Identifying a diastereomeric salt for a challenging chiral resolution

Importance of the Topic

The Medicines for Malaria Venture (MMV) is dedicated to discovering and delivering affordable, effective anti-malarial drugs for populations at greatest risk. A key challenge in the development of the SJ557733 chemotype was isolating a single enantiomer of a chiral carboxylic acid intermediate with high yield and enantiomeric excess (ee). Traditional preparative supercritical fluid chromatography (SFC) proved time-consuming and resource-intensive, creating a bottleneck in the program.

Objectives and Study Overview

This study aimed to develop and scale up an efficient chiral resolution method for the target intermediate (+)-2. By leveraging high-throughput automated screening on the Big Kahuna platform, the team sought to identify optimal diastereomeric salt formation conditions to isolate the desired enantiomer in days rather than months.

Methodology and Instrumentation

A 96-well microplate-based salt screening was executed using Unchained Labs’ Big Kahuna system configured for preformulation. Key aspects:

• Chiral counterions: Eleven amino alcohols including four stereoisomers of 1-amino-2-indanol.
• Solvent systems: Twenty individual solvents and mixtures (e.g., EtOAc, EtCN:heptane, MeOH:H₂O).
• Counterion-to-racemate ratios: 1:1 and 2:1.

Instrumentation used:

• Automated powder dispenser with integrated balance.
• Four-tip liquid dispensers (ambient and heated).
• Heating/cooling and stirring stations.
• Microplate filters and robotic arm gripper.

Main Results and Discussion

Initial screening yielded one moderate hit: trans-1-amino-2-indanol in ethyl acetate with 38% yield and 72% ee. A focused follow-up screen with all four indanol stereoisomers in EtCN:heptane (1:1) at a 2:1 ratio revealed that (1R,2R)-trans-1-amino-2-indanol provided exceptional solubility contrast (~1000×) between diastereomers. Scale-up of these conditions at 16.4 g scale produced the 2:1 salt in 94% yield and 99.3% ee. Subsequent acid wash and extraction delivered the free (+)-2 acid in 85% yield and 99.3% ee.

Benefits and Practical Applications

This approach eliminated the need for preparative SFC, significantly reducing development time and resource requirements. The crystallization-based resolution is readily scalable and cost-effective, accelerating the supply of enantiopure intermediate for downstream synthesis and clinical development.

Future Trends and Opportunities

High-throughput salt screening can be applied to a wide range of chiral APIs. Integration with predictive modeling and machine learning could further streamline counterion and solvent selection. Advances in automated platforms will continue to reduce cycle times in process research and development.

Conclusion

By employing a systematic high-throughput diastereomeric salt screen, MMV and Unchained Labs overcame a long-standing chiral resolution challenge in two weeks. The optimized salt crystallization method delivered high yield and ee, enabling progression of a promising anti-malarial candidate.

References

1. Guiguemde, W. A. et al. Chemical genetics of Plasmodium falciparum. Nature. 2010;465:311–315.