Apixaban Synthesis Process Eliminating Ullmann Reaction
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Solution Overview
Problem
Current processes for preparing Apixaban are complex, costly, and environmentally unfriendly, involving harsh conditions, high metal loading, and erratic yields, with a need for simpler, cost-effective methods using inexpensive starting materials to produce high yields of the drug and its intermediates.
Innovation Solution
A simplified process involving a single inorganic base for acylation and cyclization steps, using aniline as a starting material, and eliminating the need for expensive reagents and harsh conditions, with specific steps including nitrating and chlorinating agents in non-halogenated solvents, and reduction using hydrazine hydrate and Raney Nickel, to produce Apixaban in high purity and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional processes are used to prepare Apixaban, then the drug can be produced, but the process is complex, costly, and involves harsh conditions with erratic yields
Solution Approach 1:
The patent segments the synthesis process into distinct modular stages: acylation of aniline with halovaleryl halide, cyclization to form piperidinone, nitration to introduce nitro group, condensation with hydrazono compound, and final aminolysis. Each stage is optimized independently with specific reagents and conditions, allowing for better control and reduced overall complexity while improving yields at each step.
Solution Approach 2:
The patent employs parameter changes by selecting specific reagents and conditions for each transformation: using triethylamine as base in acylation, formic acid for cyclization, nitric acid for nitration, and methanolic ammonia for aminolysis. Temperature parameters are precisely controlled (e.g., 0-5°C for acylation, reflux for cyclization and nitration, 60-70°C for aminolysis), which stabilizes the process and improves yield consistency.
2Reliability
If expensive reagents and harsh conditions are used, then reaction proceeds, but operational costs increase and environmental impact worsens
Solution Approach 1:
The patent replaces expensive reagents with cheaper alternatives: using triethylamine instead of costly bases, formic acid instead of expensive cyclizing agents, and methanolic ammonia instead of expensive aminolysis reagents. These inexpensive reagents maintain reaction reliability while significantly reducing operational costs and environmental burden.
Solution Approach 2:
The patent converts potentially harmful reactions into beneficial outcomes by using mild, selective reagents. For example, the nitration step uses controlled nitric acid treatment that selectively introduces the nitro group without excessive side reactions, and the condensation uses hydrazono compound that provides high selectivity. This approach maintains reliability while reducing hazardous waste.
3Productivity
If multiple bases and costly reagents are used for acylation and cyclization, then intermediates are formed, but the process becomes costly and operationally complex
Solution Approach 1:
The patent employs triethylamine as a universal base for multiple transformations including acylation and as an acid scavenger throughout the process. This single reagent performs multiple functions, eliminating the need for multiple different bases and reducing both material costs and operational complexity while maintaining high intermediate yields.
Solution Approach 2:
The patent uses formic acid as an intermediary reagent that facilitates cyclization by providing controlled acidity and forming transient intermediates that drive the reaction forward. This intermediary approach allows the cyclization to proceed efficiently without requiring harsh conditions or expensive catalysts, improving intermediate yield while reducing costs.
4Productivity
If Ullmann reaction with copper catalyst is used, then ester compound is formed, but metal loading is high and yields are erratic
Solution Approach 1:
The patent extracts and eliminates copper catalyst and Ullmann reaction conditions from the synthesis pathway. Instead, it employs a direct condensation reaction between the nitro-piperidinone intermediate and hydrazono compound under mild basic conditions to form the pyrazolo[3,4-c]pyridine core. This removal of metal catalysis eliminates the erratic yields and high metal loading associated with Ullmann reactions while improving both productivity and reliability.
Solution Approach 2:
The patent substitutes the mechanical Ullmann coupling mechanism (requiring copper catalyst, high temperature, and prolonged reaction time) with a chemical condensation mechanism using hydrazono compound under milder conditions. This substitution replaces a metal-dependent mechanical system with a more reliable chemical transformation that proceeds with consistent high yields.
5Manufacturing precision
If lengthy reaction times and high temperatures are used, then transformation is complete, but energy consumption increases and productivity decreases
Solution Approach 1:
The patent optimizes temperature and time parameters for each step: acylation at 0-5°C for 1-2 hours, cyclization at reflux for 2-4 hours, nitration at 0-5°C for 1-2 hours, condensation at room temperature for 12-24 hours, and aminolysis at 60-70°C for 12-24 hours. These precisely controlled parameters ensure complete transformation while minimizing energy consumption and maximizing productivity.
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 better yields and improved purity of Apixaban with reduced environmental impact and operational costs, avoiding the use of hazardous materials and cumbersome procedures, while using inexpensive starting materials.
Implementation Method 1
reduction using hydrazine hydrate and Raney Nickel
Implementation Method 2
reduction using hydrazine hydrate and Raney Nickel
Data Source
Figure 1
AI summary
The present invention refers to novel process for the preparation of Apixaban. Further, the invention also related to a process for the preparation of intermediate of Apixaban from very basic and cheap row material i.e. Aniline which is widely commercially available. The present invention provides process for preparation of Apixaban using a different sequence of synthetic steps and does not involve use of Ullmann reaction.