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【结 构 式】 
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【分子编号】24948 【品名】L-glutamine 【CA登记号】56-85-9 |
【 分 子 式 】C5H10N2O3 【 分 子 量 】146.14608 【元素组成】C 41.09% H 6.9% N 19.17% O 32.84% |
合成路线1
该中间体在本合成路线中的序号：(V)Antineopleston A10 (A10) can be obtained by two different ways: 1) A10 has been synthesized in two steps: Condensation of phenylacetic acid (I) with L-glutamine (V) to give phenylacetyl-L-glutamine (VI), followed by intramolecular cyclization of the latter. In the first step (I) is activated by reacting with various reagents such as HOSu (N-hydroxysuccinimide) (II) in the presence of DCC, DCC (N,N-dicyclohexylcarbodiimide) or 2-mercaptothiazoline (III) in the presence of DCC to afford the intermediates (IVa), (IVb) and (IVc), respectively. Without isolation, the intermediate (IVa), (IVb) or (IVc) is treated with a solution of L-glutamine in CH3CN:H2O (2:1) containing NaHCO3 to give (VI) in 60, 87 and 82% yields, respectively. In the second step (VI) is converted to the activated intermediate (IXa) or (IXb) by treatment with CDI (1,1'-carbonydiimidazole) (VII) or HOSu (VIII) in the presence of DCC. Finally, intramolecular cyclization of (IXa) or (IXb) is effected by treating the latter at 80 C to yield A10 in 85 or 82% yield, respectively. 2) Reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords phenylacetyl-L-glutamine (VI), which is heated at 160 C to give A10.
| 【1】 Verhoef, J.; Schmitz, F.-J.; Fluit, A.C.; Milatovic, D.; 13th Intl Cong Chemother (Aug. 28-Sept. 2, Vienna) 1983, 50, 2, PS 12.4-11-4. |
| 【2】 Burzynski, S.R. (Burzynski Research Institute); Purified antineoplaston factions and methods of treating neoplastic disease. EP 0069232; JP 5032548; JP 5058886; JP 58010521; US 4470970 . |
| 【3】 Burzynski, S.R.; Hai, T.T.; Antineoplaston A10. Drugs Fut 1985, 10, 2, 103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (IVa) | 24947 | 1-[(2-phenylacetyl)oxy]-2,5-pyrrolidinedione | C12H11NO4 | 详情 | 详情 | |
| (IVb) | 28896 | phenylacetic anhydride | C16H14O3 | 详情 | 详情 | |
| (IVc) | 28897 | 2-phenyl-1-(2-thioxo-1,3-thiazolidin-3-yl)-1-ethanone | C11H11NOS2 | 详情 | 详情 | |
| (IXa) | 28899 | (3S)-4-(1H-imidazol-1-yl)-4-oxo-3-[(2-phenylacetyl)amino]butanamide | C15H16N4O3 | 详情 | 详情 | |
| (IXb) | 28900 | (3S)-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-4-oxo-3-[(2-phenylacetyl)amino]butanamide | C16H17N3O6 | 详情 | 详情 | |
| (I) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (II) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (III) | 28895 | 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide | 96-53-7 | C3H5NS2 | 详情 | 详情 |
| (V) | 24948 | L-glutamine | 56-85-9 | C5H10N2O3 | 详情 | 详情 |
| (VI) | 28898 | (2S)-4-amino-4-oxo-2-[(2-phenylacetyl)amino]butyric acid | C12H14N2O4 | 详情 | 详情 | |
| (VII) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (VIII) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new scaleable two-step synthesis of thalidomide was reported: The reaction of L-glutamine (I) with N-(ethoxycarbonyl)phthalimide (II) gives the N-phthaloyl-L-glutamine (III), which is finally cyclized by means of carbonyldimidazole (CDI) and dimethylaminopyridine.
| 【1】 Muller, G.W.; et al.; A two step synthesis of thalidomide. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst ORGN 079. |
| 【2】 Muller, G.W.; et al.; A concise two-step synthesis of thalidomide. Org Process Res Dev 1999, 3, 2, 139. |
| 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) | 24948 | L-glutamine | 56-85-9 | C5H10N2O3 | 详情 | 详情 |
| (II) | 10283 | ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide | 22509-74-6 | C11H9NO4 | 详情 | 详情 |
| (III) | 32017 | (2S)-5-amino-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid | C13H12N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Antineoplaston AS2-5 (AS2-5) can be obtained in the following way (1,2): N-Phenylacetyl-L-glutamine sodium is synthesized in two steps. In the first step, phenylacetic acid (I) is treated with N-hydroxysuccinimide (B) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (A) in acetonitrile to give intermediate (Ia). In the second step, (Ia) is reacted without purification with L-glutamine (II) in the presence of NaHCO3 in 1:1 acetonitrile-water mixture to afford N-phenylacetyl-L-glutamine (III) in 87% yield. Compound (III) is then converted to sodium salt in aqueous solution by treatment with aqueous sodium hydroxide solution (pH 7). In a large scale preparation reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords N-phenyiacetyl L-glutamine sodium.
| 【1】 Burzynski, S.R. (Burzynski Research Institute); Purified antineoplaston fractions and methods of treating neoplastic disease. US 4558057 . |
| 【2】 Berman, E.M.; Gregor, V.E.; Showalter, H.H.D. (Pfizer Inc.); Benzoselenino[4,3,2-cd]indazole compound, compositions comprising the compounds and processes for producing the compounds. AU 8544154; EP 0170412; ES 8704956 . |
| 【3】 Khalid, M.; Burzynski, S.R.; Antineoplaston AS2-5. Drugs Fut 1986, 11, 5, 364. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (Ia) | 24927 | tert-butyl (2R,3aR,7aR,10aR)-8-(dimethoxymethyl)-5-(5-hexenyl)-10-oxo-2-vinyl-2,3,5,6,7,7a,10,10a-octahydropyrrolo[2,3-i]isoquinoline-1(4H)-carboxylate | C27H42N2O5 | 详情 | 详情 | |
| (A) | 24945 | N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide | 25952-53-8 | C8H17N3 | 详情 | 详情 |
| (I) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (II) | 24948 | L-glutamine | 56-85-9 | C5H10N2O3 | 详情 | 详情 |
| (III) | 24949 | (2S)-5-amino-5-oxo-2-[(2-phenylacetyl)amino]pentanoic acid | C13H16N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)4-Nitrocinnamic acid (I) was activated as the succinimidyl ester (II) upon treatment with N-hydroxysuccinimide (NHS) and dicyclohexylcarbodiimide (DCC). Subsequent coupling of (II) with L-glutamine (III) afforded the N-acyl glutamine (IV). A second reaction of (IV) with NHS and DCC produced the active ester (V). Finally, thermal cyclization of (V), with concomitant racemization, led to the desired 2,6-piperidinedione.
| 【1】 Hendry, L.B.; Design of drugs involving receptor-ligand-DNA interactions. WO 9514791 . |
| 【2】 Hendry, L.B.; Computer-based design and screening of molecules using DNA interactions. US 5888741 . |
| 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) | 34546 | (E)-3-(4-nitrophenyl)-2-propenoic acid | 619-89-6 | C9H7NO4 | 详情 | 详情 |
| (II) | 34547 | 1-[[(E)-3-(4-nitrophenyl)-2-propenoyl]oxy]-2,5-pyrrolidinedione | C13H10N2O6 | 详情 | 详情 | |
| (III) | 24948 | L-glutamine | 56-85-9 | C5H10N2O3 | 详情 | 详情 |
| (IV) | 34548 | (2S)-5-amino-2-[[(E)-3-(4-nitrophenyl)-2-propenoyl]amino]-5-oxopentanoic acid | C14H15N3O6 | 详情 | 详情 | |
| (V) | 34549 | (E)-N-((1S)-4-amino-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-4-oxobutyl)-3-(4-nitrophenyl)-2-propenamide | C18H18N4O8 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The title compound was prepared by two related procedures. The acylation of L-glutamine (I) with 10-undecenoyl chloride (II) under Schotten-Baumann conditions afforded N-undecenoylglutamine (III). This was then cyclized to the title glutarimide derivative by treatment with dicyclohexylcarbodiimide and N-hydroxysuccinimide.
| 【1】 Fox, D.J.; Grainger, D.J.; Reckless, J.; Warren, S.G.; Design, synthesis, and preliminary pharmacological evaluation of N-acyl-3-aminoglutarimides as broad-spectrum chemokine inhibitors in vitro and anti-inflammatory agents in vivo. J Med Chem 2002, 45, 2, 360. |
| 【2】 Grainger, D.J.; Tatalick, L.M. (NeoRx Corp.); Cpds. and methods to inhibit or augment an inflammatory response. WO 0042071 . |