Vonoprazan fumarate preparation method

A technology for methyl methylamine fumarate and compound, which is applied in the field of drug preparation, can solve the problems of complicated post-processing, long synthesis steps, unfriendly environment and the like, and achieves simple and easy post-processing, mild reaction conditions, and low cost. low cost effect

Active Publication Date: 2015-08-26
山东康美乐医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Purpose of the invention: The preparation of vonoprazan fumarate in the prior art has defects such as long synthesis steps, cumbersome process, complicated post-treatment, low yield, and u...

Method used

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Examples

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Embodiment 1

[0037] 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile

[0038]In a 500m reaction flask, add 200ml of acetonitrile, 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (50g, 0.27mol), N,N-diisopropylethylamine (41.6g, 0.32mol ) and 4-N, N-dimethylaminopyridine (4.69g, 38.4mmol), stirred at room temperature. Control the temperature of the reaction solution not higher than 30°C, and add dropwise a mixed solution of 3-pyridinesulfonyl chloride (52.5 g, 0.29 mol) in 100 ml of acetonitrile. After dropping, react at 25°C for 2 hours. After the reaction is complete, add 300ml of purified water to the reaction solution, control the temperature of the reaction solution not higher than 30°C, add concentrated hydrochloric acid dropwise to adjust the pH value to 4-5, and stir at 25°C for 2 hours. Filter, wash with acetonitrile and water mixture, collect the solid, and dry under reduced pressure at 50°C to obtain 79.5g of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrro...

Embodiment 2

[0040] 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine fumarate

[0041] Add 30g of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile and 450ml of methanol into the reaction kettle, add Raney nickel, nitrogen replacement three times, hydrogen replacement Three times, keep 2 atmospheres, stir at 15-25°C for 5 hours, nitrogen replacement three times, filter out Raney nickel, add 4g paraformaldehyde to the filtrate, reflux at 65°C and stir for 8 hours, cool to 0°C, add in batches 10.4 g of sodium borohydride was stirred at room temperature for 4 hours. Add 450 g of purified water to terminate the reaction, concentrate, add 240 ml of dichloromethane for extraction. The organic phase was dried over anhydrous sodium sulfate. Filter, concentrate, add 300ml of isopropanol, heat to 50°C, stir to dissolve. Fumaric acid was added and stirred for 1 hour. Cool to room temperature, filter, wash with isopropanol, collect the solid, a...

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Abstract

The invention relates to the field of drug preparation researches, and especially relates to a preparation method of 1-[5-(2-fluorophenyl)-1-(pyridyl-3-ylsulfonyl)-1H-pyrryl-3-yl]-N-methyl methylamine fumarate (represented by formula I) and an intermediate thereof. The method is characterized in that the above compound represented by formula (I) is prepared through nitrogen monomethylation and salt formation with a compound represented by formula (V) as an important intermediate. The structural formula of the compound represented by formula (V) is shown in the specification, and the structural formula of the compound represented by formula (I) is also shown in the specification.

Description

technical field [0001] The invention relates to a medicine preparation technology, in particular to a preparation method of a novel gastric acid secretion inhibitor vonoprazan fumarate. Background technique [0002] Vonoprazan fumarate is a new type of gastric acid secretion inhibitor developed by Takeda Corporation of Japan. In China, Takeda Pharmaceuticals submitted a marketing application to the CFDA in December 2012, and approved clinical trials in May 2014. It is currently not on the market at home and abroad. [0003] The chemical name of Vonoprazan fumarate is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine fumarate , CAS No.: 881681-01-2. The structural formula is shown in I: [0004] [0005] Vonoprazan fumarate belongs to a new generation of potassium ion (K+) competitive acid blocker (P-CAB) inhibitors, which has a strong and long-lasting inhibitory effect on gastric acid secretion. , this product inhibits K + to H ...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 耿凤娈刘云峰刘晓君
Owner 山东康美乐医药科技有限公司
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