Ivabradine Synthesis Yield via Segmented Reductive Amination
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Solution Overview
Problem
The existing synthesis process for ivabradine results in a low yield of 1%, which is not suitable for pharmaceutical production due to its pharmaceutical interest and clinical applications.
Innovation Solution
A new synthesis process involving reductive amination, condensation, cyclization, and hydrogenation reactions using specific reducing agents, solvents, and acids to produce ivabradine with improved yield, including the use of dihydrogen in the presence of palladium on charcoal and preferred solvents like ethanol and dichloromethane.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the existing synthesis process from compound (II) through (V) is used, then the process is straightforward, but the yield of ivabradine is only 1%
Solution Approach 1:
The synthesis process is divided into distinct modular stages: reductive amination of compound (VI) to form compound (VIII), condensation with compound (IX) to form compound (X), and cyclization to form compound (V). Each stage can be independently optimized and controlled, allowing for improved overall yield while maintaining process manageability.
Solution Approach 2:
The reductive amination step is performed in advance to pre-form compound (VIII) with the desired amine functionality before the condensation and cyclization steps. This preliminary functional group installation enables subsequent reactions to proceed with higher efficiency and yield.
2Ease of manufacture
If the existing synthesis route is used, then the process is simple, but it is not suitable for pharmaceutical production due to low yield
Solution Approach 1:
The synthesis conditions are optimized by changing key parameters: using specific reducing agents (sodium triacetoxyborohydride, sodium cyanoborohydride, or dihydrogen with catalyst), controlling reaction temperatures, selecting appropriate solvents, and optimizing stoichiometry. These parameter changes transform the process from a simple but low-yield route to a manufacturable high-yield process.
Solution Approach 2:
Compound (VIII) serves as a key intermediary that accumulates the structural elements needed for final ivabradine formation. By isolating and characterizing this intermediate with predetermined formula and properties, the process enables quality control and optimization at each stage, making the overall process suitable for pharmaceutical manufacturing.
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 new process significantly increases the yield of ivabradine, making it more viable for pharmaceutical production and clinical use by providing a high-performance synthesis route.
Implementation Method 1
is subjected to a reductive amination reaction by the compound of formula (VII) in the presence of a reducing agent
Implementation Method 2
The reducing agent preferably used to carry out the reductive amination reaction of the compound of formula (VI) with the compound of formula (VII) is dihydrogen in the presence of palladium on charcoal
Implementation Method 3
which is subjected to a hydrogenation reaction to yield ivabradine of formula (I)
Data Source
AI summary
Preparing ivabradine (I) comprises: reductive amination of aldehyde compound (VI) with N'-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1(6),2,4-trienyl]methyl]-N'-methyl-propane-1,3-diamine (VII) in the presence of reducing agent to give (bicyclo[4.2.0]octatrienylmethyl)-propane-diamine compound (VIII); condensing (VIII) with (3,4-dimethoxy-phenyl)-acetyl chloride (IX) to give substituted phenyl-acetamide compound (X); cyclizing (X); and hydrogenating 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3-dihydro-benzo[d]azepin-2-one (V). Preparing ivabradine (I) comprises: reductive amination reaction of aldehyde compound of formula (R2-CHR1-C(=O)-H) (VI) with N'-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1(6),2,4-trienyl]methyl]-N'-methyl-propane-1,3-diamine (VII) in the presence of a reducing agent, or organic solvent and its mixture or a mixture of organic solvent and water, to give (dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-propane-1,3-diamine compound of formula (VIII); condensing (VIII) with (3,4-dimethoxy-phenyl)-acetyl chloride (IX) in the presence of a base in an organic solvent, to give a substituted phenyl-acetamide compound of formula (X); cyclizing (X) in an acid medium to give 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3-dihydro-benzo[d]azepin-2-one (V); and hydrogenating (V) to give ivabradine (I), which is optionally converted into its addition salts with an acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and camphoric acid, and their hydrates. Either R1, R2 : 1-6C alkoxy groups; or CR1R2 : 1,3-dioxane, 1,3-dioxolane or 1,3-dioxepane. Independent claims are included for: (1) (dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-propane-1,3-diamine compound (VIII); and (2) a substituted phenyl-acetamide compound (X). [Image] ACTIVITY : Cardiant; Antianginal; Antiarrhythmic. MECHANISM OF ACTION : None given.