Preparation technology for vonoprazan fumarate

A technology for the preparation of vonoprazan fumarate and its preparation technology, which is applied in the field of preparation technology of vonoprazan fumarate, can solve the problems of many impurities, unsuitability for large-scale industrial production, cumbersome reaction operation steps, etc., and achieve high yield High efficiency, less impurities, and more efficient synthesis steps

Active Publication Date: 2016-02-03
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0012] This route is prepared by reducing cyano group to aldehyde, but the reaction steps are cumbersome and there are many impurities; part of the route is the same as Reaction Formula 1, using toxic reagent liquid bromine and gas hydrogen chloride that corrodes equipment, which is still not suitable for industrialized large-scale production

Method used

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  • Preparation technology for vonoprazan fumarate
  • Preparation technology for vonoprazan fumarate
  • Preparation technology for vonoprazan fumarate

Examples

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Embodiment 1

[0038] Embodiment 1: Preparation of o-fluorostyrylamine (Ⅲ)

[0039] 24 mL of o-fluoroacetophenone, 46.2 g of ammonium acetate, and 60 ml of ethanol were sequentially added into a 150 ml round-bottomed flask, heated to reflux, and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain 16.7 g of o-fluorostyrylamine (III), with a yield of 72.8% and a purity of 99.8% by HPLC.

Embodiment 2

[0040] Embodiment 2: Preparation of o-fluorostyrylamine (Ⅲ)

[0041] Into a 150ml round bottom flask, add 24mL o-fluoroacetophenone, 30.8g ammonium acetate, and 60ml ethanol in sequence, heat to reflux, stir and react for 6 hours, after the reaction, concentrate under reduced pressure to obtain 16.6g o-fluorostyrylamine (Ⅲ) , yield 72.0%, HPLC purity 99.5%.

Embodiment 3

[0042] Embodiment 3: the preparation of o-fluorostyrylamine (Ⅲ)

[0043] 24 mL of o-fluoroacetophenone, 15.4 g of ammonium acetate, and 60 ml of methanol were sequentially added into a 150 ml round-bottomed flask, heated to reflux, and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain 15.6 g of o-fluorostyrylamine (III), with a yield of 68% and a purity of 99.7% by HPLC.

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Abstract

The invention relates to a preparation technology for vonoprazan fumarate. The preparation method comprises: reacting 2'-fluoroacetophenone (II) with ammonium acetate to generate 1-(2-fluorophenyl)ethen-1-amine (III), then reacting with 2-bromopropanal for cyclization for generating 2-(2-fluorophenyl)-4-methyl-1H-pyrrole (IV), reacting the compound IV with 3-pyridinesulfonyl chloride to generate 5-(2-fluorophenyl)-3-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole (V), then performing N-bromosuccinimide substitution to generate 5-(2-fluorophenyl)-3-bromomethyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole (VI), and finally performing methylamination reaction and salt forming, so as to obtain vonoprazan fumarate. The method avoids usage of a toxic reagent liquid bromine and hydrogen chloride gas capable of corroding equipment in the prior art, possesses the advantages of simple technological route, mild reaction conditions, controllable operation, environment friendliness and high product yield, and is suitable for large-scale industrialized production.

Description

technical field [0001] The invention relates to a preparation process of vonoprazan fumarate, which belongs to the field of drug synthesis. Background technique [0002] Vonoprazan fumarate (Vonoprazanfumarate) is a potassium ion competitive acid blocker developed by Takeda Corporation of Japan. It was launched in Japan on December 26, 2014. Its trade name is Takecab. Gastric ulcer, duodenal ulcer, Helicobacter pylori eradication. Its chemical name is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine fumarate. Its structural formula is as follows: [0003] [0004] At present, several synthetic routes of vonorazan fumarate have been reported: [0005] 1) The synthetic route reported in patent WO2007026916 is shown in Reaction Formula 1: [0006] Reaction 1: [0007] [0008] The synthesis steps of this method are cumbersome, and liquid bromine is used in the synthesis process, which is poisonous and hydrogen chloride gas corrodes t...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 陈雨沈晓艳姚云成
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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