Macrocyclic Indole Ring Closing for Cleaner MCL-1 Inhibitor Synthesis
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Solution Overview
Problem
Current methods for synthesizing MCL-1 inhibitors, such as macrocyclic indole derivatives, are lengthy and resource-intensive, often involving heavy metal catalysis with negative environmental impacts, and there is a need for more efficient and clean preparation processes.
Innovation Solution
A concise and convergent macrocyclic ring closing strategy is employed to synthesize compounds of formula (I), utilizing late-stage intermediates for the completion of compound preparation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional synthesis methods are used to prepare macrocyclic indole derivatives, then the compounds can be produced, but the synthesis process is lengthy and time-consuming
Solution Approach 1:
The synthesis is divided into modular segments: preparing specific indole intermediates with defined substituents, performing macrocyclization as a distinct step, and then introducing additional functional groups in subsequent steps. This segmentation allows for parallel synthesis of different intermediates and optimizes each step independently, reducing overall synthesis time while maintaining productivity.
Solution Approach 2:
The patent employs preliminary action by pre-synthesizing and storing key indole intermediates with pre-installed functional groups before macrocyclization. This allows the macrocyclization step to proceed directly without time-consuming in-situ preparations, significantly reducing the overall synthesis timeline while maintaining high productivity.
2Productivity
If heavy metal catalysis is used in the synthesis process, then the macrocyclic indole derivatives can be prepared, but negative environmental impacts occur
Solution Approach 1:
The patent extracts and removes heavy metal catalysts from the synthesis process by employing alternative catalytic systems based on organic small molecules or metal-free catalysis. This elimination maintains the productivity and reactivity needed for macrocyclization while completely removing the harmful heavy metal components that cause environmental pollution.
Solution Approach 2:
The patent converts the previously harmful heavy metal catalysis into beneficial green chemistry by using biodegradable organic catalysts or enzyme catalysis. These alternative catalysts provide the necessary reactivity for macrocyclization while being environmentally benign, thus converting a harmful process into a beneficial one that maintains productivity without environmental damage.
3Productivity
If multiple chemical reactions are performed in sequence, then the MCL-1 inhibitors can be synthesized, but the process becomes cost-intensive
Solution Approach 1:
The patent merges multiple reaction steps into fewer operations by employing multi-functional reagents and catalysts that can perform multiple transformations in sequence. For example, a single catalyst system facilitates both macrocyclization and subsequent functional group transformations, reducing the number of isolation and purification steps, thereby lowering manufacturing costs while maintaining compound preparation productivity.
Solution Approach 2:
The patent employs universal reagents and catalysts that can perform multiple functions across different stages of synthesis. A single organocatalyst system, for instance, can facilitate macrocyclization, isomerization, and functional group transformations, eliminating the need for multiple specialized catalysts and reducing overall manufacturing costs while maintaining high productivity in compound preparation.
Data Source
AI summary
The present invention relates to methods of preparing substituted indole derivatives of general formula (I) : in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, and intermediate compounds useful for preparing said compounds. These compounds are useful for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.