Improved protocol for synthesizing (3Z,6Z)-3-benzylidene-6-[(5-tert-butyl-1H-imidazol-4-yl)methylidene]piperazine-2,5-dione (plinabulin)

Plinabulin is a selective small-molecule tumor vascular-disrupting agent that may also be used to treat chemotherapy-induced neutropenia. However, the original synthetic procedure of plinabulin exhibits several limitations. The raw material, ethyl isocyanoacetate, is expensive, with an unpleasant odor that may harm workers. The intermediates generally require purification using column chromatography, which is not a preferred purification method on a large scale. In addition, the extended synthetic route does not satisfy the requirements of green chemistry. Therefore, a novel, improved method of synthesizing plinabulin is reported based on the syntheses and isolation of the key intermediate 8, 4-( tert -butyl)-1 H -imidazole-5-carbaldehyde, and the final product. The advantages of this method include simple post-treatment, less residual solvent, nontoxicity, and convenient execution. Furthermore, the final product is obtained via a one-pot method, which satisfies the requirements of green chemistry and is thus suitable for use in industrial production.