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【结 构 式】 
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【分子编号】37576 【品名】3-amino-2,6-piperidinedione；3-aminopiperidine-2,6-dione；2-amino-Glutarimide；Glutamimide;a-Aminoglutarimide 【CA登记号】2353-44-8 |
【 分 子 式 】C5H8N2O2 【 分 子 量 】128.1308 【元素组成】C 46.87% H 6.29% N 21.86% O 24.97% |
合成路线1
该中间体在本合成路线中的序号：(IV)The esterification of N2-(benzyloxycarbonyl)-D,L-glutamine (I) with methyl iodide and KHCO3 in DMF gives the corresponding methyl ester (II), which is cyclized to benzyl D,L-2,6-dioxo-3-piperidinecarbamate (III) by heating. The hydrogenolysis of (III) with H2 over Pd/C in methanol yields D,L-2-aminoglutarimide (IV), which is condensed with 2-chloroethyl isocyanate (V) in DMF affording 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)urea (VI). Finally, this compound is nitrosated in the usual way with NaNO2 in formic acid.
| 【1】 Johnston, T.P.; et al.; The synthesis of potential anticancer agents. XXXVI. N-Nitrosoureas. II. Haloalkyl derivatives. J Med Chem 1966, 9, 6, 892-911. |
| 【2】 Woodman, R.J.; Castaner, J.; PCNU. Drugs Fut 1981, 6, 8, 481. |
| 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) | 37578 | N(2)-[(benzyloxy)carbonyl]glutamine | C13H16N2O5 | 详情 | 详情 | |
| (II) | 37579 | methyl 5-amino-2-[[(benzyloxy)carbonyl]amino]-5-oxopentanoate | C14H18N2O5 | 详情 | 详情 | |
| (III) | 37575 | benzyl 2,6-dioxo-3-piperidinylcarbamate | C13H14N2O4 | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 11237 | 1-Chloro-2-isocyanatoethane; 2-Chloroethyl isocyanate | 1943-83-5 | C3H4ClNO | 详情 | 详情 |
| (VI) | 37577 | N-(2-chloroethyl)-N'-(2,6-dioxo-3-piperidinyl)urea | C8H12ClN3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)A novel solid-phase synthesis of thalidomide has been described: The coupling of phthalic anhydride (I) with hydroxymethyl polystyrene resin (II) by means of triethylamine and 4-dimethylaminopyridine (DMAP) in DMF affords the resin-linked acid (III), which is then condensed with alpha-aminoglutarimide (IV) by means of diisopropylcarbodiimide (DIC) and N-hydroxybenzotriazole (HOBt) in DMF to provide amide (V). Finally, thalidomide is obtained by treatment of resin (V) with TFA in refluxing toluene.
| 【1】 Schaefer, K.; Li, P.-K.; Xiao, Z.; Firestine, S.; Solid-phase synthesis of thalidomide and its analogues. J Comb Chem 2002, 4, 2, 149. |
| 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) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (III) | 54083 | 2-(methoxycarbonyl)benzoic acid | n/a | C9H8O4 | 详情 | 详情 |
| (IV) | 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 |
| (V) | 54084 | methyl 2-{[(2,6-dioxo-3-piperidinyl)amino]carbonyl}benzoate | n/a | C14H14N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Cyclization of N-(benzyloxycarbonyl)glutamine (I) by means of CDI in refluxing THF gives 3-(benzyloxycarbonylamino)piperidine-2,6-dione (II), which is deprotected with H2 over Pd/C in ethyl acetate/4N HCl to yield 3-aminopiperidine-2,6-dione hydrochloride (III). Bromination of 2-methyl-3-nitrobenzoic acid methyl ester (IV) with NBS in CCl4 provides 2-(bromomethyl)-3-nitrobenzoic acid methyl ester (V), which is cyclized with the aminopiperidine (III) by means of triethylamine in hot DMF to afford 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (VI). Finally, the nitro group of compound (VI) is reduced with H2 over Pd/C in methanol (1, 2).
| 【1】 Sorbera, L.A.; Castaner, J.; Bayes, M.; CC-5013. Drugs Fut 2003, 28, 5, 425. |
| 【2】 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. |
| 【3】 Stirling, D.I.; Muller, G.W.; Chen, R.S.-C. (Celgene Corp.); Substd. 2-(2,6-dioxopiperidin-3-yl)-phthalimides and -1-oxoisoindolines and method of reducing TNFalpha levels. EP 0925294; US 5635517; WO 9803502 . |
| 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) | 37578 | N(2)-[(benzyloxy)carbonyl]glutamine | C13H16N2O5 | 详情 | 详情 | |
| (II) | 37575 | benzyl 2,6-dioxo-3-piperidinylcarbamate | C13H14N2O4 | 详情 | 详情 | |
| (III) | 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 |
| (IV) | 62310 | Methyl 3-nitro-o-toluate; 2-Methyl-3-nitrobenzoic acid | 59382-59-1 | C9H9NO4 | 详情 | 详情 |
| (V) | 62309 | methyl 2-(bromomethyl)-3-nitrobenzoate | 98475-07-1 | C9H8BrNO4 | 详情 | 详情 |
| (VI) | 62311 | 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-piperidinedione | C13H11N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)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 .
| 【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 |