MLN-576, XR-11576, -Drug Synthesis Database

【结构式】

【药物名称】MLN-576, XR-11576

【化学名称】N-[2-(Dimethylamino)-1(R)-methylethyl]-4-methoxybenzo[a]phenazine-11-carboxamide

【CA登记号】

【分子式】C₂₃H₂₄N₄O₂

【分子量】388.47333

【开发单位】Xenova (Originator), Millennium (Licensee)

【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, DNA Topoisomerase I Inhibitors, DNA Topoisomerase II Inhibitors

合成路线1 合成路线2

合成路线1

The oxidation of 5-methoxy-1-tetralone (I) with SeO2 gives 5-methoxy-1,2-naphthoquinone (II), which is cyclized with 2,3-diaminobenzoic acid (II) by means of HCl in refluxing ethanol to yield 4-methoxybenzo[a]phenazine-11-carboxylic acid (IV). Finally, this acid is converted into the target amide by its condensation with N1,N1,2(R)-trimethylethane-1,2-diamine (V) by means of CDI in DMF.

参考文献中间体

【1】 Vicker, N.; Burgess, L.; Chuckowree, I.S.; et al.; Novel angular benzophenazines: Dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents. J Med Chem 2002, 45, 3, 721.
【2】 Vicker, N.; Folkes, A.J.; Wang, S.; Milton, J.; Denny, W.A. (Xenova Group plc); Benzo[a]phenazin-11-carboxamide derivs. and their use as joint inhibitors of topomerase I and II. WO 0146157 .

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)	18568	5-methoxy-3,4-dihydro-1(2H)-naphthalenone	33892-75-0	C₁₁H₁₂O₂	详情	详情
(II)	47913	5-methoxy-1,2-naphthalenedione		C₁₁H₈O₃	详情	详情
(III)	47914	2,3-diaminobenzoic acid		C₇H₈N₂O₂	详情	详情
(IV)	47915	4-methoxybenzo[a]phenazine-11-carboxylic acid		C₁₈H₁₂N₂O₃	详情	详情
(V)	47916	(2R)-N(1),N(1)-dimethyl-1,2-propanediamine; N-[(2R)-2-aminopropyl]-N,N-dimethylamine		C₅H₁₄N₂	详情	详情

合成路线2

The intermediate chiral diamine (IV) (see Scheme no. 28794701a, intermediate (V)) is prepared as follows: Reduction of N-Boc-D-alanine methyl ester (I) with DIBAL affords N-Boc-alaninal (II), which is reductively aminated with dimethylamine in the presence of NaBH3CN to afford the Boc-protected diamine (III). The N-Boc group of (III) is finally removed under acidic conditions to provide the target (R)-diamine (IV).

参考文献中间体

【1】 Vicker, N.; Burgess, L.; Chuckowree, I.S.; et al.; Novel angular benzophenazines: Dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents. J Med Chem 2002, 45, 3, 721.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	47916	(2R)-N(1),N(1)-dimethyl-1,2-propanediamine; N-[(2R)-2-aminopropyl]-N,N-dimethylamine	C₅H₁₄N₂	详情	详情
(VI)	55655	methyl (2R)-2-[(tert-butoxycarbonyl)amino]propanoate	C₉H₁₇NO₄	详情	详情
(VII)	55656	tert-butyl (1R)-1-methyl-2-oxoethylcarbamate	C₈H₁₅NO₃	详情	详情
(VIII)	55657	tert-butyl (1R)-2-(dimethylamino)-1-methylethylcarbamate	C₁₀H₂₂N₂O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)