Development of a Liquid-Phase Process for Recycling Resolving Agents within Diastereomeric Resolutions

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Development of a Liquid-Phase Process for Recycling Resolving Agents within Diastereomeric Resolutions

Frederico Castelo Ferreira et al

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Org. Process Res. Dev. 10, 784-793 (2006)

This paper describes a liquid-phase process for recycling of resolving agents used in the diastereomeric resolution of chiral bases. The process is applicable to the resolution of any chiral base by an organic acid resolving agent which takes place in a polar solvent. The resolving agent is first of all separated from the diastereomeric complex by addition of aqueous HCl. The initial stage of process development is selection of a water-immiscible extracting organic solvent to recover the resolving agent from the resulting acidic aqueous solution. Either distillation or organic solvent nanofiltration is subsequently used to exchange the resolving agent from the extracting organic solvent back into the polar resolution solvent. This choice between these two technologies for solvent exchange depends on the relative boiling points of the two solvents. The resolution of PPI2, a racemic amine by di-p-toluoyl-l-tartaric acid (DTTA), was selected as an example of a typical resolution used in an organic process. Using the conventional process, this resolution requires 1.75 mol equiv of DTTA for each mole of racemic base fed to resolution, and thus the bulk of the DTTA ends up in the mother liquor. Using the recycling process, DTTA from both mother liquor and crystals was recovered and recycled over seven consecutive resolutions, while the final product enantiomeric excess and resolution yield were maintained at 100% and 40%, respectively. In this way the DTTA requirement was decreased from 1.75 to 0.26 DTTA mol equiv, reducing the amount of fresh resolving agent needed for each resolution by 85%.