ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

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

Huanhuan Chen, Yuqi Liu, Ruonan Jiang, Xinyue Yu, Mingze Qin, and Ping Gong

Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China

E-mail: qinmingze001@126.com

Received: 8 November 2022  Accepted: 17 February 2023

Abstract:

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)-1H-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.

Keywords: Plinabulin; One-pot synthesis; Green chemistry; Vascular-disrupting agent; Process optimization

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-02742-2

Chemical Papers 77 (7) 3803–3810 (2023)