Process and equipment for preparing ivabradine intermediate benzazepine skeleton

A technology of ivabradine and its preparation process, which is applied in the field of drug preparation, can solve the problems of unfriendly environment and harsh reaction conditions, and achieve the effects of reducing production cost, less pollution of three wastes, and high atom economy

Pending Publication Date: 2022-07-22
新沂市法斯特医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The invention provides a preparation process and equipment for the skeleton of an ivabradine intermediate benzazepine, which solves the technical problems of harsh reaction conditions and unfriendly environment in related technologies

Method used

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  • Process and equipment for preparing ivabradine intermediate benzazepine skeleton
  • Process and equipment for preparing ivabradine intermediate benzazepine skeleton
  • Process and equipment for preparing ivabradine intermediate benzazepine skeleton

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Embodiment 1

[0046] refer to Figure 1-Figure 10 As shown, a preparation process and equipment of an ivabradine intermediate benzazepine skeleton, specifically, the preparation process of the ivabradine intermediate benzazepine skeleton, comprising the following steps:

[0047]S1: Using benzocyclobutanone and N-heterocyclopropane as starting materials, under the synergistic catalysis of palladium / Lewis acid, a cross-dimerization ring expansion reaction occurs between benzocyclobutanone and N-heterocyclopropane to generate Ts (p-toluenesulfonyl) protected benzazepines, for subsequent use;

[0048] S2: Dissolve the Ts-protected benzoazepine compound in S1 in THF (tetrahydrofuran) solution, and cool the reaction solution to 0° C. for subsequent use;

[0049] S3: The reaction solution in S2 was added dropwise to the THF (tetrahydrofuran) solution of samarium diiodide in a state of stirring, until the titration was completed, and the reaction temperature was 0 °C and continued to stir for 1 h....

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Abstract

The invention relates to the field of medicine preparation, and particularly discloses a process and equipment for preparing an ivabradine intermediate benzazepine skeleton, the preparation process comprises the following steps: S1, taking benzocyclobutanone and N-heterocyclic propane as initial raw materials, under the concerted catalysis of palladium / lewis acid, carrying out a reaction on the initial raw materials to obtain a crude product; the preparation method comprises the following steps: carrying out cross dimerization ring expansion reaction between benzocyclobutanone and N-heterocyclic propane to generate a Ts (p-toluenesulfonyl) protected benzoazepine ketone compound for later use; the preparation equipment comprises a polymerization reaction kettle, a reaction kettle cold water group, a liquid pump, an automatic potentiometric titrator, a chemical stirrer, a centrifugal extractor and a distillation kettle. The benzazepine ketone medical intermediates with various structures can be prepared on a large scale, the synthesis route is short, the synthesis period is short, post-treatment is easy, the product purity is high, extraction of three wastes can be greatly reduced, and the productivity can be further improved.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparation, in particular to a process and equipment for preparing an ivabradine intermediate benzazepine skeleton skeleton. Background technique [0002] Ivabradine was developed by Servier. In October 2005, the European Medicines Agency approved the marketing of ivabradine, which is clinically used for the treatment of patients with stable angina pectoris associated with sinus tachycardia, who cannot tolerate or have contraindications to receptor blockers. [0003] Ivabradine, molecular formula C 27 H 36 N 2 O 5 , the chemical name is 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl]-methylamino]propane base)-1,3,4,5-tetrahydro-2hydro-benzazepin-2-one, the structure is as image 3 shown. [0004] The synthesis of ivabradine mainly includes two key intermediates: benzazepine-2-one and chiral benzocyclobutanamine. Among them, the benzoazepine skeleton is an important nitroge...

Claims

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Application Information

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IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 赵东兵王中辉
Owner 新沂市法斯特医药科技有限公司
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