-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(+)-8-(3-Methylureido)-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-10-acetic acid

【CA登记号】173156-08-6, 173155-70-9 (monohydrochloride), 173155-69-6 (undefined isomer)

【分子式】C₁₇H₁₅N₅O₄

【分子量】353.3402

【开发单位】Aventis Pharma (Originator)

【药理作用】Antiepileptic Drugs, NEUROLOGIC DRUGS, AMPA Antagonists

合成路线1 合成路线2

合成路线1

The condensation of 2-bromo-1-indanone (I) with 1-methylimidazole-2-carboxamide (II) in hot DMF produced the tetracyclic ammonium salt (III), which was further demethylated to (IV) by means of imidazole at 160 C. Regioselective nitration of (IV) employing KNO3 in H2SO4 produced nitro derivative (V), which was reduced to amine (VI) by catalytic hydrogenation over Pd/C. Amine (VI) was converted to urea (VII) by treatment with methyl isocyanate. Subsequent base-catalyzed condensation of (VII) with glyoxylic acid monohydrate (VIII) produced hydroxyacid (IX). This was dehydrated with ZnCl2 and acetic anhydride to give unsaturated acid (X), which was finally hydrogenated over Pd/C to furnish the title compound.

参考文献中间体

【1】 Genevois-Borella, A.; Aloup, J.-C.; Audiau, F.; Barreau, M.; Mignani, S.; Ribeill, Y.; Damour, D.; Jimonet, P. (Aventis Pharma SA); Imidazo (1,2-a)-indeno (1,2-e) pyrazin-4-one derivs. and pharmaceutical compsns. containing same. US 5807859; WO 9526350 .

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)	39723	2-bromo-1-indanone	1775-27-5	C₉H₇BrO	详情	详情
(II)	39724	1-methyl-1H-imidazole-2-carboxamide		C₅H₇N₃O	详情	详情
(III)	39725	3-methyl-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-3-ium bromide		C₁₄H₁₂BrN₃O	详情	详情
(IV)	39726	5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one		C₁₃H₉N₃O	详情	详情
(V)	39727	8-nitro-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one		C₁₃H₈N₄O₃	详情	详情
(VI)	39728	8-amino-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one		C₁₃H₁₀N₄O	详情	详情
(VII)	39729	N-methyl-N'-(4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl)urea		C₁₅H₁₃N₅O₂	详情	详情
(VIII)	39730	2,2-dihydroxyacetic acid		C₂H₄O₄	详情	详情
(IX)	39731	2-hydroxy-2-(8-[[(methylamino)carbonyl]amino]-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetic acid		C₁₇H₁₅N₅O₅	详情	详情
(X)	39732	2-(8-[[(methylamino)carbonyl]amino]-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-ylidene)acetic acid		C₁₇H₁₃N₅O₄	详情	详情

合成路线2

In a related procedure, tetracyclic compound (IV) was first condensed with glyoxylic acid (VIII) giving hydroxyacid (XI), which was dehydrated to (XII) with ZnCl2 and Ac2O. Subsequent nitration of (XII) with KNO3 and H2SO4 afforded nitro derivative (XIII). Reduction of (XIII) with simultaneous esterification using iron and HCl in MeOH gave rise to amino ester (XIV). Urea (XV) was then obtained by condensation of (XIV) with methyl isocyanate. Finally, saponification of the ester group provided the title carboxylic acid.

参考文献中间体

【1】 Boireau, A.; Bohme, G.A.; Mignani, S.; et al.; 8-Methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines: Highly potent in vivo AMPA antagonists. Bioorg Med Chem Lett 2000, 10, 6, 591.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	39726	5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one	C₁₃H₉N₃O	详情	详情
(VIII)	39730	2,2-dihydroxyacetic acid	C₂H₄O₄	详情	详情
(XI)	39733	2-hydroxy-2-(4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetic acid	C₁₅H₁₁N₃O₄	详情	详情
(XII)	39734	2-(4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-ylidene)acetic acid	C₁₅H₉N₃O₃	详情	详情
(XIII)	39735	2-(8-nitro-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-ylidene)acetic acid	C₁₅H₈N₄O₅	详情	详情
(XIV)	39736	methyl 2-(8-amino-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetate	C₁₆H₁₄N₄O₃	详情	详情
(XV)	39737	methyl 2-(8-[[(methylamino)carbonyl]amino]-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetate	C₁₈H₁₇N₅O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)