Cocrystallization-Induced Spontaneous Deracemization: A General Thermodynamic Approach to Deracemization

Area of Science:

• Chirality and stereochemistry
• Organic chemistry
• Crystallization science

Background:

• Enantiomerically pure compounds are crucial, especially in pharmaceuticals.
• Crystallization-induced diastereomeric transformation can yield 100% desired enantiomers from racemic mixtures.
• This method requires the compound to form a salt, limiting its application.

Purpose of the Study:

• To introduce cocrystallization as a method for thermodynamic deracemization.
• To overcome the salt formation limitation of existing deracemization techniques.
• To demonstrate a general, single-step thermodynamic deracemization process applicable to chiral compounds.

Main Methods:

• Development of a novel thermodynamic deracemization process using cocrystallization.
• Application of the process to a model chiral fungicide: (R,S)-4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)pentan-3-one.
• Investigation of cocrystal formation for achieving enantiomeric enrichment.

Main Results:

• Successfully demonstrated a single thermodynamic deracemization process based on cocrystallization.
• Overcame the limitation of requiring salt formation for deracemization.
• Achieved deracemization of the model chiral fungicide (R,S)-4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)pentan-3-one.

Conclusions:

• Cocrystallization offers a general and effective approach for thermodynamic deracemization.
• This novel method expands the applicability of deracemization beyond salt-forming compounds.
• The study paves the way for developing new cocrystallization-based deracemization strategies.