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Synthesis method of ivabradine hydrochloride key intermediate

A technology of ivabradine hydrochloride and synthesis method, which is applied in chemical instruments and methods, carboxylate preparation, carboxylate preparation and other directions, can solve problems such as high price

Active Publication Date: 2021-09-14
株洲壹诺生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage is that compound 9 is used as the starting material, which is expensive

Method used

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  • Synthesis method of ivabradine hydrochloride key intermediate
  • Synthesis method of ivabradine hydrochloride key intermediate
  • Synthesis method of ivabradine hydrochloride key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] According to the reaction route of reaction formula (1)-(7), the first step: the reaction formula of reaction formula (1) is as follows:

[0047]

[0048] The method for preparing compound 2 in reaction formula (1) is as follows: take compound 1 (veratraldehyde), malonic acid, and catalyst 1 into the reaction bottle, add the reaction solvent of reaction formula (1), shake and dissolve, and set up the reaction Temperature and reaction time, heat to reflux for water separation reaction, after the reaction, cool down to room temperature and add water to stir, filter, wash with water, and dry to obtain compound 2. The specific reaction parameters are shown in the table below:

[0049]

[0050] Compound 2 1 H-NMR data: 1 H-NMR (400MHz, CDCl 3 ): δ: 3.98 (s, 3H), 3.99 (s, 3H), 7.46 (d, 1H), 7.70 (d, 1H), 7.90 (d, 1H), 8.32 (s, 1H).

[0051] Mass spectral data of compound 2: ESI+[M+H] + = 253.1

[0052] The second step: the reaction formula of reaction formula (2) ...

Embodiment 2

[0089] According to the synthesis method of Example 1, the difference is that the specific reaction parameters are changed.

[0090] The reaction parameters of reaction formula (1) are as follows:

[0091]

[0092] Compound 2 1 H-NMR data: 1 H-NMR (400MHz, CDCl 3 ): δ: 3.99 (s, 3H), 3.99 (s, 3H), 7.45 (d, 1H), 7.70 (d, 1H), 7.90 (d, 1H), 8.32 (s, 1H).

[0093] Mass spectral data of compound 2: ESI+[M+H] + =253.1

[0094] The reaction parameters of reaction formula (2) and reaction formula (3) are as follows:

[0095]

[0096] Compound 2 1 H-NMR data: 1 H-NMR (400MHz, CDCl 3 ): δ: 3.99 (s, 3H), 3.99 (s, 3H), 7.46 (d, 1H), 7.70 (d, 1H), 7.91 (d, 1H), 8.32 (s, 1H).

[0097] Mass spectral data of compound 4: ESI+[M+H] + =211.1

[0098] The reaction parameters of reaction formula (4) are as follows:

[0099]

[0100] Compound 5 1 H-NMR data: 1 H-NMR (400MHz, CDCl 3 ): δ: 7.02 (s, 1H), 6.78 (s,1H), 3.85 (s, 6H), 3.01 (t,2H), 2.69 (t,2H)

[0101] Mass spectra...

Embodiment 3

[0115] According to the synthesis method of Example 1, the difference is that the specific reaction parameters are changed.

[0116] The reaction parameters of reaction formula (1) are as follows:

[0117]

[0118] Compound 2 1 H-NMR data: 1 H-NMR (400MHz, CDCl 3 ): δ: 3.98 (s, 3H), 3.99 (s, 3H), 7.44 (d, 1H), 7.70 (d, 1H), 7.91 (d, 1H), 8.32 (s, 1H).

[0119] Mass spectral data of compound 2: ESI+[M+H] + =253.1

[0120] The reaction parameters of reaction formula (2) and reaction formula (3) are as follows:

[0121]

[0122] Compound 2 1 H-NMR data: 1 H-NMR (400MHz, CDCl 3 ): δ: 3.98 (s, 3H), 3.99 (s, 3H), 7.45 (d, 1H), 7.71 (d, 1H), 7.91 (d, 1H), 8.32 (s, 1H).

[0123] Mass spectral data of compound 4: ESI+[M+H] + =211.1

[0124] The reaction parameters of reaction formula (4) are as follows:

[0125]

[0126] Compound 5 1 H-NMR data: 1 H-NMR (400MHz, CDCl 3 ): δ: 7.01 (s, 1H), 6.78 (s,1H), 3.85 (s, 6H), 3.00 (t,2H), 2.68 (t,2H)

[0127] Mass spectra...

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Abstract

The invention relates to the technical field of medicine synthesis, and concretely relates to a synthesis method of an ivabradine hydrochloride key intermediate. The synthesis method is carried out according toa reaction route shown in the specification. The key ivabradine hydrochloride key intermediate compound 8 is synthesized. The synthesis method has the advantages of low raw material price, unharsh reaction conditions and high product yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a key intermediate of ivabradine hydrochloride. Background technique [0002] Ivabradine hydrochloride (Ivabradine hydrochlorid), chemical name: 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutane-1-yl )methyl]-methylamino]propyl)-1,3,4,5-tetrahydro-2hydro-benzazepine-2-one hydrochloride, is the first specific sinoatrial node If current selection It is a drug for the treatment of stable angina pectoris in the past 20 years because it simply slows down the heart rate, and it can significantly improve the quality of life of patients with heart failure. [0003] The synthetic route of ivabradine hydrochloride is reported in Chinese Journal of Medicinal Chemistry 20 (2), 106-109; in 2010, the improved method as follows: [0004] [0005] Among them, the reaction conditions of the fifth step reaction are extremely harsh, requiring liquid ammon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/09C07C62/34
CPCC07C51/09C07C67/08C07C51/363C07C51/38C07C51/36C07C51/353C07C2602/06C07C62/34C07C69/757C07C59/64
Inventor 于欢庆徐群杰谢子刚张树磊
Owner 株洲壹诺生物技术有限公司
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