KPU-2；NPI-2358；Plinabulin, -Drug Synthesis Database

【结构式】

【药物名称】KPU-2；NPI-2358；Plinabulin

【化学名称】3(Z)-Benzylidene-6(Z)-(5-tert-butyl-1H-imidazol-4-ylmethylene)piperazine-2,5-dione

【CA登记号】714272-27-2

【分子式】C₁₉H₂₀N₄O₂

【分子量】336.3877

【开发单位】Nereus Pharmaceuticals, Inc. (US)

【药理作用】Tubulin Polymerization Inhibitor；Oncolytic；Vascular-Disrupting Agent

合成路线1 合成路线2

合成路线1

2,5-Piperazinedione (I) is acylated with acetic anhydride at 110 oC in the presence of catalytic NaOAc to afford the diacetyl derivative (II). Claisen condensation of N,N’-diacetyl-2,5-piperazinedione (II) with 5-tert-butylimidazole-4-carbaldehyde (III) by means of Cs2CO3 in DMF at room temperature leads to the monoacetylated (imidazolylmethylene) piperazinedione (IV), which is finally condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at 80 °C. In a related alternative method, diketopiperazine (II) is first condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at room temperature, yielding the benzylidene piperazinedione (VI), which is subsequently condensed with the imidazole-aldehyde (III) by means of Cs2CO3 in hot DMF .

参考文献中间体

【1】 Hayashi, Y., Grodberg, J., Palladino, M. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins dehydrophenylahistins and analogs thereof. EP 1529044, JP 2006511534, WO 2004054498.
【2】 Palladino, M.A., Lloyd, G.K., Hayashi, Y., Nicholson, B. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof. EP 1711487, JP 2007520565, WO 2005077940.
【3】 Palladino, M., Lloyd, G.K., Hayashi, Y. (Nereus Pharmaceuticals, Inc). Analogs of dehydrophenylahistins and their therapeutic use. EP 1926724, US 2007078138, WO 2007035841.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	29800	2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl)	106-57-0	C₄H₆N₂O₂	详情	详情
(II)	19188	1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE	3027-05-2	C₈H₁₀N₂O₄	详情	详情
(III)	69002	5-tert-butylimidazole-4-carbaldehyde;5-(1,1-dimethylethyl)-1H-Imidazole-4-carboxaldehyde;4-(1,1-dimethylethyl)-1H-Imidazole-5-carboxaldehyde	714273-83-3	C₈H₁₂N₂O	详情	详情
(IV)	69003	(Z)-1-acetyl-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione		C₁₄H₁₈N₄O₃	详情	详情
(V)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(VI)	19189	1-acetyl-3-[(Z)-benzylidene]-2,5-piperazinedione		C₁₃H₁₂N₂O₃	详情	详情

合成路线2

The intermediate 5-tert-butylimidazole-4-carbaldehyde (III) is prepared by reaction of ethyl pivaloyl acetate (VII) with sulfuryl chloride in chloroform to provide the 2-chloro derivative (VIII), which is cyclized with formamide (IX) in the presence of a trace of water in a sealed tube at 150 oC, affording ethyl 5-tert-butylimidazole-4-carboxylate (X). Reduction of ester (X) with LiAlH4 in THF gives alcohol (XI), which is finally oxidized to the target carbaldehyde (III) using MnO2 in acetone .

参考文献中间体

【1】 Hayashi, Y., Grodberg, J., Palladino, M. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins dehydrophenylahistins and analogs thereof. EP 1529044, JP 2006511534, WO 2004054498.
【2】 Palladino, M.A., Lloyd, G.K., Hayashi, Y., Nicholson, B. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof. EP 1711487, JP 2007520565, WO 2005077940.
【3】 Palladino, M., Lloyd, G.K., Hayashi, Y. (Nereus Pharmaceuticals, Inc). Analogs of dehydrophenylahistins and their therapeutic use. EP 1926724, US 2007078138, WO 2007035841.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	69002	5-tert-butylimidazole-4-carbaldehyde;5-(1,1-dimethylethyl)-1H-Imidazole-4-carboxaldehyde;4-(1,1-dimethylethyl)-1H-Imidazole-5-carboxaldehyde	714273-83-3	C₈H₁₂N₂O	详情	详情
(VII)	69004	ethyl 4,4-dimethyl-3-oxopentanoate;Ethyl pivaloylacetate	17094-34-7	C₉H₁₆O₃	详情	详情
(VIII)	69005	ethyl 2-chloro-4,4-dimethyl-3-oxopentanoate		C₉H₁₅ClO₃	详情	详情
(IX)	16598	Formamide	75-12-7	CH₃NO	详情	详情
(X)	69006	ethyl 5-(tert-butyl)-1H-imidazole-4-carboxylate		C₁₀H₁₆N₂O₂	详情	详情
(XI)	69007	(5-(tert-butyl)-1H-imidazol-4-yl)methanol		C₈H₁₄N₂O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)