KRAS G12C Intermediate Synthesis Using Co-Crystal Scale-Up
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Solution Overview
Problem
There is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, particularly those with KRAS mutations, as KRAS mutations confer resistance to EGFR targeted therapies and provide important information prior to TKI therapy.
Innovation Solution
An improved, efficient, scalable process is developed for synthesizing intermediate compounds, such as compound 5M, which are useful for KRAS G12C inhibitors, involving the use of specific intermediates and co-crystals to enhance the synthesis process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional synthesis processes are used for KRAS inhibitors, then the production is simpler and faster, but the efficiency and scalability are insufficient
Solution Approach 1:
The patent applies preliminary action by pre-forming co-crystals of intermediates before the main synthesis reaction. This pre-organization of materials in a specific crystalline structure enables more efficient subsequent reactions, improving overall productivity while the modular nature of co-crystal formation keeps process complexity manageable
Solution Approach 2:
The patent utilizes parameter changes by controlling crystallization conditions (temperature, solvent, concentration) to form specific co-crystal polymorphs. These controlled parameter changes enable reproducible, scalable synthesis with improved efficiency, while the systematic approach to parameter control prevents excessive complexity
2Productivity
If new synthesis processes are developed for KRAS inhibitors, then the efficiency and scalability improve, but the process becomes more complex
Solution Approach 1:
The patent applies segmentation by dividing the synthesis into discrete, modular steps with isolated co-crystal formation and characterization stages. This segmentation enables scalable production through standardized repeating units while maintaining manufacturing ease through clear procedural boundaries and intermediate purification points
Solution Approach 2:
The patent uses co-crystals as intermediary forms that facilitate the synthesis process. These intermediary co-crystalline structures serve as stable, characterizable intermediates that simplify scale-up while the systematic intermediary steps maintain manufacturing ease through well-defined transformation processes
Data Source
AI summary
The present invention relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound 5M, having the structureuseful for the synthesis of compounds that target KRAS G12C mutations, such as