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-Npivaloyl-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.

Organocatalytic Decarboxylative Cyanomethylation of Difluoromethyl and Trifluoromethyl Ketones

“…The trifluoromethyl group is a key structural motif in several anticonvulsants, metalloproteinase inhibitors, CJ‐17,493, a Neurokinin 1 receptor antagonist, ZK (+)‐216348, a potent glucocorticoid receptor agonist, and HIV drugs such as Efavirenz . Examples of therapeutics exhibiting a difluoromethylene or difluoromethyl group are the HIV‐1 protease inhibitor A‐79285 and Eflornithine, an inhibitor of ornithine decarboxylase used for the treatment of facial hirsutism and African sleeping sickness. In recent years, we have developed an interest in catalytic nucleophilic addition reactions with trifluoromethyl ketone substrates .…”

Separation Strategies for Processing of Dilute Liquid Streams

“…The newly developed method "Varicol" is proposed to be more efficient than the traditional simulated moving-bed technique. Another form of chiral resolution process for the separation of racemic mixture of difluoromethylornithine (DFMO HCl) in industrial scale has been proposed by Perrin et al [197] involving a multicolumn continuous enantioselective chromatographic process coupled with enantioselective crystallization process. The other chromatographic techniques used for chiral separation are high-performance liquid chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC), thin-layer chromatography (TLC), and capillary electrochromatography (CEC).…”

A Partial Classical Resolution/Preparative Chiral Supercritical Fluid Chromatography Method for the Rapid Preparation of the Pivotal Intermediate in the Synthesis of Two Nonsteroidal Glucocorticoid Receptor Modulators

“…SMB and Varicol chromatography are the separation method of choice for chiral resolution when scalability and long-term viability are key process requirements. These techniques are well-suited for the preparation of kilogram quantities of enantiomerically pure material because they require minimal supervision once steady state is reached by virtue of their continuous operation. − The Varicol process has been combined with enantioselective crystallization on a metric ton scale . As a complementary approach, the development of an SFC chiral separation requires minimal resources because the method scales up linearly from analytical to preparative scale.…”

“…3−5 The Varicol process has been combined with enantioselective crystallization on a metric ton scale. 6 As a complementary approach, the development of an SFC chiral separation requires minimal resources because the method scales up linearly from analytical to preparative scale. SFC processes do not require much liquid cosolvent.…”