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Ivabradine hydrochloride impurity and preparation method and application thereof

An ivabradine hydrochloride and impurity technology is applied in the field of ivabradine hydrochloride impurity and its preparation, which can solve the problems of large content, optimal selection, unknown structure and the like, and achieves simple operation, mild reaction conditions, guaranteed safety and high efficiency. Effectiveness

Inactive Publication Date: 2016-06-15
徐建立
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventor found during the research and experiment of process route selection that no matter the preparation method based on the existing literature and patent reports or the self-developed preparation process, there will always be an impurity with unknown structure and large content in the final preparation. Its production cannot be avoided by optimizing the selection of the preparation process
Moreover, the impurity is also heat-sensitive. In the subsequent preparation stability experiment, it was found that the content of the impurity gradually increased as the investigation time increased, especially when the storage temperature was higher than 25°C, the content of the impurity increased significantly. The most abundant impurity, which has a potential risk to the safety of the formulated product

Method used

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  • Ivabradine hydrochloride impurity and preparation method and application thereof
  • Ivabradine hydrochloride impurity and preparation method and application thereof
  • Ivabradine hydrochloride impurity and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of intermediate III

[0031] In 500 mL of acetonitrile, 50 g (0.3 mol) of starting material II, 30 g (0.33 mol) of oxalic acid, and 138 g (0.67 mol) of dicyclohexylcarbodiimide were added, and the reaction was stirred for 3 h. After the reaction, filter, evaporate the filtrate to dryness under reduced pressure, and recrystallize the residue with isopropyl acetate to obtain 52 g of off-white solid, namely Intermediate III, with a yield of 75%.

Embodiment 2

[0032] Embodiment 2: the preparation of intermediate III

[0033] In 500 mL of dichloromethane, 50 g (0.3 mol) of starting material II, 30 g (0.33 mol) of oxalic acid, and 138 g (0.67 mol) of dicyclohexylcarbodiimide were added, and the reaction was stirred for 3 h. After the reaction, filter, evaporate the filtrate to dryness under reduced pressure, and recrystallize the residue with isopropyl acetate to obtain 56 g of off-white solid, ie intermediate III, with a yield of 81%.

Embodiment 3

[0034] Embodiment 3: the preparation of intermediate III

[0035] In 500 mL of acetone, add 50 g (0.3 mol) of starting material II, 30 g (0.33 mol) of oxalic acid, and 138 g (0.67 mol) of dicyclohexylcarbodiimide, and stir for 3 hours. After the reaction, filter, evaporate the filtrate to dryness under reduced pressure, and recrystallize the residue with isopropyl acetate to obtain 49 g of off-white solid, namely Intermediate III, with a yield of 71%.

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Abstract

The invention discloses an ivabradine hydrochloride impurity and a preparation method and application thereof. The impurity has thermal sensitivity, it is found in preparation stability tests that the impurity content is gradually increased along with inspection time increasing, specially when the storage temperature is higher than 25 DEG C, the impurity content is obviously increased, the quality of ivabradine hydrochloride is restricted, and potential toxic and side effects exist. The ivabradine hydrochloride impurity can be used for quality control over the ivabradine hydrochloride raw material and a preparation thereof, and the safety and effectiveness of using a product in clinic are guaranteed. The method for preparing the ivabradine hydrochloride impurity is easy to operate, the reaction condition is mild, and the high-purity ivabradine hydrochloride impurity can be obtained.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to an ivabradine hydrochloride impurity and a preparation method and application thereof. Background technique [0002] Ivabradine hydrochloride (Ivabradinehydrochloride) was developed by the French company Servier and was first launched in Ireland in 2006. It has obvious curative effect on patients with chronic stable angina pectoris who are forbidden or intolerant of β-receptor blockers and have normal sinus rhythm. , can be used clinically to treat various myocardial ischemia, such as angina pectoris, myocardial infarction and related rhythm disorders, and is a new generation of cardiovascular drugs with very broad therapeutic prospects. Its chemical name is 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]-methyl}( Methyl)amino]propyl}-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one hydrochloride, the structural formula is as follows: [0003] [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16G01N30/02
CPCC07D223/16G01N30/02G01N2030/027
Inventor 徐建立
Owner 徐建立
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