KRAS Inhibitor Intermediate Cocrystallization for Scalable Synthesis
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Solution Overview
Problem
There is a need for efficient and scalable synthesis methods for intermediate compounds that inhibit KRAS G12C mutations, which are prevalent in various cancers and confer resistance to EGFR targeted therapies.
Innovation Solution
A method involving cocrystallization of a compound of Formula 4 with compounds of Formula (B) or (11), followed by reaction with phosphoryl chloride and (s)-1-boc-3-methylpiperazine, to produce compound 5M, which is then used to synthesize KRAS inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional synthesis methods are used to prepare intermediate compounds for KRAS G12C inhibitors, then the synthesis process is simpler, but the efficiency and scalability are insufficient
Solution Approach 1:
The synthesis process is divided into distinct modular stages: cocrystallization of compound 4 with chiral auxiliary (Formula B or 11) to obtain enantiomerically pure intermediate 5M, followed by reaction with phosphoryl chloride and (s)-1-boc-3-methylpiperazine. This segmentation allows each step to be optimized independently for both efficiency and scalability while maintaining overall process simplicity.
2Productivity
If conventional synthesis methods are used, then the process is easier to implement, but it lacks scalability for industrial production
Solution Approach 1:
The cocrystallization step with chiral auxiliary (Formula B or 11) is performed in advance to establish enantiomeric purity of intermediate 5M before subsequent reactions. This preliminary chiral resolution step enables scalable production of optically pure KRAS G12C inhibitor intermediates while simplifying downstream processing by eliminating the need for complex chiral separations later in the synthesis.
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 method enables the efficient production of KRAS inhibitors, potentially leading to effective treatments for cancers with KRAS mutations, such as pancreatic cancer, lung adenocarcinoma, and colorectal cancer, by providing high potency and selectivity for KRAS G12C.
Implementation Method 1
obtaining a compound of Formula 5M from a compound of Formula 4 through cocrystallization with a compound of Formula (B), or with a compound of Formula (11)
Data Source
Figure 1~2-1
Figure 2-2~2-3
Figure 2-4~2-5
AI summary
The present invention relates to an improved, efficient, scalable process to prepare intermediate compounds, such as compound 5M, having the structure useful for the synthesis of compounds that target KRAS G12C mutations, such as