Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof

An enantioselective, omeprazole technology, applied in the field of chemical synthesis of drugs, can solve the problems of large usage of chiral ligands, difficulty in industrial production, waste of omeprazole raw materials, etc., and achieve optical purity of the product. And the effect of high chemical purity and easy operation

Active Publication Date: 2012-12-12
SHANGHAI HUILUN BIOLOGICAL TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] As can be seen from the above, the method for preparing optically active chiral omeprazole mainly contains: the one is to adopt the method for chiral resolution reagent to resolve racemate omeprazole, but traditional resolution method is very It is difficult to effectively split omeprazole, and this method will waste half of the omeprazole raw material; the second is to use biochemical methods, using biological enzymes to oxidize omeprazole sulfide or to omeprazole Meprazole sulfone is reduced to obtain (S)-omeprazole, but this method requires special experimental equip

Method used

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  • Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof
  • Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof
  • Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof

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Experimental program
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Effect test

Embodiment 1

[0053] The preparation of embodiment 1 (S)-omeprazole

[0054] In a 500mL three-necked flask, omeprazole sulfide (32.9g, 100mmol) was suspended in toluene (150mL), and (R)-(+)-1,1,2-triphenyl-1,2- Ethylene glycol (5.8g, 20mmol) and water (0.18g, 10mmol) were reacted by heating at 55°C for 10 minutes. Tetraisopropyl titanate (5.8 g, 20 mmol) was added dropwise, and the reaction was continued at 55° C. for 50 minutes. Stop heating, cool to room temperature, add imidazole (0.68g, 10mmol), react for 5 minutes, then slowly add 80% cumene hydroperoxide (19.0g, 100mmol) dropwise, and stir at room temperature for 3 hours. After chromatographic analysis, the HPLC purity of the crude reaction product was 96%, and the ee value was 95%.

Embodiment 2

[0055] The preparation of embodiment 2 (S)-omeprazole

[0056] In a 500mL three-necked flask, omeprazole sulfide (32.9g, 100mmol) was suspended in toluene (150mL), and (R)-(+)-1,1,2-triphenyl-1,2- Ethylene glycol (5.8g, 20mmol) and water (0.18g, 10mmol) were reacted by heating at 55°C for 10 minutes. Tetraisopropyl titanate (5.8 g, 20 mmol) was added dropwise, and the reaction was continued at 55° C. for 50 minutes. Stop heating, cool to room temperature, add diisopropylethylamine (1.3g, 10mmol), react for 5 minutes, then slowly add 80% cumene hydroperoxide (19.0g, 100mmol) dropwise, and stir at 30°C 2 hours. After chromatographic analysis, the HPLC purity of the crude reaction product was 95%, and the ee value was 88%.

Embodiment 3

[0057] The preparation of embodiment 3 (S)-omeprazole

[0058] In a 500mL three-necked flask, omeprazole sulfide (32.9g, 100mmol) was suspended in toluene (150mL), and (R)-(+)-1,1,2-triphenyl-1,2- Ethylene glycol (5.8g, 20mmol) and water (0.18g, 10mmol) were reacted by heating at 30°C for 10 minutes. Tetraisopropyl titanate (5.8 g, 20 mmol) was added dropwise, and the heating reaction was continued at 30°C for 120 minutes. Stop heating, cool to room temperature, add imidazole (0.68g, 10mmol), react for 5 minutes, then slowly add 80% cumene hydroperoxide (19.0g, 100mmol) dropwise, and stir at room temperature for 3 hours. After chromatographic analysis, the HPLC purity of the crude reaction product was 86%, and the ee value was 52%.

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Abstract

The invention relates to a preparation method for high-enantioselectivity synthesized (S)-omeprazole. The method comprises under catalysis of a complex formed by chiral alcohol ligand (R)-(+)-1, 1, 2-triphenyl-1, 2, glycol and alkoxy titanium, utilizing an oxidant to a prochiral compound omeprazole thioether to perform selective catalytic oxidation to obtain optically pure enantiomer (S)-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridyl)-methyl] sulfinyl]-1H-benzimidazole ((S)-omeprazole). (S)-omeprazole further reacts with alkali to form salt, and (S)-omeprazole metal salt with medical values is obtained. The preparation method is economical and simple and convenient to operate, optical purity and chemical purity of a product are high, and the preparation method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis medicine preparation, and relates to a method for preparing (S)-omeprazole and its salt with anti-peptic ulcer activity through enantioselective catalytic oxidation. Background technique [0002] The chemical structure of Omeprazole is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfoxide]-1H-benzene Bimidazole is a new class of anti-peptic ulcer drugs and proton pump inhibitors, developed by the Swedish company Astra, listed in Sweden in 1988, is the world's first clinical proton pump inhibitor (proton pump inhibitor, PPI). Because omeprazole has strong acid-suppressing effect, high cure rate, short cure time, can eliminate refractory ulcer crisis, and is safe and reliable, it has become an important drug for gastric and duodenal ulcer and flow esophagitis. It not only became one of the best-selling drugs in the world at that time, but also greatly promoted the development...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 李文华秦继红
Owner SHANGHAI HUILUN BIOLOGICAL TECH CO LTD
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