Identifying a diastereomeric salt for a challenging chiral resolution

Significance of the Topic

The Medicines for Malaria Venture (MMV) sought an efficient method to obtain a key chiral intermediate for an anti-malarial candidate, SJ557733. Traditional routes were lengthy, involving supercritical fluid chromatography and multi-step synthesis. Rapid identification of a scalable, high-yield resolution is critical to accelerate drug development against resistant Plasmodium parasites.

Objectives and Study Overview

This study aimed to discover a diastereomeric salt resolution to isolate (+)-2, a chiral carboxylic acid intermediate, directly from its racemate. The collaboration between MMV and Unchained Labs leveraged high-throughput screening on the Big Kahuna platform to explore counterions and solvent systems, aiming for high yield, enantiomeric excess and scalability.

Methodology and Instrumentation

The team conducted two automated salt screening campaigns using the Big Kahuna system configured for preformulation. Key steps included:

• Dispensing racemic intermediate and chiral amino alcohols into 96-well plates
• Formation of diastereomeric salts at controlled temperature and mixing
• Solvent addition and crystallization in diverse solvent mixtures
• Automated filtration and transfer of supernatants
• Chiral HPLC analysis on Chiralpak AD-H columns to quantify solubility and enantiomeric excess

Main Results and Discussion

Primary screening of 11 amino alcohols and 12 solvents yielded a moderate hit with trans-1-amino-2-indanol in ethyl acetate. A focused follow-up screen refined parameters: 1S,2S-trans-amino-indanol at a 2:1 molar ratio in a 1:1 propionitrile-heptane mixture produced a >1000-fold solubility difference between diastereomers. Scaling to 16.4 g racemate delivered 14.3 g of the desired salt (94% yield, 99.3% ee), which was converted to the free acid (+)-2 in 85% yield (99.3% ee).

Benefits and Practical Applications

Ultrafast identification of optimal resolution conditions reduced problem-solving from over a year to two weeks. The high-throughput diastereomeric salt approach offers:

• Significant time and resource savings
• High purity and enantiomeric excess suitable for scale-up
• Flexibility to screen diverse counterions and solvent systems

Future Trends and Applications

Advances in automation and screening will further streamline chiral resolution. Integration with data analytics and machine learning may predict optimal salt pairs and solvents, expanding to other challenging APIs and accelerating early-stage drug development.

Conclusion

This work demonstrates that high-throughput diastereomeric salt screening can rapidly solve complex chiral separation challenges. The identified protocol for (+)-2 enabled MMV to resume development of a promising anti-malarial candidate with a robust and scalable route.

Reference

• Guiguemde WA et al Chemical genetics of Plasmodium falciparum Nature 2010 465 311-315