Apixaban Preparation with Phase-Transfer Catalysis and Crystallization
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Solution Overview
Problem
Existing methods for preparing apixaban, particularly its polymorphic form N-1, face challenges in achieving high yields, purity, and scalability while avoiding costly and environmentally harmful materials, and require time-efficient processes.
Innovation Solution
A process involving cyclization with potassium carbonate and a phase transfer catalyst, followed by amidation and controlled crystallization in the presence of specific solvents, such as methanol and dichloromethane, under varying pressures and temperatures, to produce apixaban with high purity and efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If numerous preparation steps are used to prepare apixaban, then the process can achieve high purity, but the production time increases and productivity decreases
Solution Approach 1:
The patent combines multiple preparation steps into a one-pot synthesis procedure. The cyclization, amidation, and crystallization steps are integrated into a single reaction vessel and process flow, eliminating the need for separate purification steps and reducing overall production time while maintaining high purity (>99.5%)
Solution Approach 2:
The patent employs preliminary action by using a phase transfer catalyst in the cyclization step to pre-form the intermediate compound with high purity before the amidation step. This preliminary purification through phase transfer catalysis avoids the need for subsequent complex purification procedures, streamlining the overall process
2Ease of manufacture
If conventional preparation methods are used, then apixaban can be produced, but costly and environmentally harmful materials are required
Solution Approach 1:
The patent changes the chemical parameters of the reaction system by using potassium carbonate as a base and a phase transfer catalyst (such as tetrabutylammonium bromide) to enable the cyclization step. These parameter changes allow the use of cheaper, environmentally friendly reagents while maintaining high reaction efficiency and product purity
Solution Approach 2:
The patent employs disposable or easily removable reagents such as potassium carbonate and phase transfer catalysts that can be simple filtration or extraction processes to remove. These replace expensive, environmentally harmful reagents with cheaper alternatives that pose minimal environmental risk
3Productivity
If existing synthesis procedures are used, then apixaban intermediates can be prepared, but the yields are insufficient and purity is compromised
Solution Approach 1:
The patent uses a phase transfer catalyst as an intermediary substance that facilitates the cyclization reaction between the starting material and the intermediate compound. This intermediary enables the reaction to proceed with high yield (>90%) and high purity by mediating the transformation and preventing side reactions
Solution Approach 2:
The patent optimizes reaction parameters including temperature, solvent choice, and catalyst concentration to achieve optimal yield and purity. By carefully controlling these parameters, the process achieves both high productivity and high manufacturing precision simultaneously
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 apixaban with high purity (>99.5%) and yield, reduces production costs, and is suitable for large-scale industrial production, minimizing impurities and solvent use.
Implementation Method 1
cyclizing the compound of formula (III) in the presence of potassium carbonate, a first solvent, and a phase transfer catalyst
Implementation Method 2
reacting the compound of formula (IV) with NH3 to obtain apixaban of formula (V), preferably at a temperature of 80°C or more
Implementation Method 3
optionally crystallizing apixaban of formula (V), especially optionally crystallizing apixaban polymorphic form N-1
Data Source
Figure 1a
Figure 1b~2
Figure 3
AI summary
The present invention relates to process for preparing apixaban, in particular polymorphic form N-1 thereof, as well as to a method for the preparation of crystalline apixaban, especially apixaban polymorphic form N-1.