Apixaban Glycol Ester Amidation for Faster Reaction
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Solution Overview
Problem
Current methods for preparing Apixaban, an active pharmaceutical ingredient used as an anticoagulant, require long reaction times and high temperatures, which are inefficient and may not consistently produce the desired polymorphic form N−1, affecting the drug's physical-chemical and therapeutic properties.
Innovation Solution
A process involving an amidation reaction using a glycol ester of Apixaban, which proceeds faster and more efficiently than conventional esters, allowing for the production of Apixaban in the thermodynamically stable form N−1 with reduced reaction time and avoiding residual solvents, utilizing anhydrous or aqueous ammonia in a glycol solvent at moderate temperatures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional amidation reaction using Apixaban ethyl ester is performed, then Apixaban can be produced, but the reaction requires long reaction time (at least 12 hours) and high temperature (90°C)
Solution Approach 1:
The patent changes the chemical structure parameter of the ester group from conventional ethyl ester to glycol ester (specifically 1,2-propyleneglycol ester). This structural modification of the ester group fundamentally alters the reactivity of the substrate, enabling the amidation reaction to proceed much faster (3 hours vs 12 hours) while maintaining moderate temperature conditions (80-90°C). The glycol ester's unique structure with hydroxyl groups adjacent to the ester carbonyl enhances the electrophilicity and facilitates nucleophilic attack by ammonia.
2Manufacturing precision
If conventional amidation reaction is performed to produce Apixaban, then the product can be obtained, but the desired polymorphic form N−1 is not consistently produced
Solution Approach 1:
The patent modifies the reaction conditions parameters including temperature (80-90°C range), solvent system (glycol solvent), and substrate structure (glycol ester) to create an optimized reaction environment that consistently yields polymorphic form N−1. The specific combination of these parameters creates favorable conditions for the thermodynamic stabilization of form N−1, ensuring reliable and consistent production of the desired polymorphic form.
3Productivity
If high temperature (90°C or higher) is used for amidation reaction, then reaction can proceed, but energy consumption increases and side reactions may occur
Solution Approach 1:
The patent changes the substrate from conventional ester to glycol ester, which fundamentally alters the activation energy requirement of the amidation reaction. The glycol ester's enhanced reactivity allows the reaction to proceed efficiently at lower temperatures (80-90°C compared to 90°C or higher), thereby reducing energy consumption while maintaining high reaction efficiency and productivity.
4Productivity
If conventional ester is used in amidation reaction, then reaction can proceed, but glycol ester provides faster reaction rate
Solution Approach 1:
The patent incorporates the glycol ester synthesis as a preliminary step before the amidation reaction. The Apixaban acid is first reacted with 1,2-propyleneglycol to form the glycol ester intermediate, which is then used in the amidation reaction. This preliminary action of creating the reactive glycol ester intermediate enables the subsequent fast amidation reaction, overall improving the efficiency of the synthetic route despite the additional step.
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 process significantly reduces reaction time, achieving 99% conversion in 3 hours at 80-90°C, maintains the stability and purity of Apixaban form N−1, and minimizes residual solvent presence, meeting regulatory standards for pharmaceutical quality.
Implementation Method 1
A process involving an amidation reaction using a glycol ester of Apixaban, which proceeds faster and more efficiently than conventional esters
Implementation Method 2
achieving 99% conversion in 3 hours at 80-90°C
Data Source
AI summary
Object of the present invention is an improved process for the preparation of Apixaban, through new intermediates which undergo to a faster amidation reaction. Impurities of Apixaban are also identified and quantified.