Protected Allylic Alcohols for Macrocyclic MCL-1 Ring Closure
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Solution Overview
Problem
Existing synthetic methods for Mcl-1 inhibitors, such as compounds A1 and A2, face challenges with low yield and purity, especially when scaled up for commercial production, and require environmentally undesirable solvents and chromatography for purification.
Innovation Solution
The proposed processes involve the use of protected allylic alcohol intermediates and environmentally friendly solvents, with improved reaction conditions that minimize impurities and eliminate the need for chromatography, resulting in higher yields and crystalline intermediates that facilitate scale-up and purification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing synthetic methods are used for Mcl-1 inhibitors, then the compounds can be prepared, but the yield and purity are low and chromatography is required for purification
Solution Approach 1:
The patent applies preliminary action by introducing a protecting group on the alcohol portion of the allylic alcohol intermediate before performing the sulfonamide addition reaction. This pre-protection step prevents unwanted side reactions and impurity formation during the synthesis, thereby improving yield and eliminating the need for chromatography-based purification in subsequent steps.
Solution Approach 2:
The patent uses a protected allylic alcohol intermediate as an intermediary species in the synthesis pathway. This intermediate, with its alcohol protecting group in place, serves as a stable and pure starting material for the sulfonamide addition reaction, enabling higher yield and cleaner reaction profiles without requiring chromatographic purification.
2Productivity
If existing synthetic methods are used, then Mcl-1 inhibitors can be synthesized, but environmentally undesirable solvents and chromatography are required
Solution Approach 1:
The patent applies parameter changes by modifying the reaction conditions and protecting group strategies to achieve the sulfonamide addition reaction with higher efficiency and cleaner profiles. This enables the use of environmentally friendly solvents and eliminates the need for chromatography, thereby reducing environmental harm while maintaining synthesis efficiency.
3Productivity
If the synthesis is scaled up for commercial production, then productivity increases, but yield and purity deteriorate
Solution Approach 1:
The patent applies preliminary action by establishing the protecting group installation step before the sulfonamide addition reaction. This pre-protection measure ensures that the intermediate is pure and stable, which is critical for maintaining high yield and purity even when the synthesis is scaled up for commercial production.
Solution Approach 2:
The protected allylic alcohol intermediate serves as a reliable intermediary that maintains its purity and reactivity characteristics across different scales. This intermediary enables consistent, high-quality production at commercial scales without the yield and purity deterioration that typically occurs with scaling.
Data Source
AI summary
Provided herein are processes for synthesizing Mcl-1 inhibitors and intermediates such as compound F that can be used to prepare them where the variable PG is as defined herein. In particular, provided herein are processes for synthesizing compound A1, and salts or solvates thereof and compound A2, and salts and solvates thereof.