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Preparation method of dimer impurity in ivabradine hydrochloride intermediate

A technology of ivabradine hydrochloride and dimer, which is applied in the field of medicine and biology, can solve difficult problems and achieve the effect of simple synthesis method and high sample purity

Inactive Publication Date: 2020-05-22
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the course of the research, it was found that the dimer impurity exists in a small amount (below 0.5%) by using the synthetic method of the literature, and it is difficult to obtain a sufficient amount of the impurity reference substance by separating the reaction solution

Method used

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  • Preparation method of dimer impurity in ivabradine hydrochloride intermediate
  • Preparation method of dimer impurity in ivabradine hydrochloride intermediate
  • Preparation method of dimer impurity in ivabradine hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] step 1:

[0037] Add 10.0 g of compound 2 and 100 ml of dimethyl sulfoxide into the reaction flask, add 6.6 g of potassium tert-butoxide in batches under stirring, and continue stirring at room temperature for 30 minutes after the addition is complete.

[0038] Add a dimethyl sulfoxide solution of 3-bromo-1-propanol dropwise to the system (the molar ratio of compound 2 to 3-bromo-1-propanol is 1:1.3), after the drop is complete, stir at room temperature for 30 minutes.

[0039] The system was heated to 40-50° C. and stirred for reaction, and the reaction process was monitored by TLC until compound 2 was completely consumed.

[0040] The system was cooled down to room temperature, 200ml of purified water was added dropwise to the system to precipitate crystals, and the temperature was further lowered to 0-10°C to stir and crystallize for 1 hour. After filtering, the filter cake was rinsed with purified water until neutral, and dried to obtain compound 3.

[0041] S...

Embodiment 2

[0049] step 1:

[0050] Add 10.0 g of compound 2 and 100 ml of dimethyl sulfoxide into the reaction flask, add 6.6 g of potassium tert-butoxide in batches under stirring, and continue stirring at room temperature for 30 minutes after the addition is complete.

[0051] Add dropwise the dimethyl sulfoxide solution of 3-bromo-1-propanol in the system (the molar ratio of compound 2 and 3-bromo-1-propanol is 1:1 ), dropwise, stirred at room temperature for 30 minutes.

[0052] The system is heated to 30～40 The reaction was stirred at °C, and the reaction process was monitored by TLC until compound 2 was completely consumed.

[0053] The system was cooled down to room temperature, 200ml of purified water was added dropwise to the system to precipitate crystals, and the temperature was further lowered to 0-10°C to stir and crystallize for 1 hour. After filtering, the filter cake was rinsed with purified water until neutral, and dried to obtain compound 3.

[0054] Step 2:

...

Embodiment 3

[0062] step 1:

[0063] Add 10.0 g of compound 2 and 100 ml of dimethyl sulfoxide into the reaction flask, add 6.6 g of potassium tert-butoxide in batches under stirring, and continue stirring at room temperature for 30 minutes after the addition is complete.

[0064] Add dropwise the dimethyl sulfoxide solution of 3-bromo-1-propanol in the system (the molar ratio of compound 2 and 3-bromo-1-propanol is 1:2 ), dropwise, stirred at room temperature for 30 minutes.

[0065] The system is heated to 50～60℃ The reaction was stirred, and the reaction process was monitored by TLC until compound 2 was completely consumed.

[0066] The system was cooled down to room temperature, 200ml of purified water was added dropwise to the system to precipitate crystals, and the temperature was further lowered to 0-10°C to stir and crystallize for 1 hour. After filtering, the filter cake was rinsed with purified water until neutral, and dried to obtain compound 3.

[0067] Step 2:

[0068...

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Abstract

The invention relates to a preparation method of a dimer impurity in an ivabradine hydrochloride intermediate. The impurity is an intermediate produced in a synthesis process for 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzoazo-2-one. The dimer impurity involved in the invention is 3,3'-propane-1,3-diylbis(7,8-dimethoxy-1,3-dihydro-2H-3-benzoazo-2-one. The preparation method for the dimer impurity comprises the following steps: nucleophilic substitution, sulfonic acid esterification, condensation and the like. The method disclosed by the invention is simple, the obtained sample is high in purity and can be used for links of research and development, production, quality standard establishment and quality control of an ivabradine hydrochloride process, and technical support is provided for medication safety of ivabradine hydrochloride.

Description

technical field [0001] The invention relates to a method for preparing and separating dimer impurities in an ivabradine hydrochloride intermediate, and belongs to the field of medical biotechnology. Background technique [0002] Ivabradine hydrochloride (English name: Ivabradine Hydrochloride), chemical name: S-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobutane Base)methyl]-N-(methyl)amino}propyl}-1,3,4,5-tetrahydro-2H-3-benzazepine -2-Keto hydrochloride is an anti-anginal drug developed by Servier, France. It was approved for marketing in Europe by the European Drug Evaluation Bureau in November 2005. Ivabradine is a selective and specific cardiac pacemaker If inhibitor. Drug, by inhibiting the high flow of If inflow in the sinoatrial node, delays the diastolic depolarization of the action potential of pacemaker cells, thereby slowing down the heart rate. The drug is suitable for patients with chronic stable angina pectoris with coronary artery disease, heart rate > 6...

Claims

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Application Information

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IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 夏中宁白秉信王仕伟
Owner 北京鑫开元医药科技有限公司
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