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Preparation method of vonoprazan

A synthesis method and fluorophenyl technology, applied in the field of medicine, can solve the problems of unfriendly environment, long synthesis route, unstable intermediate and the like, and achieve the effects of convenient industrial production, convenient quality control and few synthesis steps

Active Publication Date: 2019-01-18
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0066] Purpose of the invention: The existing technology for preparing Vonorazan has defects such as long synthetic route, cumbersome process, low yield, unstable intermediate, unfriendly to the environment, and high price of starting materials in the market.

Method used

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  • Preparation method of vonoprazan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] (1) Preparation of ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate.

[0093] Add ethyl 3-oxopropionate (12.8 g, 110 mmol) and tetrahydrofuran (80 mL) to a 250 mL reaction flask, add sodium ethoxide (7.5 g, 110 mmol) in batches, stir at room temperature for 0.5 hours, add dropwise 2- Bromo-2'-fluoroacetophenone (21.7g, 100 mmol) in tetrahydrofuran (20 mL) was reacted at room temperature for 4 hours. Concentrate under reduced pressure, add water (100 mL), stir at room temperature for 0.5 hours, and filter to obtain ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate (yield: 97.9%, HPLC purity : 98.88%).

[0094] (2) Preparation of ethyl 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-pyrrole-3-carboxylate

[0095] Add ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate (20.2 g, 80 mmol), pyridine-3-sulfonamide (15.2 g, 96 mmol) into a 250 mL reaction flask ) and glacial acetic acid (100 mL), reacted at 100°C for 12 hours, and concentrated under reduced pressure. Add water (100 ...

Embodiment 2

[0102] (1) Preparation of ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate.

[0103] Add ethyl 3-oxopropionate (12.8 g, 110 mmol) and tetrahydrofuran (80 mL) to a 250 mL reaction flask, add sodium ethoxide (6.8 g, 100 mmol) in batches, stir at room temperature for 0.5 hours, add dropwise 2- Bromo-2'-fluoroacetophenone (21.7g, 100 mmol) in tetrahydrofuran (20 mL) was reacted at room temperature for 4 hours. Concentrate under reduced pressure, add water (100 mL), stir at room temperature for 0.5 hours, and filter to obtain ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate (yield: 93.6%, HPLC purity : 98.29%).

[0104] (2) Preparation of ethyl 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-pyrrole-3-carboxylate

[0105]Add ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate (20.2 g, 80 mmol), pyridine-3-sulfonamide (15.2 g, 96 mmol) into a 250 mL reaction flask ) and glacial acetic acid (100 mL), reacted at 80°C for 12 hours, and concentrated under reduced pressure. Add water (100 mL...

Embodiment 3

[0112] (1) Preparation of ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate.

[0113] Add ethyl 3-oxopropionate (12.8 g, 110 mmol), tetrahydrofuran (80 mL) and triethylamine (7.5 g, 110 mmol) into a 250 mL reaction flask, stir at room temperature for 0.5 hours, then add 2-bromo - 2'-fluoroacetophenone (21.7 g, 100 mmol) in tetrahydrofuran (20 mL), react at room temperature for 4 hours. Concentrate under reduced pressure, add water (100 mL), stir at room temperature for 0.5 hours, and filter to obtain ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate (yield: 93.2%, HPLC purity : 98.49%).

[0114] (2) Preparation of ethyl 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-pyrrole-3-carboxylate

[0115] Add ethyl 4-(2-fluorophenyl)-2-formyl-4-oxobutanoate (20.2 g, 80 mmol), pyridine-3-sulfonamide (15.2 g, 96 mmol) into a 250 mL reaction flask ) and glacial acetic acid (100 mL) at 100°C for 6 hours. Concentrate under reduced pressure, add water (100 mL), adjust its pH to 9 with saturate...

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Abstract

The invention relates to a preparation method of vonopraza. The preparation method of the vonoprazan, provided by the invention, comprises the following steps of taking 2-bromo-2'-fluoroacetophenone shown as a formula 3 as a starting raw material; reacting with 3-oxoethyl propionate to generate 4-(2-fluorophenyl)-2-formacyl-4-oxoethyl butyrate shown as a formula 39; then carrying out cyclization reaction on 4-(2-fluorophenyl)-2-formacyl-4-oxoethyl butyrate and pyridine-3-sulfonamide to generate 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-ethyl formate shown as a formula 40; then carrying out reduction and substation reaction to generate 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-yl]-N-methyl methylamine shown as a formula 1, i.e., the vonoprazan. The preparationmethod of the vonoprazan, provided by the invention, has the characteristics of few synthesis steps and high yield.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of vonorazan fumaric acid vonorazan intermediate. Background technique [0002] Vonoprazan Fumarate is a new type of gastric acid secretion inhibitor developed by Takeda Corporation of Japan. It was first approved for marketing in Japan in December 2014 (trade name Takecab) for the treatment of gastric acid-related diseases. Vonorazan fumarate belongs to a new generation of potassium ions (K + ) competitive acid blocker (P-CAB), which is a reversible proton pump inhibitor. After this product enters the human body, in the final step of gastric parietal cell acid secretion, by inhibiting K + to H + -K + - The combination of ATPase (proton pump) terminates the secretion of gastric acid to achieve the effect of acid suppression. This product has a strong and long-lasting inhibitory effect on gastric acid secretion. And vonoprazan is the last and most imp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 梁松军刘斐苗华明张启超梁晓艳李路路万刚强
Owner 迪嘉药业集团股份有限公司
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