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Process for preparing key intermediate of ivabradine

An intermediate and key technology, applied in the field of organic synthesis, can solve problems such as difficult reduction of cyano groups, difficult control of reactions, and complicated post-processing.

Inactive Publication Date: 2015-01-07
王晓伟
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are obvious defects in this method: the relatively toxic ethyl chloroformate reagent is used in the preparation process, and two-step reduction is required. The cyano group reduction is relatively difficult, and it is difficult to react with borane and other toxic, difficult-to-operate reagents. Control and post-processing are complicated, and it is difficult to realize industrialization
However, the yield of this method is low

Method used

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  • Process for preparing key intermediate of ivabradine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Under nitrogen protection, in a 500 ml four-neck round bottom flask, add 150 ml of pretreated anhydrous tetrahydrofuran, and add 0.1 mol of 4,5-dimethoxy-1-carbamoylbenzocyclocycline under stirring butane. In an ice-water bath, slowly add PdCl with stirring 2 / NaBH 4 (where NaBH 4 0.2mol, PdCl 2 1 mmol), after the dropwise addition was completed, the temperature was slowly raised to 50° C., and the reaction was carried out for 2 hours, and the reaction was monitored by TCL to complete. The reaction solvent tetrahydrofuran was distilled off in vacuo. Neutralize to neutral with 200 ml of saturated aqueous sodium bicarbonate solution, extract with 100 ml of dichloroethane, wash with saturated sodium chloride, and finally dry with anhydrous magnesium sulfate to obtain light yellow oil 1-(S)-4, 5-dimethoxy-1-methylaminomethylbenzocyclobutane, the yield is 90.2%, and the purity is above 98%.

Embodiment 2

[0022] Under nitrogen protection, in a 500 ml four-neck round bottom flask, add 150 ml of pretreated anhydrous tetrahydrofuran, and add 0.1 mol of 4,5-dimethoxy-1-carbamoylbenzocyclocycline under stirring butane. In an ice-water bath, slowly add PdCl with stirring 2 / NaBH 4 (where NaBH 4 0.3mol, PdCl 2 2 mmol), after the dropwise addition was completed, the temperature was slowly raised to 30° C., and the reaction was carried out for 3 hours, and the reaction was monitored by TCL to complete. The reaction solvent tetrahydrofuran was distilled off in vacuo. Neutralize to neutral with 200 ml of saturated aqueous sodium bicarbonate solution, extract with 100 ml of dichloroethane, wash with saturated sodium chloride, and finally dry with anhydrous sodium sulfate to obtain light yellow oil 1-(S)-4, 5-Dimethoxy-1-methylaminomethylbenzocyclobutane, the yield is 95.8%, and the purity is above 98%.

Embodiment 3

[0024] Under nitrogen protection, in a 500 ml four-neck round bottom flask, add 150 ml of pretreated anhydrous tetrahydrofuran, and add 0.1 mol of 4,5-dimethoxy-1-carbamoylbenzocyclocycline under stirring butane. In an ice-water bath, slowly add PdCl with stirring 2 / NaBH 4 (where NaBH 4 0.1mol, PdCl 2 1 mmol), after the dropwise addition was completed, the temperature was slowly raised to 40° C., and the reaction was carried out for 3 hours, and the reaction was completed by TCL monitoring. The reaction solvent tetrahydrofuran was distilled off in vacuo. Neutralize to neutral with 200 ml of saturated aqueous sodium bicarbonate solution, extract with 100 ml of dichloroethane, wash with saturated sodium chloride, and finally dry with anhydrous magnesium sulfate to obtain light yellow oil 1-(S)-4, 5-dimethoxy-1-methylaminomethylbenzocyclobutane, the yield is 92.7%, and the purity is above 98%.

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Abstract

The invention relates to a process for preparing the key intermediate of ivabradine, belonging to the field of inorganic synthesis. The process mainly comprises the following reaction steps: under the protection of inert gas, dissolving 4, 5-dimethoxy-1-methylamine formyl benzocyclobutane in anhydrous tetrahydrofuran, cooling in an ice water bath, slowly adding PdCl2 / NaBH4 under the condition of mixing, slowly heating to 30-50 DEG C after the dropwise adding is finished, reacting for 2-3 hours under the condition of TCL monitoring till the reaction is completely finished; and distilling the reaction solvent tetrahydrofuran out under a vacuum condition, washing with an alkali lye, extracting and drying to obtain a light yellow oily substance.

Description

technical field [0001] The invention relates to a method for preparing a key intermediate of ivabradine, which belongs to the field of organic synthesis, in particular to a method for reducing (S)-4,5-dimethoxy-1-methylamine with sodium borohydride and its auxiliary agent Formylbenzocyclobutane method. Background technique [0002] Ivabradine (Ivabradine) is a drug developed by Swiss Sewell Company (also known as Servier Company) for the treatment of chronic stable angina pectoris with contraindication or intolerance to β-blockers and normal sinus rhythm . Its chemical name is: (+)-3-[3-[N-[4,5-dimethoxybenzocyclobutanyl-1(S)-methyl]-N-methylamino]propyl ]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine -2-one hydrochloride. [0003] Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated ion channel (If) selective blocker, which belongs to the HCN (hyperpolarization activated cyclic nucleotidegated) ion channel family. If current is a kind of cardiac pac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/74C07C213/02
Inventor 王晓伟
Owner 王晓伟
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