Bicyclic RET Inhibitor Intermediate Synthesis
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Solution Overview
Problem
Current methods for preparing RET inhibitors are complex, involve lengthy reaction steps, and have low overall yields, making them unsuitable for industrial production.
Innovation Solution
A novel method for preparing a RET inhibitor using specific intermediates of formulas (V) and (VI) with improved yield and purity, optimized for industrial production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the preparation method from patent WO 2018071454 A is used, then the RET inhibitor can be prepared, but the process is complex with 10 steps and low overall yield
Solution Approach 1:
The patent combines multiple reaction steps into fewer steps by using key intermediates (V) and (VI) that can be prepared in advance and stored. Specifically, the preparation of the bicyclic core structure is merged with the final coupling step, reducing the total number of steps from 10 to a more manageable process while improving overall yield through optimized reaction conditions and intermediate stability.
Solution Approach 2:
The patent applies preliminary action by preparing and isolating key intermediates (V) and (VI) before the final coupling step. These intermediates contain pre-formed functional groups and structural features that will be used in subsequent reactions, allowing for better control of the overall synthesis process and improved yield by avoiding repeated purification steps.
2Reliability
If multi-kinase inhibitors are used for RET treatment, then clinical treatment is available, but selectivity is poor and side effects are high
Solution Approach 1:
The patent applies local quality by designing the bicyclic inhibitor with specific functional groups and structural features that are tailored to interact with the RET kinase active site. The compound contains a bicyclic core structure with specific substituents (R1-R6 groups) that provide localized interactions with key residues in the RET binding pocket, enhancing selectivity while reducing off-target effects on other kinases.
Solution Approach 2:
The patent uses parameter changes by systematically varying the substituents on the bicyclic core structure to optimize the balance between potency and selectivity. By changing parameters such as the nature of R groups, their positions, and stereochemistry, the patent achieves high selectivity for RET over other kinases, thereby reducing side effects associated with multi-kinase inhibition.
Data Source
AI summary
The present invention provides an intermediate of a bicyclic inhibitor and a preparation method therefor. The present invention particularly relates to an intermediate as shown in formula (VI) and a preparation method therefor. The reaction method uses initial raw materials that are cheap and easy to obtain. The synthesis process is mature, the product quality is stable, the yield and purity are high, the key reagents can be recycled, the production cost is reduced, and the method is suitable for large-scale industrial production and application.