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Preparation method of vonoprazan fumarate intermediate

A compound and solvent technology, applied in the field of preparation of vonoprazan fumarate intermediates, can solve the problems of unsuitable industrial production, increase production costs and the like, and achieve the effects of low price, low production cost and mild reaction conditions

Active Publication Date: 2021-06-15
枣庄市润安制药新材料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, expensive reagents such as silver trifluoromethanesulfonate or gold trichloride need to be used in the second step, which increases the production cost and is not suitable for industrial production

Method used

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  • Preparation method of vonoprazan fumarate intermediate
  • Preparation method of vonoprazan fumarate intermediate
  • Preparation method of vonoprazan fumarate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Add 1,4-dioxane (20mL), o-fluorobenzonitrile (3.63g, 30mmol), triethylamine (3.34g, 33mmol) and 20% aqueous ammonium sulfide (11.2g, 33 mmol). The temperature of the reaction solution was raised to 55 °C and continued to stir for 6 h, then cooled to room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain intermediate II (4.61 g, 99%). 1 H NMR (Methanol-d 4， 400MHz) δ8.54-8.50 (m, 1H); 7.48-7.44 (m, 1H); 7.24-7.14 (m, 2H).

Embodiment 2

[0054] Add 1,4-dioxane (20mL), o-fluorobenzonitrile (3.63g, 30mmol), triethylamine (3.34g, 33mmol), sodium sulfide nonahydrate (7.9g, 33mmol) to a 100mL reaction flask in sequence ) and water (10 mL). The temperature of the reaction solution was raised to 55 °C and continued to stir for 6 h, then cooled to room temperature. According to the post-processing method of Example 1, Intermediate II (4.52 g, 97%) was obtained.

[0055] Preparation of Intermediate I

Embodiment 3

[0057] Intermediate II (15.5 g, 100 mmol), furan (136.1 g, 2 mol) and methanol (500 mL) were sequentially added to a 1000 mL reaction flask. After nitrogen replacement three times, the temperature of the reaction solution was raised to 30-40°C and irradiated with a mercury lamp for 5 hours. Furan and methanol were recovered by distillation, and the remaining residue was recrystallized from ethyl acetate and petroleum ether to obtain intermediate I (15.3 g, 81%). 1 H NMR (CDCl 3，400MHz) δ9.85 (s, 1H); 9.31 (brs, 1H); 7.67-7.62 (m, 1H); 7.56-7.50 (m, 1H); 7.24-7.05 (m, 4H).

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Abstract

The invention provides a preparation method of a vonoprazan fumarate intermediate, and particularly provides a preparation method of a compound shown as a formula I. The preparation method comprises the following steps: reacting o-fluorobenzonitrile with a sulfur reagent to obtain a compound shown as a formula II, and then reacting the compound shown as the formula II with furan under an illumination condition to obtain a compound shown as the formula I. The method disclosed by the invention is short in route, mild in reaction condition, low in production cost and very suitable for industrial production, and the used starting materials and reagents are low in price.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and specifically, the invention provides a preparation method of a fumaric acid vonoprazan intermediate. Background technique [0002] Vonorazan fumarate, chemical name: 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine fumarate, It is a new type of oral anti-acid drug launched by Japanese pharmaceutical company Takeda and its partner Otsuka in Japan on February 27, 2015. It is mainly used for the treatment of gastric acid-related diseases. Vonorazan fumarate belongs to potassium ion (K + ) a new class of inhibitors of competitive acid blockers (P-CAB), which have fast-acting, strong and long-lasting inhibitory effects on gastric acid secretion; meanwhile, in the last step of gastric acid secretion in parietal cells, by inhibiting K + to H + , K + - The combination of ATPase (proton pump) also has an early termination effect on gastric acid secretion. In clinical tr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/333C07C327/48
CPCC07D207/333C07C327/48
Inventor 张奉志杨修东陈善任徐欣张美堂葛均官郭鹏
Owner 枣庄市润安制药新材料有限公司
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