Regadenoson Synthesis via Copper-Catalyzed Coupling
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Solution Overview
Problem
Current methods for synthesizing Regadenoson, a selective A2A adenosine receptor agonist, are inefficient for large-scale production due to the use of protecting groups and multiple steps, leading to unsatisfactory yields and high anomer impurity levels.
Innovation Solution
A novel synthetic route involving the preparation of 2-chloro adenosine followed by coupling with pyrazole-2-carboxamide, using Lewis acids and specific solvents, and subsequent reactions with methanolic ammonia and pyrazole-4-carboxamide in the presence of bases, to minimize anomer impurities and optimize yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If protecting groups are used in synthesis methods, then the synthesis can be performed with good selectivity, but the number of steps increases and yield decreases
Solution Approach 1:
The invention removes protecting groups from the synthesis pathway entirely. The method uses direct coupling of 2-chloroadenosine with pyrazole-4-carboxamide in the presence of copper catalyst and ligand, eliminating the need for separate protection and deprotection steps while maintaining high selectivity and improving overall yield.
Solution Approach 2:
The invention changes the reaction parameters by introducing specific ligands (such as amino acids or amines) and copper catalysts that enable selective coupling without protecting groups. This parameter change allows the reaction to proceed with high selectivity directly, avoiding the traditional protection-deprotection sequence.
2Manufacturing precision
If multiple synthesis steps are used, then the desired product can be obtained with high purity, but the synthesis time and complexity increase
Solution Approach 1:
The invention merges multiple steps into a single coupling reaction. By combining the coupling of 2-chloroadenosine with pyrazole-4-carboxamide in one pot using copper catalyst and ligand system, the method achieves high purity product in a single step, dramatically reducing synthesis time and procedural complexity.
Solution Approach 2:
The invention uses copper catalyst and ligand as intermediaries to facilitate the direct coupling reaction. These intermediaries enable the reaction to proceed with high selectivity and purity in a single step, eliminating the need for multiple intermediate isolation and purification steps.
3Ease of manufacture
If traditional synthesis methods are used for large scale production, then the existing protocols can be followed, but the yield and purity are unsatisfactory
Solution Approach 1:
The invention employs a self-service mechanism where the copper catalyst and ligand system automatically ensures high selectivity and purity during the coupling reaction. The ligand-copper complex acts as a self-regulating system that maintains reaction selectivity even at large scale, eliminating the need for additional purification steps while achieving high purity product.
Solution Approach 2:
The invention optimizes reaction parameters specifically for large-scale production by using stable copper catalysts and ligands that maintain consistent performance at scale. The method uses readily available starting materials and simple reaction conditions that are easily scalable while maintaining high purity yields.
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
This method provides a shorter, more efficient synthesis pathway with reduced anomer impurities and high purity (>99.5%), suitable for large-scale production of Regadenoson.
Implementation Method 1
WO 2012/149196 A1 provides a process for the preparation of Regadenoson by the condensation reaction of 2-chloroadenosine with 1H-pyrazole-4-carboxylic acid amide in presence of a resin based copper catalyst.
Data Source
AI summary
The present invention relates to a novel process for the preparation of (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide.