Preparation method for ivabradine impurities

An ivabradine and impurity technology is applied in the field of preparation of ivabradine impurities, and achieves the effects of high purity, improved drug safety and simple preparation method

Inactive Publication Date: 2018-08-21
ZHEJIANG JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The relevant impurities of ivabradine have been reported in the standard number JX20120088 of the "Standards for Registration of Imported Drugs of the State Food and Drug Administration". Impurities S33173 and S33174 are reported in the standards. It is found that there are literatures publicly reporting the specific preparation methods of these two impurities

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  • Preparation method for ivabradine impurities
  • Preparation method for ivabradine impurities
  • Preparation method for ivabradine impurities

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Embodiment 1

[0045] Embodiment 1: the preparation of impurity A

[0046] 15g of the compound of formula 1a, 65g of potassium carbonate and 300ml of acetone were mixed and stirred. Add 41.5 g of benzyl bromide dropwise to the system at a uniform speed, and after the addition is completed, the temperature is raised to reflux for overnight reaction. After the reaction was completed, it was lowered to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 37 g of the compound of formula 2, which was directly injected into the next step without purification.

[0047] 37g of the compound of formula 2 and 180ml of ethanol were mixed and stirred. Add 160ml of aqueous solution mixed with 6.3g of sodium hydroxide at a uniform speed, and after the addition is complete, raise the temperature to 50°C for reaction. After the reaction, cool to room temperature. Most of the ethanol was distilled off under reduced pressure, 200ml of ethyl acetate and...

Embodiment 2

[0054] The synthesis of embodiment 2 impurity B

[0055] 30g of the compound of formula 1b, 120g of sodium carbonate and 600ml of toluene were mixed and stirred. Add 82g of benzyl chloride dropwise to the system at a constant speed, and after the addition, raise the temperature to 60°C to react overnight. After the reaction was completed, it was lowered to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 50 g of the compound of formula 2, which was directly injected into the next step without purification.

[0056] 30g of the compound of formula 2 and 180ml of ethanol were mixed and stirred. Add 100ml of aqueous solution mixed with 6.3g of potassium hydroxide at a constant speed, and after the addition is complete, rise to 45°C for reaction. After the reaction, cool to room temperature. Most of the ethanol was distilled off under reduced pressure, 200ml of ethyl acetate and 150ml of water were added for extraction,...

Embodiment 3

[0063] Embodiment 3: the preparation of impurity A

[0064] 5g of the compound of formula 1a and 3.75g of 2,2-dimethoxyethylamine were mixed and dissolved in 50ml of dichloromethane, and stirred evenly. Then drop into 6.3g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 4.4g 1-hydroxybenzotriazole (HOBT) successively, after adding, room temperature reaction. After the reaction, the reaction system was added to 100ml of saturated aqueous sodium bicarbonate solution for extraction, and the aqueous layer was back-extracted once with 100ml of dichloromethane, the dichloromethane layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.8g of the compound of formula 2a . No purification required, directly submitted to the next step.

[0065] In a 100ml one-necked flask, add 5g of the compound of formula 2a, 10ml of glacial acetic acid and 3ml of concentrated hydrochloric acid, and react overnight at room temperature afte...

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Abstract

The invention discloses a preparation method for ivabradine impurities. According to the preparation method, 3-hydroxy-4-methoxyphenylacetic acid (as shown in a formula 1a) and 4-hydroxy-3-methoxyphenylacetic acid (as shown in a formula 1b) are respectively used as a starting raw material and subjected to multiple steps of reactions to prepare two impurities of ivabradine. The preparation method of the invention is simple and realizes high-purity preparation; and the prepared impurities can be used for qualitative and quantitative analysis so as to improve the medication safety of ivabradine.

Description

technical field [0001] The invention relates to a preparation method of ivabradine impurity. Background technique [0002] Ivabradine (Ivabradine), the chemical name is 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-triene-7- Base]-methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, Molecular formula: C 27 h 36 N 2 o 5 , relative molecular weight: 468, is a new anti-angina pectoris drug developed by the French Servier company, which was listed in the first batch in Ireland in 2006. It has obvious curative effect and can be used clinically to treat various myocardial ischemia, such as angina pectoris, myocardial infarction and related rhythm disorders. It is a new generation of cardiovascular drugs with very broad treatment prospects. Its structural formula is shown in the formula:. [0003] [0004] According to the preparation method of ivabradine reported in the existing literature, in the preparation process, the methyl group ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
CPCC07D223/16Y02P20/55
Inventor 陈玉龙钟宏班朱建荣张蓓蓓郭四根
Owner ZHEJIANG JINGXIN PHARMA
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