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Synthesis process of (L)-pantoprazole

A synthesis process, pantoprazole technology, applied in the field of synthesis process of levo-pantoprazole, can solve the problems of poor selectivity, low yield, difficult post-treatment and purification, etc.

Inactive Publication Date: 2017-05-10
QINGDAO YUNTIAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The object of the invention is to overcome the defects of low yield, poor selectivity and difficult post-treatment purification in the existing synthetic technique of L-pantoprazole, and provide a new synthetic technique of L-pantoprazole, the synthetic technique Good stereoselectivity, high product yield, mild conditions, simple steps, and easier post-treatment purification

Method used

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  • Synthesis process of (L)-pantoprazole
  • Synthesis process of (L)-pantoprazole
  • Synthesis process of (L)-pantoprazole

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Synthesis of Pantoprazole Thioether

[0031] In a 500ml flask, add 250ml of mixed solvent (mixed solvent is composed of tetrahydrofuran and water with a volume ratio of 3:1), and then 21.62g (100mmol) of 5-difluoromethoxy-2-mercapto-1H-benzimidazole , 2.54g (10mmol) of iodine, 97.75g of base (cesium carbonate, 300mmol) and 26.89g (120mmol) of 2-chloromethyl-3,4-dioxypyridine hydrochloride were added to the flask, stirred at 30-50°C Reacted for 1.5 hours, cooled to room temperature, extracted with dichloromethane, washed with water, recrystallized from petroleum ether / dichloromethane, and vacuum-dried to obtain 35.87g of pantoprazole sulfide shown in formula I, with a yield of 97.65% and a purity of 99.45%. .

Embodiment 2

[0033] Synthesis of Pantoprazole Thioether

[0034] In a 500ml flask, add 250ml of mixed solvent (mixed solvent is composed of tetrahydrofuran and water with a volume ratio of 3:1), and then 21.62g (100mmol) of 5-difluoromethoxy-2-mercapto-1H-benzimidazole , 1.27g (5mmol) of iodine, 31.8g of alkali (sodium carbonate, 300mmol) and 24.65g (110mmol) of 2-chloromethyl-3,4-dioxypyridine hydrochloride were added to the flask, stirred at 30-50°C Reacted for 2 hours, cooled to room temperature, extracted with dichloromethane, washed with water, recrystallized from petroleum ether / dichloromethane, and vacuum-dried to obtain 36.05 g of pantoprazole sulfide shown in formula I, with a yield of 98.14% and a purity of 99.27%. .

Embodiment 3

[0036] Synthesis of Pantoprazole Thioether

[0037] In a 500ml flask, add 250ml of mixed solvent (the mixed solvent is composed of tetrahydrofuran and water with a volume ratio of 2:1), and then 21.62g (100mmol) of 5-difluoromethoxy-2-mercapto-1H-benzimidazole , 1.78g (7mmol) of iodine, 65.16g of base (cesium carbonate, 200mmol) and 33.61g (150mmol) of 2-chloromethyl-3,4-dioxypyridine hydrochloride were added to the flask, stirred at 30-50°C Reacted for 2 hours, cooled to room temperature, extracted with dichloromethane, washed with water, recrystallized from petroleum ether / dichloromethane, and vacuum-dried to obtain 35.54 g of pantoprazole sulfide shown in formula I, with a yield of 96.73% and a purity of 99.49%. .

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Abstract

The invention discloses a synthesis process of (L)-pantoprazole. The synthesis process comprises the following steps: 1) in the presence of iodine and alkali, 5-(difluoromethoxy)-2-mercapto-1H-benzimidazole and 2-(chloromethyl)-3,4-dimethoxypyridine hydrochloride are subjected to stirring reaction to obtain the pantoprazole thioether as shown in the formula I, and the pantoprazole thioether represented by the formula I shown in the specification and hydrogen peroxide are subjected to oxidation reaction in the presence of (R)-(-)-binaphthol phosphate to obtain the (L)-pantoprazole. The synthesis process is good in stereo selectivity, high in the product yield, mild in the conditions, simple in the steps and easier in after-treatment and purification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis process of L-pantoprazole. Background technique [0002] Pantoprazole, the chemical name is 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl-1H-benzimidazole, produced by Germany Byk Developed by Gulden, it is mainly used to treat duodenal and gastric ulcers and relieve moderate to severe reflux esophagitis. So far, it has been listed in more than 20 countries and regions including the United States, the United Kingdom, and Germany. It is the third proton pump inhibitor in the world after omeprazole and lansoprazole. The compound has a sulfur-containing chiral center. Studies have shown that L-pantoprazole has better curative effect than D-pantoprazole in the treatment of the above diseases, and has higher bioavailability and less toxic side effects. . The specific structure of L-pantoprazole is as follows: [0003] [0004] There are also...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 许士娜
Owner QINGDAO YUNTIAN BIOTECH
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