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High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity

A compound, high-purity technology, applied in organic chemistry and other fields

Active Publication Date: 2015-09-23
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no relevant report on analyzing and solving the purity and impurity problems of the above-mentioned intermediates and final products in the prior art

Method used

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  • High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity
  • High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity
  • High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

[0107] At 20-25°C, the crude product (17g) was dissolved in dichloromethane (33mL), added dropwise with n-heptane (66mL), stirred for 30 minutes, filtered, and the filter cake was air-dried at 20-25°C for 3 hours to obtain Intermediate of Formula II 11.1 g. Yield: 65%, purity: 97.64%, impurity of formula III: 0.21%.

[0108] Preparation of Vonoprazan Fumarate (with reference to CN102421753A specification page 57 embodiment 5)

[0109] Add methanol (30.5mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3- Formaldehyde (6.0 g, 18.3 mol), methanol solution of methylamine (2.5 g, 30-33% methylamine, 23.8 mol), stirred for 1.5 hours. Cool down to 0~10℃, add NaBH dropwise 4 (346mg, 9.16mol) of N,N-dimethylacetamide solution (9.1mL), the temperature in the system was controlled at 0-10°C during the dropwise addition, and the reaction was tracked by TLC after the dropwise ad...

Embodiment 2

[0113] Preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

[0114] At 20-25°C, the crude product (17g) was dissolved in dichloromethane (33mL), added dropwise with n-heptane (99mL), stirred for 30 minutes, filtered, and the filter cake was air-dried at 20-25°C for 3 hours to obtain Product 11.9 g. Yield: 70%, purity: 97.57%, impurity of formula III: 0.25%.

[0115] Preparation of Vonoprazan Fumarate

[0116] Add methanol (30mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde to a 200ml round bottom flask in sequence at 20-25°C (6.0 g, 18.3 mol), methanol solution of methylamine (2.1 g, 30-33% methylamine, 20.1 mol), stirred for 1.5 hours. Cool down to 0~10℃, add NaBH dropwise 4 (346mg, 9.16mol) of N,N-dimethylformamide solution (9.1mL), the temperature in the system was controlled at 0-10°C during the dropwise addition, and the reaction was tracked by TLC after the dropwise addition. 1N hydrochloric acid (35 mL)...

Embodiment 3

[0120] Preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

[0121] At 20-25°C, the crude product (17g) was dissolved in dichloromethane (33mL), added dropwise with n-heptane (132mL), stirred for 30 minutes, filtered, and the filter cake was air-dried at 20-25°C for 3 hours to obtain Product 12.2g. Yield 72%, purity: 98.01%, chlorinated impurity of formula III: 0.22%.

[0122] Preparation of Vonoprazan Fumarate

[0123] Add methanol (30mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde to a 200ml round bottom flask in sequence at 20-25°C (6.0g, 18.3mol), methanol solution of methylamine (2.5g, 30-33% methylamine, 23.8mol), stirred for 1.5 hours. Cool down to 0~10℃, add NaBH dropwise 4 (311mg, 8.24mol) of N,N-dimethylacetamide solution (9.1mL), the temperature in the system was controlled at 0-10°C during the dropwise addition, and the reaction was tracked by TLC after the dropwise addition. 1N hydrochloric acid ...

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Abstract

The invention provides a high-purity Vonoprazan Fumarate compound and a preparation method thereof. The purity of the Vonoprazan Fumarate compound shown in structural formula I is higher than 99.6%, and the content of an impurity compound shown in formula IV is lower than 0.1%. The invention further provides an intermediate of the high-purity Vonoprazan Fumarate compound, a preparation method of the intermediate, the Vonoprazan Fumarate impurity compound and a preparation method thereof. Vonoprazan Fumarate products are high in purity and little in impurity content, and the preparation methods are simple and easy to operate, low in cost and little in energy consumption and are of great significance to industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a high-purity Vonoprazan Fumarate and a preparation method thereof, a high-purity Vonoprazan Fumarate intermediate and a preparation method thereof, impurities contained in Vonoprazan Fumarate and the intermediate thereof, and a preparation method of the impurities. Background technique [0002] Vonoprazan Fumarate (TAK-438, also known as Vonoprazan fumarate, formula I), chemical name 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H -Pyrrole-3-methylamine fumarate, a novel potassium ion-competitive acid inhibitor (P-CAB), can inhibit the last step of gastric acid secretion by the parietal cells by inhibiting K + to H + -K + - The combination of ATPase can stop the secretion of gastric acid in advance, and has a strong and long-lasting inhibitory effect on gastric acid secretion. [0003] [0004] The synthetic methods reported in the prior art (such as CN102421753A) a...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 赵俊宗在伟赵骞付锐吕伟
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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