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Efficient crystallization-induced dynamic resolution of alpha-substituted carboxylic acids
Susanne Kiau1, Robert P Discordia, Gary Madding
1Process Research and Development Department, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, New Jersey 08903-0191, USA. susanne.kiau@bms.com
The Journal of Organic Chemistry
|June 5, 2004
Summary
This study introduces a new method for creating pure chiral alpha-substituted carboxylic acids using crystallization-induced dynamic resolution (CIDR). This technique efficiently resolves racemic mixtures into highly enantiomerically enriched products.
Area of Science:
- Organic Chemistry
- Chiral Synthesis
- Crystallization
Background:
- Chiral alpha-substituted carboxylic acids are important building blocks in pharmaceuticals and fine chemicals.
- Efficient methods for obtaining enantiomerically pure compounds are crucial for drug development and synthesis.
- Existing resolution techniques can be time-consuming and may require extensive optimization.
Purpose of the Study:
- To develop a novel and efficient route for the enantioselective synthesis of chiral alpha-substituted carboxylic acids.
- To utilize crystallization-induced dynamic resolution (CIDR) for resolving racemic mixtures of these compounds.
- To optimize resolution conditions using parallel experimentation and kinetic studies.
Main Methods:
- Crystallization-induced dynamic resolution (CIDR) of diastereomeric salts formed with chiral amines.
- Use of (1R,2S)-2-amino-1,2-diphenylethanol as a resolving agent.
- Parallel experimentation for rapid screening of resolution conditions.
- Kinetic studies to investigate the influence of various parameters (temperature, catalyst concentration, solvent polarity) on resolution efficiency.
Main Results:
- Successful resolution of racemic alpha-bromo acid and alpha-thiobenzoyl acid with high yields and enantiomeric excess (ee).
- Achieved up to 90% yield and 88% ee for the R-enantiomer of alpha-bromo acid.
- Obtained 74% yield and 90% ee for alpha-thiobenzoyl acid.
- Demonstrated further enrichment to enantiomeric homogeneity via crystallization.
- Developed a telescoped, two-step process yielding S-alpha-thiobenzoyl acid with >99.6% ee in 63% yield.
Conclusions:
- CIDR provides a reliable and efficient method for obtaining enantiomerically enriched chiral alpha-substituted carboxylic acids.
- Parallel experimentation and kinetic studies are valuable tools for optimizing CIDR processes.
- The developed method offers a practical route for accessing enantiopure chiral carboxylic acids, potentially applicable to pharmaceutical synthesis.