5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride -Drug Synthesis Database

【结构式】

【分子编号】15864

【品名】5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride

【CA登记号】3027-38-1

【分子式】C₁₂H₅NO₅

【分子量】243.17544

【元素组成】C 59.27% H 2.07% N 5.76% O 32.9%

与该中间体有关的原料药合成路线共 6 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5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(I)

This compound can be obtained by two related ways: 1) The reduction of 3-nitronaphthalene-1,8-dicarboxylic acid anhydride (I) with H2 over Pd/C in DMF gives the corresponding 3-amino-anhydride (II), which is then treated with N,N-dimethylethylenediamine in refluxing toluene or ethanol. (2,3) 2) The reaction of anhydride (I) with N,N-dimethylethylenediamine as before gives 2-[2-(dimethylamino)ethyl]-5-nitro-1H-benz[d,e]isoquinoline-1,3 (2H)-dione (III), which is reduced with H2 or HCOONH4 (4) over Pd/C , or with Sn-HCl at 90-100 C. (1)

参考文献中间体

合成目标

【1】 Brana, M.F.; Martinez Sanz, A.; Perez Alvarez-Ossorio, R.; Martinez Roldan, C.; Rodan Fernandez de Gamboa, C. (Made Labs.); Naphthalimides, process for their preparation and pharmaceutical compositions containing them. DE 2823987 .
【2】 Nishimura, N.; Askew, B.; Patel, V.F.; Elbaum, D.; Habgood, G.; Kim, J.L.; Handley, M.; Booker, S.; Germain, J.; Kim, T.-S.; Yuan, C.C. (Amgen Inc.); Substd. benzylamine derivs. and methods of use. US 2003134836; WO 0407457 .
【3】 Castaner, J.; Castaner, R.M.; Eastland, G.; Amonafide. Drugs Fut 1990, 15, 9, 879.
【4】 Zee-Cheng, R.K.Y.; Cheng, C.C.; N-(Aminoalkyl)imide antineoplastic agents. Synthesis and biological activity. J Med Chem 1985, 28, 9, 1216-22.
【5】 Fernández Braña, M.; Martínez Sanz, A.; Castellano, J.M.; Martínez Roldan, C.; Roldan Fernández de Gamboa, C.; Synthesis and cytostatic activity of benz(de)isoquinolin-1,3-diones. Structure-activity relationships. Eur J Med Chem - Chim Ther 1981, 16, 3, 207-212.

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)	15864	5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride	3027-38-1	C₁₂H₅NO₅	详情	详情
(II)	31171	5-amino-1H,3H-benzo[de]isochromene-1,3-dione		C₁₂H₇NO₃	详情	详情
(III)	31172	2-[2-(dimethylamino)ethyl]-5-nitro-1H-benzo[de]isoquinoline-1,3(2H)-dione		C₁₆H₁₅N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The condensation of tert-butoxycarbonyl-D-alanine (I) with ethylenediamine (II) gives the corresponding protected diamide (III), which is deprotected in acidic medium to the diamide (IV). The reduction of (IV) with diborane in THF yields the (R,R)-4,7-diazadecane-2,9-diamine (V), which is finally condensed with 3-nitronaphthalene-1,8-dicarboxylic acid anhydride (VI) in refluxing ethanol and salified with methanesulfonic acid.

参考文献中间体

合成目标

【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Bisnafide Mesylate. Drugs Fut 1996, 21, 3, 239.
【2】 Sun, J.-H. (DuPont Pharmaceuticals Co.); Bis-naphthalimides containing amino-acid derived linkers as anticancer agents. EP 0506008; EP 0577753; JP 1994506229; US 5206249; WO 9217453 .

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)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(II)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情
(III)	15861	tert-butyl N-[(1R,8R)-1,8,12,12-tetramethyl-2,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-yl]carbamate		C₁₈H₃₄N₄O₆	详情	详情
(IV)	15862	(2R)-2-amino-N-(2-[[(2R)-2-aminopropanoyl]amino]ethyl)propanamide		C₈H₁₈N₄O₂	详情	详情
(V)	15863	(2R)-N(1)-(2-[[(2R)-2-aminopropyl]amino]ethyl)-1,2-propanediamine; N-[(2R)-2-aminopropyl]-N-(2-[[(2R)-2-aminopropyl]amino]ethyl)amine		C₈H₂₂N₄	详情	详情
(VI)	15864	5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride	3027-38-1	C₁₂H₅NO₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Treatment of 3-nitro-1,8-naphthalic anhydride (I) with mercuric oxide and aqueous sodium acetate, and then with refluxing concentrated HCl provided a mixture of decarboxylation products (II) and (III). Condensation of this mixture with L-methionine methyl ester (IV) in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, followed by chromatographic separation of isomers, yielded the desired 6-nitronaphthalenecarboxamide (V). Further reduction of the nitro group with SnCl2 in ethanol gave amine (VI), which was reductively condensed with S-triphenylmethyl-N-Boc-cysteinal (VII) in the presence of sodium cyanoborohydride, acetic acid, and molecular sieves to afford (VIII). Then, hydrolysis of methyl ester with lithium hydroxide in THF-water gave acid (IX), and finally, deprotection of trityl and tert-butoxycarbonyl groups with an excess of trifluoroacetic acid in the presence of ethanedithiol provided the title compound as the trifluoroacetate salt.

参考文献中间体

合成目标

【1】 Ito, Y.; Kato, H.; Yasuda, S.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Benzamide deriv.. EP 0640601; US 5395832; US 5500422; WO 9214705 .
【2】 Baudoin, B.; Burns, C.; Commercon, A.; Guitton, J.-D. (Aventis Pharma SA); Novel farnesyl transferase inhibitors, their preparation and pharmaceutical compsns. containing same. JP 1998501259; WO 9534535 .

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)	15864	5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride	3027-38-1	C₁₂H₅NO₅	详情	详情
(II)	17948	6-nitro-1-naphthoic acid		C₁₁H₇NO₄	详情	详情
(III)	17949	3-nitro-1-naphthoic acid	4507-84-0	C₁₁H₇NO₄	详情	详情
(IV)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(V)	17951	methyl (2S)-4-(methylsulfanyl)-2-[(6-nitro-1-naphthoyl)amino]butanoate		C₁₇H₁₈N₂O₅S	详情	详情
(VI)	17952	methyl (2S)-2-[(6-amino-1-naphthoyl)amino]-4-(methylsulfanyl)butanoate		C₁₇H₂₀N₂O₃S	详情	详情
(VII)	17953	tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate		C₂₇H₂₉NO₃S	详情	详情
(VIII)	17954	methyl (2S)-2-[(6-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino]-1-naphthoyl)amino]-4-(methylsulfanyl)butanoate		C₄₄H₄₉N₃O₅S₂	详情	详情
(IX)	17955	(2S)-2-[(6-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino]-1-naphthoyl)amino]-4-(methylsulfanyl)butyric acid		C₄₃H₄₇N₃O₅S₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

The reaction of 3-nitro-1,8-naphthalic anhydride (I) with diethylenetriamine (II) in cool ethanol gives the cyclic monoamide (III). The reaction of the 3-nitro-1,8-naphthalic anhydride (I) with 3-aminobenzoic acid (IV) in hot DMSO/pyridine gives the corresponding cyclic naphthalamide (V). Finally, the benzoic acid (V) is condensed with the amine group of (III) by means of CDI in DMSO to afford the target bis naphthalamide.

参考文献中间体

合成目标

【1】 Suzuki, K.; Yamada, Y.; Asao, T.; Noguchi, K.; Wakida, M. (Taiho Pharmaceutical Co., Ltd.); Naphthalimidobenzamide derivs.. EP 1020446; US 6300331; WO 0001672 .

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)	15864	5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride	3027-38-1	C₁₂H₅NO₅	详情	详情
(II)	55379	2,2'-Diaminodiethylamine; 2,2'-Iminodiethylamine; Bis(beta-Aminoethyl)amine; Diethylentriamine; N-(2-Aminoethyl)-1,2-ethanediamine	111-40-0	C₄H₁₃N₃	详情	详情
(III)	55424	2-{2-[(2-aminoethyl)amino]ethyl}-5-nitro-1H-benzo[de]isoquinoline-1,3(2H)-dione		C₁₆H₁₆N₄O₄	详情	详情
(IV)	26638	3-Aminobenzoic acid	99-05-8	C₇H₇NO₂	详情	详情
(V)	55382	3-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzoic acid		C₁₉H₁₀N₂O₆	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

2,6-Dichloro-3-nitrobenzoic acid (I) was condensed with aniline (II) to produce the anilinobenzoic acid (III), which was subsequently cyclized to the acridinone (IV) upon treatment with POCl3. Displacement of the chloride group of (IV) with 1,4-bis(3-aminopropyl)piperazine (V) in DMF afforded adduct (VI). The nitro group of (VI) was reduced by catalytic hydrogenation in the presence of Raney-Ni and formic acid, and the intermediate formamide was further cyclized under acidic conditions to the imidazoacridinone (VII). Finally, conversion of the primary amino group of (VII) to the target imide was achieved by heating with 3-nitro-1,8-naphthalenedicarboxylic anhydride (VIII) in DMF.

参考文献中间体

合成目标

【1】 Cholody, W.M.; Michejda, C.J.; Kosakowska-Cholody, T. (US Department of Health & Human Services); 1,8-Naphthalimide imidazo[4,5,1-de]acridones with anti-tumor activity. WO 0166545 .

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)	52274	2,5-Dichloro-3-nitrobenzoic acid	88-86-8	C₇H₃Cl₂NO₄	详情	详情
(II)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(III)	52275	6-chloro-3-nitro-2-(phenylamino)benzoic acid		C₁₃H₉ClN₂O₄	详情	详情
(IV)	52276	1-chloro-4-nitro-9(10H)-acridinone		C₁₃H₇ClN₂O₃	详情	详情
(V)	52277	1,4-Bis(3-aminopropyl)piperazine; N,N'-Bis(3-Aminopropyl)piperazine; Bis aminopropyl piperazine; 1,4-Di(3-aminopropyl)piperazine	7209-38-3	C₁₀H₂₄N₄	详情	详情
(VI)	52278	1-({3-[4-(3-aminopropyl)-1-piperazinyl]propyl}amino)-4-nitro-9(10H)-acridinone		C₂₃H₃₀N₆O₃	详情	详情
(VII)	52279	5-({3-[4-(3-aminopropyl)-1-piperazinyl]propyl}amino)-6H-imidazo[4,5,1-de]acridin-6-one		C₂₄H₃₀N₆O	详情	详情
(VIII)	15864	5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride	3027-38-1	C₁₂H₅NO₅	详情	详情

合成路线6

该中间体在本合成路线中的序号：(II)

The condensation of 3-aminobenzoic acid (I) with 3-nitro-1,8-naphthalic anhydride (II) in hot DMSO/pyridine gives the corresponding cyclic naphthalmide (III), which is condensed with diethylenetriamine (IV) by means of CDI in DMF to yield the benzamide (V). The reaction of (V) with CDI in DMF affords the imidazolylcarbonyl derivative (VI), which is condensed with 1-methylpiperazine (VII) in THF to provide the piperazinocarbonyl compound (VIII). Finally, the amino group of (VIII) is condensed with 3-nitro-1,8-naphthalic anhydride (II) in DMSO/pyridine to give the target bis-cyclic imide.

参考文献中间体

合成目标

【1】 Suzuki, K.; Yamada, Y.; Asao, T.; Noguchi, K.; Wakida, M. (Taiho Pharmaceutical Co., Ltd.); Naphthalimidobenzamide derivs.. EP 1020446; US 6300331; WO 0001672 .

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)	26638	3-Aminobenzoic acid	99-05-8	C₇H₇NO₂	详情	详情
(II)	15864	5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride	3027-38-1	C₁₂H₅NO₅	详情	详情
(III)	55382	3-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzoic acid		C₁₉H₁₀N₂O₆	详情	详情
(IV)	55379	2,2'-Diaminodiethylamine; 2,2'-Iminodiethylamine; Bis(beta-Aminoethyl)amine; Diethylentriamine; N-(2-Aminoethyl)-1,2-ethanediamine	111-40-0	C₄H₁₃N₃	详情	详情
(V)	55383	N-{2-[(2-aminoethyl)amino]ethyl}-3-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzamide		C₂₃H₂₁N₅O₅	详情	详情
(VI)	55384	N-{2-[(2-aminoethyl)amino]ethyl}-3-(1H-imidazol-1-ylcarbonyl)-5-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzamide		C₂₇H₂₃N₇O₆	详情	详情
(VII)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(VIII)	55385	N-{2-[(2-aminoethyl)amino]ethyl}-3-[(4-methyl-1-piperazinyl)carbonyl]-5-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzamide		C₂₉H₃₁N₇O₆	详情	详情

Extended Information