Osimertinib Synthesis via Hydrazine Reduction
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Solution Overview
Problem
Existing processes for preparing osimertinib, an EGFR inhibitor used in treating advanced non-small cell lung cancer, are not suitable for large-scale production due to the need for ion exchange chromatography for purification and the use of hazardous gaseous H2 at high pressure.
Innovation Solution
A process involving the reaction of compound of formula (2) with hydrazine or ammonium formate in the presence of a catalyst, such as Pd or Pt on carbon, in a solvent like 2-methyl tetrahydrofuran, to obtain compound of formula (3), which is then transformed into osimertinib or its salt.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If gaseous H2 at high pressure is used for reduction, then reduction efficiency is improved, but safety hazard increases
Solution Approach 1:
The patent changes the physical state parameter of the reducing agent from gaseous H2 at high pressure to liquid or solid form hydrazine or ammonium formate, which can be handled at atmospheric pressure, thereby maintaining reduction efficiency while eliminating safety hazards associated with high-pressure gas handling
Solution Approach 2:
The patent employs readily available, stable compounds like hydrazine or ammonium formate as reducing agents instead of requiring specialized high-pressure H2 gas systems, making the process safer and more suitable for large-scale production while maintaining effectiveness
2Manufacturing precision
If ion exchange chromatography is used for purification, then product purity is improved, but process complexity increases
Solution Approach 1:
The patent extracts and eliminates the complex ion exchange chromatography step from the process by designing a reduction reaction that produces minimal impurities, allowing purification to be achieved through simpler filtration and washing operations
Solution Approach 2:
The patent segments the purification process into simple sequential steps (filtration, washing, drying) instead of requiring a single complex chromatography step, making the overall process easier to implement at large scale while maintaining product purity
3Productivity
If stoichiometric amount of acid is used for reduction, then reduction completeness is improved, but waste generation increases
Solution Approach 1:
The patent converts the potential harm of using excess reagents into a benefit by selecting hydrazine or ammonium formate as reducing agents that decompose into harmless or easily removable byproducts (N2, H2O, CO2, NH3), eliminating the need for neutralization steps and reducing waste generation
Solution Approach 2:
The patent designs the reduction process using reagents that naturally decompose into volatile or water-soluble byproducts that can be easily removed during standard workup procedures, eliminating the need for additional neutralization and waste treatment steps
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 enables the preparation of osimertinib suitable for high-scale production without the use of hazardous gaseous H2, simplifying purification and improving safety and efficiency.
Implementation Method 1
Reacting compound of formula (2) with hydrazine or ammonium formate in a presence of a catalyst in a solvent to obtain compound of formula (3)
Implementation Method 2
The key step in Osimertinib preparation is reduction of compound of formula (2) to prepare compound of formula (3)
Data Source
AI summary
The invention deals with a novel process for preparation of the pharmaceutically useful product Osimertinib of formula (1).