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首页> 外文期刊>Organic process research & development >Purification of difluoromethylornithine by global process optimization: Coupling of chemistry and chromatography with enantioselective crystallization
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Purification of difluoromethylornithine by global process optimization: Coupling of chemistry and chromatography with enantioselective crystallization

机译：通过全局工艺优化纯化二氟甲基鸟氨酸：化学和色谱法与对映选择性结晶的耦合

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摘要

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.
机译：描述了纯化公吨对映体纯的二氟甲基鸟氨酸（DFMO HCl）的工业方法。氨基酸DFMO HCl环化形成内酰胺，内酰胺用新戊酰氯酰化形成rac-N-新戊酰基-DFMO内酰胺（4）。与直接拆分外消旋DFMO HCl（1）相比，内酰胺4的分离效果更高。提出了一种混合手性拆分方法来分离4的对映体。该方法涉及多柱连续对映选择性色谱法（VARICOL）与（D）-N-新戊酰-DFMO内酰胺5的对映选择性结晶。基于良好的共晶点，与单独的色谱方法相比，它可提供更高的VARICOL方法生产率和更低的纯化成本。使用最终的化学修饰（水解）以高化学纯度和过量对映体形式形成（D）-DFMO（6）和（L）-DFMO的单一对映体。全球优化方法被用于设计经济的工业流程，该方法基于对VARICOL工艺和对映选择性结晶的参数研究，以获得最大的回收率和纯度，同时显着降低了制造单个对映异构体的成本。给出了全局过程优化的详细描述。

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