Rivaroxaban Crystalline Form K Synthesis Process
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for synthesizing rivaroxaban are inefficient on an industrial scale due to low yields, tedious chromatographic purification, use of toxic solvents, and environmental concerns, requiring large solvent volumes that are difficult to recover and reuse, and resulting in impurities that can be harmful.
Innovation Solution
A process involving the reaction of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride with 5-chlorothiophene-2-carbonyl chloride in 1-methylimidazole, allowing for high-yield production with reduced solvent use, easy solvent recovery, and minimal inorganic base addition, resulting in a new polymorphic form K of rivaroxaban with improved purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If chromatographic purification is used to purify rivaroxaban, then purity is improved, but manufacturing complexity and time consumption increase significantly
Solution Approach 1:
The invention extracts and eliminates the need for complex chromatographic purification steps by redesigning the synthesis route to inherently produce higher purity product. The new process removes the purification bottleneck while maintaining or improving purity through better reaction selectivity and fewer impurity-generating steps.
Solution Approach 2:
The invention performs preliminary action by optimizing the synthesis pathway beforehand to prevent impurity formation rather than requiring subsequent purification. The reaction conditions and sequence are designed in advance to minimize byproduct generation, eliminating the need for tedious chromatographic separation.
2Manufacturing precision
If large volumes of organic solvents are used for recrystallization, then purity is improved, but solvent recovery difficulty and environmental impact worsen
Solution Approach 1:
The invention changes the parameters of the crystallization process by using smaller solvent volumes and potentially different solvent systems that allow for easier recovery. The crystallization conditions are optimized to achieve high purity with minimal solvent, improving both environmental sustainability and cost-effectiveness.
Solution Approach 2:
The invention emphasizes solvent recovery and reuse by minimizing solvent consumption and designing the process to facilitate easy solvent separation and regeneration. This reduces waste disposal costs and environmental impact while maintaining product purity.
3Productivity
If toxic solvents and reagents are used in synthesis, then reaction efficiency is improved, but product safety and regulatory compliance worsen
Solution Approach 1:
The invention converts harmful toxic solvents and reagents into safer alternatives without sacrificing reaction efficiency. By selecting greener chemistry options that maintain or improve yield and reaction rate, the process eliminates toxic substance handling while preserving productivity benefits.
Solution Approach 2:
The invention replaces expensive toxic reagents with cheaper, safer alternatives that are easier to handle and dispose of responsibly. The new reagent system maintains reaction efficiency while reducing regulatory burden and safety requirements.
4Manufacturing precision
If multiple process steps are used for synthesis, then product purity is improved, but production time and cost increase
Solution Approach 1:
The invention merges multiple separate process steps into fewer integrated operations. By combining reaction and purification steps or eliminating intermediate isolation steps, the process reduces total production time while maintaining product purity through continuous or telescoped processing.
Solution Approach 2:
The invention implements continuous processing where possible, eliminating idle time between steps. Reactions are designed to flow continuously into the next stage without interruption, maintaining productive action throughout the synthesis sequence while ensuring product quality.
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 yields (>90%) and purity (>99% HPLC) with reduced solvent consumption, avoids hazardous reagents, and produces a stable polymorphic form K with enhanced bioavailability and chemical stability, suitable for pharmaceutical formulations.
Implementation Method 1
the obtained solvent-containing crude product is further recrystallized from acetic acid
Implementation Method 2
the product is obtained by precipitation and filtration after cooling the reaction mixture
Data Source
Figure 1
AI summary
The present invention relates to new polymorphic form K of rivaroxaban and to a process of its crystallization.