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Preparation method of vonoprazan fumarate

A technology of vonoprazan fumarate and Schiff base, which is applied in the field of compound preparation, can solve the problems of low yield and unfavorable industrial scale-up production, and achieve mild reaction treatment conditions, high product purity, and high yield Effect

Inactive Publication Date: 2017-08-04
GUANGDONG SCI FINDER PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It is found through experiments that the yield is generally 50%-70%, and the content is below 96%. With the scale-up of the preparation experiment, the yield gradually decreases, which is not conducive to industrial scale-up production

Method used

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  • Preparation method of vonoprazan fumarate

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Add 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1-H-pyrrole-3-carbaldehyde (3.3Kg 10mol) to 15.5 liters of methanol, and add 33 % methylamine methanol solution (4.70Kg 50mol), and maintain the reaction at about 10°C for 6h. Add sodium cyanoborohydride (502 g 8 mol) at 10°C, react for 4 h, TLC to 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1-H-pyrrole-3-carbaldehyde The basic reaction is complete, add 4mol / L hydrochloric acid to adjust PH=7~8, concentrate to dry methanol at 45°C, add 3 liters*2 dichloromethane for extraction, combine the organic phases, dry, filter, add fumaric acid (1160 grams 10mol ), heated to reflux for 2 hours, cooled to room temperature to precipitate solids, filtered, and dried solids weighed 3.91Kg, yield: 85%, HPLC: 98.3%.

Embodiment 2

[0023] Add 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1-H-pyrrole-3-carbaldehyde (3.3Kg 10mol) to 15.5 liters of methanol, and add 33 % methylamine methanol solution (4.70Kg 50mol), and maintain the reaction at about 10°C for 6h. Add sodium triacetoxyborohydride (2.54Kg 12mol) at 0°C, react for 6 hours, TLC until the raw materials are basically reacted completely, add 4mol / L sodium hydroxide to adjust pH=7~8, concentrate to dry methanol at 45°C, add 3 liter*2 dichloromethane extraction, combined organic phases, dried, filtered, added fumaric acid (1160 g 10 mol) to the filtrate, heated to reflux for 2 h, cooled to room temperature to precipitate solids, filtered, and the dried solids weighed 4.38 Kg. Yield: 95%, HPLC: 99.2%.

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Abstract

The invention provides a preparation method of vonoprazan fumarate. The preparation method comprises the following steps of enabling 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1-H-pyrrole-3-formaldehyde and methylamine to react to generate Schiff base; using a mild boride reducing agent to reduce the Schiff base, so as to prepare vonoprazan. The preparation method has the advantages that the reaction treatment condition is mild, the yield rate is high, the product purity is high, and the like. The vonoprazan fumarate prepared by the preparation method has the advantages that the yield rate is increased to 95%, and the content of HPLC (high performance liquid chromatography) is 99%; when preparing by the sodium borohydride reduction method, the yield rate of 70%, and the content of HPLC of 96% are greatly improved.

Description

technical field [0001] The invention belongs to the field of compound preparation, and in particular relates to a method for preparing the potassium ion-competitive acid blocker drug vonoprazan fumarate by reduction with a mild boride reducing agent. Background technique [0002] Vonoprazan Fumarate belongs to a new class of inhibitors of potassium ion competitive acid blocker (Potassium-competitive acid blocker, P-CAB), which has a strong and lasting inhibitory effect on gastric acid secretion. At the same time, In the last step of gastric acid secretion by gastric parietal cells, it also has an early termination effect on gastric acid secretion by inhibiting the binding of K to H, K-ATPase (proton pump). Currently, proton pump inhibitors (PPIs) are widely prescribed for the first-line treatment of acid-related diseases. However, PPIs are not always able to provide sufficient curative effect. At the same time, the gastric acid secretion inhibitory effect may also vary from...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C57/15C07C51/41
CPCC07D401/12
Inventor 郭庆磊丁效明黄志鹏
Owner GUANGDONG SCI FINDER PHARMA TECH CO LTD
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