Vinylic Protected Alcohol Intermediate Synthesis Via Slurry Reduction
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Solution Overview
Problem
Existing synthetic methods for Mcl-1 inhibitors, such as compounds A1 and A2, face challenges in achieving high yield and purity, particularly for commercial production.
Innovation Solution
A process involving the admixing of compound B and compound C in an organic solvent to form a slurry, followed by the addition of a reducing agent, forming an intermediate that is not isolated, and then optionally crystallized, to produce compound D, which is used to synthesize compounds A1 and A2 with improved yield and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing synthetic methods are used for Mcl-1 inhibitors, then the compounds can be produced, but the yield and purity are insufficient for commercial production
Solution Approach 1:
The synthesis is divided into discrete steps with specific intermediates (compound B, compound C, compound D) that can be optimized independently. The process segments the transformation into: (a) forming a slurry of compounds B and C in organic solvent, (b) adding reducing agent to form compound D, and (c) optional crystallization to enhance purity. This segmentation allows each step to be controlled for optimal yield and purity.
Solution Approach 2:
The patent employs parameter changes by selecting specific organic solvents (nonpolar aromatic, ether, chlorinated, alcohol, acetonitrile, DMF, DMAc, NMP) and controlling reaction conditions (ambient temperature, stoichiometric ratios) to optimize both yield and purity. The reducing agent selection and crystallization parameters are adjusted to achieve superior product quality suitable for commercial production.
2Productivity
If multiple synthesis steps are used, then the Mcl-1 inhibitors can be produced, but the process complexity increases and stability decreases
Solution Approach 1:
The patent merges multiple functions into a consolidated process: compound B and compound C are admixed in one step to form a slurry, the reducing agent is added in the same reaction medium, and the intermediate compound D is formed and optionally crystallized in a single operational sequence. This merging reduces the number of discrete steps compared to traditional multi-step syntheses while maintaining high yield and purity.
Solution Approach 2:
Compound D serves as a key intermediary that bridges the transformation from starting materials (compounds B and C) to the final Mcl-1 inhibitors (compounds A1 and A2). This intermediary approach allows for optimized reaction conditions and optional crystallization to enhance purity, while maintaining a streamlined process that reduces overall complexity.
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 achieves higher yield and purity of Mcl-1 inhibitors by performing reactions at ambient conditions with milder reagents and utilizing crystalline intermediates, reducing the number of steps and improving stability.
Implementation Method 1
admixing the slurry of step (a) and a reducing agent to form a mixture comprising compound D
Data Source
AI summary
Provided herein are processes for synthesizing intermediates useful in preparing Mcl-1 inhibitors. In particular, provided herein are processes for synthesizing compound D, wherein OPG and R1 are described herein. Compound D can be useful in synthesizing compound A1, or a salt of solvate thereof, and compound A2, or a salt of solvate thereof.