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Preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde

A technology of fluorophenyl and pyrrole, which is applied in the field of preparation of vonoprazan fumaric acid intermediates, can solve the problems of cumbersome post-processing steps, affecting the quality of intermediates, and declining product yields, and achieves simple post-processing steps, The effect of improving product quality and mild reaction conditions

Pending Publication Date: 2021-10-19
SICHUAN KELUN PHARMA RES INST CO LTD
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Problems solved by technology

[0009] Synthesis of 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile by Reductive Dechlorination of 2-Chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile Using Palladium Carbon Catalyst In the process, it is easy to generate defluorinated impurities. The defluorinated impurities are very similar to the main product structural formula, and the polarity difference is very small. It is difficult to purify and separate in the subsequent steps, and the defluorinated impurities will be transferred in the Raney nickel reduction step, affecting the intermediate body weight
[0011] In the process of reducing 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile with Raney nickel, it is easy to over-reduce the nitrile group to form an over-reduced impurity, although this impurity can be removed in the post-treatment process, but The post-processing steps are cumbersome (pH adjustment, extraction, drying, concentration, crystallization and other steps are required after Raney nickel filtration), resulting in a decrease in product yield and an increase in industrial production costs

Method used

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  • Preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde
  • Preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde
  • Preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde

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Experimental program
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Effect test

Embodiment 1

[0044] Add 106.8 kg of tetrahydrofuran and 11.00 kg of 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile into the container, then add 3.00 kg of acetic acid, 4.09 kg of anhydrous sodium acetate, and a mass fraction of 3 % palladium carbon 1.10kg, and rinse the inlet with tetrahydrofuran 5.00kg. Introduce hydrogen to maintain the pressure in the kettle at 0.4±0.1MPa, control the temperature at 30±10°C and stir for 20 hours. After the reaction, the raw materials are completely reacted by HPLC monitoring. The monitoring results show that the HPLC purity of the reaction liquid is 90.03%, and the defluorinated impurity content is 0.03%. The hydrogen in the kettle was evacuated, and then the hydrogen in the kettle was completely replaced with nitrogen, and then the palladium carbon was filtered out. After the filtrate was concentrated to dryness under reduced pressure, absolute ethanol was added. After the temperature was raised to complete dissolution, purified water was added ...

Embodiment 2

[0046] Add 26.64 kg of tetrahydrofuran and 3.00 kg of 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile into the container, then add 0.82 kg of acetic acid, 1.10 kg of anhydrous sodium acetate, and a mass fraction of 3 0.30kg of palladium carbon, feed hydrogen to keep the pressure in the kettle at 0.4±0.1MPa, control the temperature at 30±10°C and stir the reaction for 20 hours. The HPLC monitoring of the raw material reaction is complete. The monitoring results show that the HPLC purity of the reaction liquid is 89.73%, and the defluorinated impurities Content 0.04%. The hydrogen in the kettle was evacuated, and then the hydrogen in the kettle was completely replaced with nitrogen, and then the palladium carbon was filtered out. After the filtrate was concentrated to dryness under reduced pressure, absolute ethanol was added, and after the temperature was raised to complete dissolution, purified water was added dropwise to crystallize. After the dropwise addition was comp...

Embodiment 3

[0048] Add 20ml of tetrahydrofuran and 100.0g of 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile into the container, then add 27.21g of glacial acetic acid, 37.18g of sodium acetate and 3% of Palladium carbon 10.0g. In a hydrogen atmosphere, after stirring and reacting at a temperature of 30±10° C. for 20 hours, the raw materials were completely reacted by HPLC monitoring. The monitoring results showed that the HPLC purity of the reaction liquid was 91.96%, and the content of defluorinated impurities was 0.04%. After the reaction is over, use diatomaceous earth to filter the palladium carbon, concentrate the filtrate to dryness under reduced pressure, add absolute ethanol, heat up to complete dissolution, add purified water dropwise to crystallize, after the dropwise addition is completed, keep warm for 1 hour after crystallization, filter, The resulting filter cake was dried to obtain the intermediate 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile, with an HPLC purity of ...

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Abstract

The invention provides a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde, which comprises the following steps of: step A, introducing hydrogen into 2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-formonitrile in a solvent, alkali and a palladium carbon catalyst, and reacting to obtain 5-(2-fluorophenyl)-1H-pyrrole-3-formonitrile; and step B, introducing hydrogen into the 5-(2-fluorophenyl)-1H-pyrrole-3-formonitrile in a solvent and raney nickel, and reacting to obtain the 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde. The method is mild in reaction condition, low in production cost, high in reaction yield and beneficial to industrial production, and the defluorination impurity content can be effectively controlled to be smaller than 0.1% and even smaller than 0.05%.

Description

technical field [0001] The invention relates to a preparation method of a fumaric acid vonoprazan intermediate, in particular to a preparation method of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde. Background technique [0002] Vonoprazan Fumarate (TAK-438) was developed by Takeda Pharmaceutical, Japan, and was approved for marketing in Japan on December 26, 2014. It is used for the treatment of gastroesophageal reflux disease, Helicobacter pylori infection, Peptic ulcer, gastric ulcer, duodenal ulcer. Its mechanism of action is proton pump inhibitor (PPI), by inhibiting K + with H + , K + -ATPase binding inhibits gastric acid secretion. This drug is the second reversible proton pump inhibitor. Compared with traditional irreversible proton pump inhibitors (omeprazole, lansoprazole), it has the advantages of rapid onset of action, long duration of action, and less damage by gastric acid. ; And compared with revaprazan (the first reversible proton pump inhibitor), it als...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/333C07D207/337
CPCC07D207/333C07D207/337
Inventor 段继龙孙灏覃时李文捷王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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