solution. After completion, it was incubated at 35-40° C. for 2 hours, and the end point of the reaction was determined by TLC. After the reaction was completed, 90 ml of 15% ammonia water was added for extraction, layered and settled, the aqueous layer was adjusted to pH=8-9 wi...

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Abstract

The invention relates to a new method for synthesizing esomeprazole through asymmetrically catalytic oxidation. The method is characterized in that (S,S)-6,6'-dyhydroxy-2,2'-biphenyl dicarboxylate is used as a chiral ligand inducer, compounds containing molybdenum are used as catalyst, isopropyl hydrogen peroxide is used as oxidant, high-content and high-optical-purity esomeprazole which is a single enantiomer of omeprazole is obtained through room-temperature catalytic oxidation of prochiral thioether compounds, and corresponding alkali metal salts of esomeprazole can be further obtained through reaction with alkali inorganic salts. After the esomeprazole and the alkali metal salts thereof obtained by adopting the method are purified, the purity can reach more than 99 percent, the optical purity can reach more than 99.5 percent and the yield can reach more than 75 percent. The method can realize high utilization ratio of raw materials, is simple, convenient and feasible and is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new method for synthesizing esomeprazole by asymmetric catalytic oxidation. Background technique [0002] Some sulfoxides have the ability to inhibit H ﹢ , K ﹢ -ATPase activity, commonly known as proton pump inhibitors, can effectively inhibit the secretion of gastric acid, and has been widely used in the treatment of gastric ulcer, duodenal ulcer, reflux esophagitis and other related diseases caused by excessive gastric acid secretion Digestive disorders. Proton pump inhibitors that have been marketed at home and abroad include omeprazole, lansoprazole, pantoprazole, rabeprazole, and tetuprazole that is in the clinical research stage. This type of drug molecule has a 2-[[(2-pyridyl)methyl]sulfinyl]-1H benzimidazole structure or a structurally related sulfoxide structure, and the sulfur atom is a stereogenic center. Therefore, these drugs are A racemic mixture ...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 宋伟国褚亚飞高东圣张福建甲宗青
Owner SHOUGUANG FUKANG PHARMA
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