Compound Separation by Cyclic, Selective Dissolution. Isolation of Diastereomeric, 1β-Methylcarbapenem Key Intermediates

A practical method for separation of the methyl esters of two diastereomeric, α-methylated, 2-azetidinon-4-ylacetic acid derivatives by selective dissolution using two solvents in which their relative solubilities are distinctly different is described. The less soluble diastereomer was first isolated from isopropanol in which the solubility of the more soluble diastereomer is 1.65 times that of the less soluble diastereomer. The more soluble diastereomer was then isolated from the mother liquor after a solvent switch to toluene in which the solubility of the more soluble diastereomer is only 1.15 times that of the less soluble diastereomer. The isolation cycle was then repeated to separate more of the diastereomers. This method is particularly useful for isolation of the more soluble component. A proposed explanation of the solubility differences suggests that the approach may be widely applicable to the separation of other structurally similar compounds.