5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one -Drug Synthesis Database

【结构式】

【分子编号】39726

【品名】5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one

【CA登记号】

【分子式】C₁₃H₉N₃O

【分子量】223.23408

【元素组成】C 69.95% H 4.06% N 18.82% O 7.17%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

The known imidazoindenopyrazinone (I) was converted to oxime (II) by treatment with isoamyl nitrite and NaH. Subsequent reduction of oxime (II) by means of zinc and AcOH produced acetamide (III), which was hydrolyzed to amine (IV) upon refluxing in 2 N HCl. After protection of amine (IV) as the N-Boc derivative (V), alkylation with 1-bromo-3-chloropropane (VI) in the presence of NaH gave rise to the spiro derivative (VII). Deprotection of the Boc group of (VII) to give amine (VIII) was effected by treatment with trifluoroacetic acid. Finally, Eschweiler-Clarke reductive alkylation of (VIII) with formaldehyde and formic acid furnished the desired N-methyl derivative.

参考文献中间体

合成目标

【1】 Jimonet, P.; Boireau, A.; Chevé, M.; et al.; Spiro-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives are mixed AMPA and NMDA glycine-site antagonists active in vivo. Bioorg Med Chem Lett 1999, 9, 20, 2921.
【2】 Aloup, J.-C.; Audiau, F.; Barreau, M.; Damour, D.; Genevois-Borella, A.; Jimonet, P.; Mignani, S.; Ribeill, Y. (Aventis Pharma SA); Spiro[heterocycle-imidazo[1,2-a]indeno[1, 2-e]pyrazine]-4'-ones, preparation thereof and drugs containing same. JP 1998508311; US 5777114; WO 9614318 .

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)	39726	5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one		C₁₃H₉N₃O	详情	详情
(II)	42829	4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10(5H)-dione 10-oxime		C₁₃H₈N₄O₂	详情	详情
(III)	42830	N-(4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide		C₁₅H₁₂N₄O₂	详情	详情
(IV)	42831	10-amino-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one		C₁₃H₁₀N₄O	详情	详情
(V)	42832	tert-butyl 4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-ylcarbamate		C₁₈H₁₈N₄O₃	详情	详情
(VI)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(VII)	42833			C₂₁H₂₂N₄O₃	详情	详情
(VIII)	42834			C₁₆H₁₄N₄O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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3

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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

合成路线4

该中间体在本合成路线中的序号：(IV)

The tetracyclic imidazoindenopyrazinone (IV) was obtained by condensation of 2-bromoindanone (I) with 1-methylimidazole-2-carboxamide (II), followed by demethylation of the resulting imidazolium salt (III) in molten imidazole at 160 C (1). Reaction of (IV) with isoamyl nitrite in the presence of NaH produced oxime (V), which was reduced with zinc powder in acetic acid to yield acetamide (VI). Regioselective methylation of (VI) using methyl iodide and NaH gave (VII). Subsequent nitration of (VII) by means of KNO3 and H2SO4 afforded the 8-nitro derivative (VIII), which was reduced to amine (IX) by hydrogenation over Pd/C. Condensation of amine (IX) with methyl isocyanate in DMF produced urea (X). Finally, the acetamido group of (X) was hydrolyzed in refluxing 6 M HCl.

参考文献中间体

合成目标

【1】 Chevé, M.; Jimonet, P.; Bohme, G.A.; et al.; 8-Methylureido-10-amino-10-methyl-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-ones: Highly in vivo potent and selective AMPA receptor antagonists. Bioorg Med Chem 2000, 8, 8, 2211.
【2】 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)	42829	4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10(5H)-dione 10-oxime		C₁₃H₈N₄O₂	详情	详情
(VI)	42830	N-(4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide		C₁₅H₁₂N₄O₂	详情	详情
(VII)	44100	N-(10-methyl-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide		C₁₆H₁₄N₄O₂	详情	详情
(VIII)	44101	N-(10-methyl-8-nitro-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide		C₁₆H₁₃N₅O₄	详情	详情
(IX)	44102	N-(8-amino-10-methyl-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide		C₁₆H₁₅N₅O₂	详情	详情
(X)	44103	N-(10-methyl-8-[[(methylamino)carbonyl]amino]-4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide		C₁₈H₁₈N₆O₃	详情	详情

Extended Information