4-nitro-1H-isoindole-1,3(2H)-dione；3-nitrophthalimide -Drug Synthesis Database

【结构式】

【分子编号】34424

【品名】4-nitro-1H-isoindole-1,3(2H)-dione；3-nitrophthalimide

【CA登记号】603-62-3

【分子式】C₈H₄N₂O₄

【分子量】192.13084

【元素组成】C 50.01% H 2.1% N 14.58% O 33.31%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XXVI)

The oxidative ring opening of 2-oxa-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (XXIII) with NaOH in methanol, followed by a treatment with CrO2Cl2 in CCl4 gives 2-methoxycarbonylmethyl-3-benzyloxymethyl-4-(tetrahydropyranyloxy)-1-cyclopentanone (XXIV), which by reaction with methyl trimethylsilylacetate (XXV) by means of butyllithium and diisopropylamine in THF is converted into 1-(methoxycarbonylmethylidene)-2-methoxycarbonylmethyl-3-benzyloxymethyl-4-(tetrahydropyranyloxy)cyclopentane (XXVI). The hydrogenation of (XXVI) with H2 over Pd/C in ethanol affords 1,2-bis(methoxycarbonylmethyl)-3-benzyloxymethyl-4-(tetrahydropyranyloxy)cyclopentane (XXVII), which is cyclized by means of potassium tert-butoxide in refluxing benzene to 2 (or 4)-methoxycarbonyl-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (XXVIII). Finally, this compound is hydrolyzed and decarboxylated in HMPT - water at 160 C giving the ketone (VIII), already obtained.

参考文献中间体

合成目标

【1】 Hayashi, M.; Konishi, Y.; Arai, Y.; 6,9-Methano-PGI2 analogues. CH 639360; DE 2912409; FR 2422635; GB 2017699; IT 1113341; US 4479966 .
【2】 Kottegoda, S.R.; Serradell, M.N.; Adaikan, P.G.; Castaner, J.; ONO-41483. Drugs Fut 1984, 9, 11, 833.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVIIIa)	34426	tert-butyl (2S)-2,5-diamino-5-oxopentanoate		C₉H₁₈N₂O₃	详情	详情
(XVIIIb)	34427	tert-butyl (2S)-5-amino-2-(4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate		C₁₇H₁₉N₃O₇	详情	详情
(XXIII)	34421	5,6,7-trimethoxy-2-benzofuran-1(3H)-one		C₁₁H₁₂O₅	详情	详情
(XXIV)	34422	3-bromo-5,6,7-trimethoxy-2-benzofuran-1(3H)-one		C₁₁H₁₁BrO₅	详情	详情
(XXV)	34423	1-naphthylmethylphosphonic acid	4730-77-2	C₁₁H₁₁O₃P	详情	详情
(XXVI)	34424	4-nitro-1H-isoindole-1,3(2H)-dione；3-nitrophthalimide	603-62-3	C₈H₄N₂O₄	详情	详情
(XXVII)	34425	ethyl 4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate		C₁₁H₈N₂O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Treatment of 3-nitrophthalimide (I) with ethyl chloroformate and triethylamine produced 3-nitro-N-(ethoxycarbonyl)phthalimide (II), which was condensed with L-glutamine tert-butyl ester hydrochloride (III) to afford the phthaloyl glutamine derivative (IV). Acidic cleavage of the tert-butyl ester of (IV) provided the corresponding carboxylic acid (V). This was cyclized to the required glutarimide (VI) upon treatment with thionyl chloride and then with triethylamine. The nitro group of (VI) was finally reduced to amine by hydrogenation over Pd/C.

参考文献中间体

合成目标

【1】 Muller, G.W.; Huang, S.-Y.; Chen, R.; et al.; Amino-substituted thalidomide analogs: Potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999, 9, 11, 1625.
【2】 Stirling, D.I.; Chen, R.S.-C.; Muller, G.W. (Celgene Corp.); Substd. 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxoisoindolines and method of reducing TNFalpha levels. EP 0925294; EP 0984955; US 5635517; WO 9803502; WO 9854170 .

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)	34424	4-nitro-1H-isoindole-1,3(2H)-dione；3-nitrophthalimide	603-62-3	C₈H₄N₂O₄	详情	详情
(II)	34425	ethyl 4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate		C₁₁H₈N₂O₆	详情	详情
(III)	34426	tert-butyl (2S)-2,5-diamino-5-oxopentanoate		C₉H₁₈N₂O₃	详情	详情
(IV)	34427	tert-butyl (2S)-5-amino-2-(4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate		C₁₇H₁₉N₃O₇	详情	详情
(V)	34428	(2S)-5-amino-2-(4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid		C₁₃H₁₁N₃O₇	详情	详情
(VI)	34429	2-[(3S)-2,6-dioxopiperidinyl]-4-nitro-1H-isoindole-1,3(2H)-dione		C₁₃H₉N₃O₆	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-nitrophthalimide (I) with ethyl chloroformate in the presence of Et3N in DMF produces the N-(ethoxycarbonyl)phthalimide derivative (II), which is condensed with glutamine tert-butyl ester (III) by means of Et3N in refluxing THF to afford the phthaloylglutamine derivative (IV). Hydrolysis of the tert-butyl ester group of compound (IV) with HCl in CH2Cl2 yields the corresponding carboxylic acid (V), which is cyclized by means of SOCl2 in the presence of pyridine and Et3N in CH2Cl2, resulting in the corresponding glutarimide (VI) . Finally, the nitro group of glutarimide (VI) is reduced by catalytic hydrogenation over Pd/C in acetone or with Sn/HCl .
Pure enantiomers of pomalidomide can been prepared using the corresponding enantiomers of glutamine tert-butyl ester (III), as the cyclization of phthaloyl-glutamine (V) takes place without racemization, resulting in the corresponding enantiomeric glutarimides. The nitrophthalimide precursor (VI) can be alternatively obtained by cyclization of N-(benzyloxycarbonyl)glutamine (VII) by means of CDI in refluxing THF to afford the glutarimide derivative (VIII), which is then N-deprotected to 2-aminoglutarimide (IX) by either hydrogenolysis over Pd/C or by treatment with HBr in AcOH. Finally, aminoglutarimide (IX) is condensed with 3-nitrophthalic anhydride (X) using AcOH at reflux .
Cyclization of 3-aminophthalic acid hydrochloride (XI) with 2-aminoglutarimide (IX) using Et3N or imidazole, optionally in the presence of AcOH in acetonitrile .
Condensation of 3-nitrophthalic anhydride (X) with glutamine (XII) in DMF yields N-(3-nitrophthaloyl)glutamine (V), which is reduced with H2 over Pd/C to give the corresponding amine (XIII). Finally, this compound undergoes cyclization by means of CDI .

参考文献中间体

合成目标

【1】 Muller, G.W., Chen, R., Huang, S.-Y. et al. Amino-substituted thalidomide analogs: Potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999, 9(11): 1625-30.
【2】 Stirling, D.I., Chen, R.S.-C., Muller, G.W. (Celgene Corp.). Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and -1-oxoisoindolines and method of reducing TNFalpha levels. EP 0925294, EP 1285916, EP 2070920, EP 2177517, EP 2305663, JP 2008050368, US 5635517, WO 1998003502.
【3】 Muller, G.W., Saindane, M.T., Ge, C., Chen, R. (Celgene Corp.). Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds. EP 1907373, JP 2008544993, US 2007004920, US 7994327, WO 2007005972.
【4】 Shah, J.H., Hunsucker, K.A., Conner, B.P. et al. (Children’s Medical Center Corp.). Synthesis of 3-amino-thalidomide and its enantiomers. CA 2430669, EP 1353672, JP 2004536784, JP 2009108077, US 2004147558, US 7812169, WO 2002064083.

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)	34424	4-nitro-1H-isoindole-1,3(2H)-dione；3-nitrophthalimide	603-62-3	C₈H₄N₂O₄	详情	详情
(II)	34425	ethyl 4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate		C₁₁H₈N₂O₆	详情	详情
(III)	68855	tert-butyl 2,5-diamino-5-oxopentanoate hydrochloride		C₉H₁₈N₂O₃.HCl	详情	详情
(IV)	68856	tert-butyl 5-amino-2-(4-nitro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate		C₁₇H₁₉N₃O₇	详情	详情
(V)	68857	5-amino-2-(4-nitro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid		C₁₃H₁₁N₃O₇	详情	详情
(VI)	68858	2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione		C₁₃H₉N₃O₆	详情	详情
(VII)	68859	5-amino-2-((benzoyloxy)amino)-5-oxopentanoic acid		C₁₂H₁₄N₂O₅	详情	详情
(VIII)	68860	3-((benzoyloxy)amino)piperidine-2,6-dione		C₁₂H₁₂N₂O₄	详情	详情
(IX)	37576	3-amino-2,6-piperidinedione；3-aminopiperidine-2,6-dione；2-amino-Glutarimide；Glutamimide;a-Aminoglutarimide	2353-44-8	C₅H₈N₂O₂	详情	详情
(X)	46407	4-nitro-2-benzofuran-1,3-dione；3-nitrophthalic anhydride	641-70-3	C₈H₃NO₅	详情	详情
(XI)	68861	3-aminophthalic acid hydrochloride;3-amino-1,2-Benzenedicarboxylicacid hydrochloride;3-amino-Phthalic acid hydrochloride	6946-22-1	C₈H₇NO₄.HCl	详情	详情
(XII)	24666	glutamine；2,5-diamino-5-oxopentanoic acid		C₅H₁₀N₂O₃	详情	详情
(XIII)	68862	5-amino-2-(4-amino-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid		C₁₃H₁₃N₃O₅	详情	详情

Extended Information