KRAS G12C Intermediate Crystallization for Scalable Synthesis
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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, especially those with KRAS mutations, as KRAS mutations confer resistance to EGFR targeted therapies and current treatments are inadequate.
Innovation Solution
An improved, efficient process for synthesizing intermediate compounds, such as compound 5M, which are useful for KRAS G12C inhibitors, involving the preparation of crystalline compositions and co-crystals using specific chemical structures and reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional synthesis methods are used for KRAS inhibitors, then the synthesis process is simpler, but the manufacturing efficiency and scalability are insufficient
Solution Approach 1:
The synthesis process is divided into multiple discrete steps with isolated intermediate compounds (compounds 1-10). Each step can be independently optimized and controlled, improving overall manufacturing efficiency while maintaining process clarity. The segmentation of the synthesis pathway into distinct stages allows for better resource management and scalability.
Solution Approach 2:
The patent introduces specific intermediate compounds (compounds 1-10) as mediators in the synthesis pathway. These intermediates serve as crucial bridging molecules that enable the transformation from starting materials to final KRAS inhibitor products. The use of well-defined intermediates facilitates process optimization and quality control at each stage of synthesis.
2Reliability
If existing treatment options are used for KRAS mutation cancers, then the treatment approach is established, but resistance to EGFR targeted therapies occurs
Solution Approach 1:
Instead of targeting EGFR receptors as in conventional therapies, the patent develops KRAS inhibitors that target the downstream KRAS protein directly. This inverted approach bypasses the EGFR resistance mechanism by acting on a different node in the signaling pathway, thereby overcoming therapy resistance while maintaining treatment effectiveness.
Solution Approach 2:
The patent employs parameter changes in the chemical structure of KRAS inhibitors (compounds 1-10) to optimize their binding affinity and selectivity for mutant KRAS proteins. By modifying molecular parameters such as substituent groups and stereochemistry, the inhibitors achieve high potency against KRAS G12C and other mutants, effectively treating cancers that have developed resistance to EGFR-targeted therapies.
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 enables the production of effective KRAS inhibitors, potentially overcoming resistance to EGFR targeted therapies and providing new treatment options for cancers with KRAS mutations.
Implementation Method 1
The present invention relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound 5M
Implementation Method 2
The present invention additional relates to a method of making a composition of formula 4a, the method comprising reacting a compound 4 with a compound B1 in the presence of 2-methyltetrahydrofuran to form the composition of formula 4a, having the structure: as crystals
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