Ivabradine Hydrobromide Synthesis via Cyclization and Resolution

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Solution Overview

Problem

Current synthetic processes for Ivabradine hydrobromide face challenges in achieving high purity and yield, with extreme reaction conditions and the use of hazardous chemicals, and limited availability of crystalline forms suitable for pharmaceutical use.

Innovation Solution

A novel synthesis process involving the cyclization of 3-(2-bromo-4,5-dimethoxy-phenyl)-propionitrile with alkali-alkylamide, followed by hydrolysis and resolution with a chiral base, to produce Ivabradine hydrobromide with improved crystallization and stability, avoiding extreme conditions and hazardous reagents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If conventional synthesis processes are used to produce Ivabradine hydrobromide, then the basic product can be obtained, but the chemical and optical purity is insufficient and hazardous chemicals must be used

Engineering Contradiction:

Improvechemical and optical purityVSAvoidhazardous chemicals

Core Design Contradiction:

Manufacturing precisionVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical parameters of the synthesis process by replacing hazardous reagents (sodium amide, liquid ammonia) with safer alternatives (alkali metal hydroxides, water, organic solvents). This parameter substitution maintains product purity while eliminating harmful factors, directly resolving the contradiction between manufacturing precision and harmful factors.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs readily available, inexpensive reagents such as potassium hydroxide, sodium hydroxide, and common organic solvents (dichloromethane, ethyl acetate, ethanol) that can be easily disposed of or recycled. These replace expensive and hazardous reagents like sodium amide and liquid ammonia, achieving high purity without compromising on safety or cost.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Productivity

If conventional synthesis processes are used, then the basic product can be obtained, but the yield is low and extreme reaction conditions are required

Engineering Contradiction:

ImproveyieldVSAvoidextreme reaction conditions

Core Design Contradiction:

ProductivityVSTemperature

Solution Approach 1:

The patent fundamentally changes the reaction conditions from extreme (liquid ammonia at -33°C, sodium amide) to mild (water or organic solvents at 0-100°C, alkali metal hydroxides). This parameter transformation enables higher yields through improved reaction efficiency and selectivity, while eliminating the need for extreme conditions that complicate the process and reduce productivity.

Inventive Principle:

Principle #35Parameter changes

3Manufacturing precision

If conventional synthesis processes are used, then the product can be obtained, but crystalline forms suitable for pharmaceutical use are limited

Engineering Contradiction:

Improvecrystalline form qualityVSAvoidscalability

Core Design Contradiction:

Manufacturing precisionVSEase of manufacture

Solution Approach 1:

The patent incorporates preliminary purification steps including filtration through celite, washing with appropriate solvents, and controlled crystallization from water or organic solvents. These preliminary actions ensure that the product is obtained in high-quality crystalline forms suitable for pharmaceutical use, while the use of water-compatible reagents and solvents facilitates easy scaling without requiring specialized equipment for handling hazardous materials.

Inventive Principle:

Principle #10Preliminary action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The process achieves high chemical and optical purity of Ivabradine hydrobromide, enabling its scalable production with enhanced stability and solubility, suitable for pharmaceutical applications.

Implementation Method 1

3-(2-bromo-4,5-dimethoxy-phenyl)-propionitrile of formula (II) is cyclized with alkali-alkylamide

Methodology Applied

Scientific EffectCyclization:

Implementation Method 2

the obtained 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid compound of formula (IV) is resolved with chiral base

Methodology Applied

Scientific EffectChiral resolution:

Implementation Method 3

the base is subjected to catalytic hydrogenation with Pd-C catalyst

Methodology Applied

Scientific EffectCatalytic hydrogenation: Catalysis

Implementation Method 4

the dihydro-benzazepine moiety is saturated to tetrahydro-benzazepine structure in during the process

Methodology Applied

Scientific EffectHydrogenation: Hydrogenation

Implementation Method 5

the crystallization Ivabradine hydrobromide is carried out by cooling the methanol or ethanol solution

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Data Source

PatentEP2566850B1Industrial process for the synthesis of ivabradine hydrobromide salt

Publication Date: 2018.04.11 RICHTER GEDEON NYRT

AI summary

Process for the synthesis of Ivabradine salts of formula (I) the chemical name of which is: 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene- 7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one salts (HQ=HCl, HBr, HI, HNO3, HClO4, (COOH)2), and new intermediates thereof. Certain crystalline forms of the acid addition salts of Ivabradine (I) with nitric acid (I, HQ=HNO3), hydrobromic acid (I, HQ=HBr), hydroiodic acid (I, HQ=HI), oxalic acid (I, HQ= (COOH)2) and perchloric acid (I, HQ=HClO4)).