Regadenoson Synthesis via 2-Fluoroadenosine and Form D Crystallization
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Solution Overview
Problem
Current methods for synthesizing regadenoson are not well-suited for large-scale production due to low yields and purification challenges, particularly with the staining nature of iodine in intermediate compounds.
Innovation Solution
A one-step process using 2-haloadenosine, such as 2-fluoroadenosine, with a metal catalyst and base to produce regadenoson in high purity and yield, along with the discovery of a new crystalline form (Form D) that can be prepared without isolating intermediates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If multi-step synthesis via 2-iodoadenosine is used, then regadenoson can be synthesized, but the yield is low and purification is problematic due to iodine staining
Solution Approach 1:
The patent changes the halogen parameter from iodine to fluorine in the 2-haloadenosine intermediate. This parameter change eliminates the staining problem associated with iodine while maintaining the reactivity needed for synthesis, thereby improving both purity and yield simultaneously
Solution Approach 2:
The patent employs 2-fluoroadenosine as a readily available, stable starting material that can be purchased commercially. This eliminates the need for complex in-situ preparation of intermediates, simplifying the process and improving overall yield by starting with a high-purity reagent
2Quantity of substance
If multi-step synthesis process is used, then regadenoson can be prepared, but the process is not suitable for large-scale synthesis
Solution Approach 1:
The patent segments the synthesis into two clean, isolated steps: (1) preparation of 2-hydrazinoadenosine from 2-fluoroadenosine, and (2) coupling with the pyrazole derivative. This segmentation makes each step easier to control and scale independently, improving ease of manufacture for large-scale production
Solution Approach 2:
The patent performs preliminary preparation of high-purity 2-fluoroadenosine as a stable intermediate that can be stored and handled easily. This preliminary action with a stable, non-staining intermediate facilitates subsequent large-scale operations without the purification complications of iodine-based methods
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 approach enables high-yield, high-purity regadenoson production suitable for large-scale synthesis and introduces a stable crystalline form (Form D) for pharmaceutical applications, improving both efficiency and purity.
Implementation Method 1
contacting a 2-haloadenosine with a 4-N-alkylcarboxamide pyrazole or a 4-carboxylate pyrazole in the presence of a metal catalyst and a base
Data Source
AI summary
This disclosure relates to an improved process for the preparation of regadenoson, pharmaceutically acceptable salts thereof, and hydrates thereof, and for the preparation of intermediates useful in the synthesis of regadenoson. The disclosure also relates to a new crystalline form of regadenoson. Processes for the preparation of the crystalline form, compositions containing the crystalline form, and methods of use thereof are also described.