Purification of Difluoromethylornithine by Global Process Optimization: Coupling of Chemistry and Chromatography with Enantioselective Crystallization

Abstract

An industrial process for the purification of metric tons of enantiomerically pure difluoromethylornithine (DFMO HCl) is described. The amino acid DFMO HCl is cyclized to form the lactam, which is acylated with pivaloyl chloride to form rac-N-pivaloyl-DFMO lactam (4). The lactam 4 provides enhanced separation compared to a direct resolution of racemic DFMO HCl (1). A hybrid chiral resolution process is proposed to separate the enantiomers of 4. This process involves a multicolumn continuous enantioselective chromatographic process (VariCol) coupled with enantioselective crystallization of (d)-N-pivaloyl-DFMO lactam 5. The interest of this hybrid process is based on a favorable eutectic point providing a higher productivity of the VariCol process and lower purification costs than the chromatographic process alone. A final chemical modification (hydrolysis) is used to form the single enantiomers of both (d)-DFMO (6) and (l)-DFMO in high chemical purity and enantiomeric excess. A global optimization approach is applied to design an economical industrial process, which is based on a parametric study of the VariCol process and enantioselective crystallization to obtain maximum recovery and purity while significantly lowering the cost of manufacturing the single enantiomers. A detailed description of the global process optimization is presented.