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Preparation method of vonoprazan fumarate intermediate namely 5-(2-fluorophenyl)-1H-pyrrole-3-methanal

A technology for vornorazan fumarate and an intermediate is applied in the field of preparation of vornorazan fumarate intermediate 5--1H-pyrrole-3-formaldehyde, and can solve harsh reaction conditions, damage and equipment corrosion Environmental problems, etc., to achieve the effect of reducing the post-reaction processing burden, reducing the difficulty of operation, and low equipment requirements

Active Publication Date: 2016-12-21
SHANDONG JINCHENG BIO PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The first of the two routes is similar to the route reported by Japanese Takeda Pharmaceutical Company patent CN102421753B, using materials such as bromine, hydrogen chloride gas, palladium carbon, diisobutyl aluminum hydride, etc., which has great industrialization difficulty and pressure on safety and environmental protection; The second route has more stringent conditions and is not conducive to the implementation of industrialization
[0010] According to patent CN102421753B and journal reports, the existing 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde synthesis routes mainly contain two: one is to use materials such as bromine and hydrogen chloride with strong corrosiveness, The corrosion of equipment and damage to the environment are very serious, and the use of flammable hydrogenation reducing agents such as palladium carbon, Raney nickel, diisobutyl aluminum hydride, etc., has great operational difficulty and potential safety hazards; the second The reaction conditions of this route are more severe, and the industrial operation is more difficult

Method used

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  • Preparation method of vonoprazan fumarate intermediate namely 5-(2-fluorophenyl)-1H-pyrrole-3-methanal
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  • Preparation method of vonoprazan fumarate intermediate namely 5-(2-fluorophenyl)-1H-pyrrole-3-methanal

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Experimental program
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Effect test

Embodiment 1

[0030] Preparation of Compound IV:

[0031] In a 2000ml reaction bottle, add 138g of 2-fluoroacetophenone, 114g of allylamine, 966ml of absolute ethanol, and 10ml of glacial acetic acid, heat the reaction system to 50°C, keep it warm for 6h, and cool to At room temperature, a large amount of solids precipitated, stirred for 1 hour, then cooled to 0-10°C, kept warm for 1 hour, filtered with suction, rinsed the filter cake with cold ethanol, and dried to obtain 165 g of white solid, compound IV, with a yield of 93%.

Embodiment 2

[0033] Preparation method 1 of compound V:

[0034] In a 3000ml reaction flask, add 160g of compound IV, 8.5g of cuprous iodide, 285g of triphenylphosphine, and 640ml of dioxane. Under nitrogen protection, stir at 40°C for 16h. TLC detects the progress of the reaction. After the reaction is completed, cool to room temperature, add 1280ml of water, then add 320ml of ethyl acetate to extract three times, combine the organic phase, add 240ml of 1% dilute hydrochloric acid to the organic phase, stir for 15min, separate the liquids, concentrate the organic phase to dryness to obtain a dark brown oil, add ethanol 240ml was dissolved, and 800ml of water was added dropwise under stirring at room temperature, and a solid precipitated out. The temperature was lowered to 5-10°C, kept for 1 hour, and filtered with suction to obtain 135g of a light yellow solid, namely compound V, with a yield of 85.4%.

Embodiment 3

[0036] Preparation method 2 of compound V:

[0037] In a 3000ml reaction flask, add 160g of compound IV, 1.7g of cuprous iodide, 474g of triphenylphosphine, and 1600ml of dioxane, under the protection of nitrogen, stir at 60°C for 24h, check the progress of the reaction by TLC, after the completion of the reaction, cool to room temperature, add 1280ml of water, then add 320ml of ethyl acetate to extract three times, combine the organic phase, add 240ml of 1% dilute hydrochloric acid to the organic phase, stir for 15min, separate the liquids, concentrate the organic phase to dryness to obtain a dark brown oil, add ethanol 240ml was dissolved, and 800ml of water was added dropwise under stirring at room temperature, and a solid precipitated out. The temperature was lowered to 5-10°C, kept for 1 hour, and filtered with suction to obtain 127g of a light yellow solid, namely compound V, with a yield of 80.3%.

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Abstract

The invention relates to a preparation method of a vonoprazan fumarate intermediate namely 5-(2-fluorophenyl)-1H-pyrrole-3-methanal, and belongs to the technical field of chemical industry. The preparation method comprises the following steps of (1) by using 2-fluoroacetophenone as an initial raw material, enabling the 2-fluoroacetophenone and allylamine to be subjected to condensation so as to obtain a compound IV; (2) under the catalysis of a metal catalyst, and under the condition that a ligand is provided, enabling the compound IV to be subjected to a ring-closing reaction so as to obtain a compound V; and (3) sequentially performing bromination, hydolysis and oxidation reactions by using the compound V so as to obtain the 5-(2-fluorophenyl)-1H-pyrrole-3-methanal. According to the preparation method disclosed by the invention, reagents of bromine, hydrogen chloride and the like, which have strong corrosivity, are prevented from being used, and flammable hydrogenation reducing agents of palladium on carbon, raneys nickel, diisobutylaluminium hydride and the like are also prevented from being used; and besides, the technological line is simple to operate, the reaction condition is mild, the product yield is high, the purity is high, and industrialized production is easy to realize.

Description

technical field [0001] The invention relates to a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, an intermediate of vonoprazan fumarate, and belongs to the technical field of medicine and chemical industry. Background technique [0002] Vonoprazan Fumarate, the chemical name is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N - Methylmethylamine fumarate, once code-named TAK-438, is a new type of gastric acid secretion inhibitor developed by Takeda Pharmaceutical Company of Japan. It was launched in Japan on December 26, 2014. The trade name is Takecab. For the treatment of non-erosive gastroesophageal reflux disease, duodenal ulcer, gastric ulcer, erosive esophagitis, etc., it has not yet been marketed in China. The chemical structure of vonorazan fumarate is as follows: [0003] [0004] 5-(2-Fluorophenyl)-1H-pyrrole-3-carboxaldehyde (1) is the key intermediate of fumaric acid vonoprazan, and the patent CN102421753B applied by Japa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/333C07D207/33
CPCC07D207/33C07D207/333
Inventor 孙滨伊茂聪马庆双王晓光张宁
Owner SHANDONG JINCHENG BIO PHARMA CO LTD
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