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【结 构 式】 
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【药物名称】Telithromycin, RU-66647, HMR-3647, Levviax, Ketek 【化学名称】11-Deoxy-3-des(hexopyranosyloxy)-6-O-methyl-3-oxo-N-[4-[4-(3-pyridyl)imidazol-1-yl]butyl]amino erythromycin A 11-N,12-O-cyclic carbamate 【CA登记号】173838-31-8, 191114-48-4 (RU-66647) 【 分 子 式 】C43H65N5O10 【 分 子 量 】812.025 |
【开发单位】Aventis Pharma (Originator), Fujisawa (Marketer), Sankyo (Marketer) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Ketolides |
合成路线1
| 【1】 Burger MT, Hiebert C，Seid M, et aL. 2006. Synthesis and antibacterial activity of novel C12 ethyl ketolides Bioorganic & Medicinal Chemistry, 14(16):5592～5604 |
| 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) | 66801 | (3S,4R,6S,7S,9S,11S,12S,13R,14S)-6-(((2R,3S,4R,6S)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-12,13-dihydroxy-4-(((4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-3,5,7,9,11,13-pentamethyloxacyclotetradecane-2,10-dione | C38H69NO13 | 详情 | 详情 | |
| (II) | 66802 | (2R,3R,4S)-6-(((3S,4R,6S,7S,9S,11S,12S,13R,14S)-6-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-pentamethyl-2,10-dioxooxacyclotetradecan-4-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate | C52H77NO15 | 详情 | 详情 | |
| (III) | 66803 | (2R,3R,4S)-6-(((3S,4R,6S,7S,9S,11S,12S,13S,14S)-6-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-pentamethyl-12-((methylsulfonyl)oxy)-2,10-dioxooxacyclotetradecan-4-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate | C53H79NO17S | 详情 | 详情 | |
| (IV) | 66805 | (2R,3R,4S)-6-(((3S,4R,6S,7S,9S,13R,14S)-6-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-pentamethyl-2,10-dioxooxacyclotetradec-11-en-4-yl)oxy)-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl benzoate | C52H75NO14 | 详情 | 详情 | |
| (V) | 66806 | (2R,3S,4R,6S)-4-(dimethylamino)-2-(((3S,4R,6S,7S,9S,13R,14S)-14-ethyl-4,13-dihydroxy-7-methoxy-3,5,7,9,11,13-pentamethyl-2,10-dioxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C37H57NO10 | 详情 | 详情 | |
| (VI) | 66807 | (2R,3S,4R,6S)-4-(dimethylamino)-2-(((3S,6S,7S,9S,13R,14S)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-pentamethyl-2,4,10-trioxooxacyclotetradec-11-en-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C37H56NO10 | 详情 | 详情 | |
| (VII) | 66808 | (2S,3R,7S,9S,10S,13S)-10-(((2R,3S,4R,6S)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-9-methoxy-3,5,7,9,11,13-pentamethyl-6,12,14-trioxooxacyclotetradec-4-en-3-yl 1H-imidazole-1-carboxylate | C41H58N3O11 | 详情 | 详情 | |
| (VIII) | 66809 | (2R,3S,4R,6S)-4-(dimethylamino)-2-(((3aR,4S,7S,10S,11S,13S,15S,15aS)-4-ethyl-11-methoxy-3a,5,7,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-(4-(pyridin-3-yl)-1H-imidazol-1-yl)butyl)tetradecahydro-1H-[1]oxacyclotetradecino[4,3-d]oxazol-10-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C50H70N5O11 | 详情 | 详情 |
合成路线2
The selective mesylation of 2'-O-acetyl-3-des(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A (I) with methanesulfonic anhydride in pyridine gives the expected 11-O-methanesulfonyl derivative (II), which is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to yield the 10,11-didehydro derivative (III). The acylation of (III) with carbonyl diimidazole (IV) by means of NaH in THF affords the 12-O-acyl derivative (V), which is finally cyclocondensed with 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) in hot acetonitrile. The intermediate compound 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) is obtained as follows: The condensation of N-(4-bromobutyl)phthalimide (VII) with 4-(3-pyridyl)imidazole (VIII) by means of NaH in DMF gives N-[4-[4-(3-pyridyl)imidazol-1-yl]butyl]phthalimide (IX), which is then treated with hydrazine in refluxing ethanol.
| 【1】 Castañer, J.; Graul, A.; HMR-3647. Drugs Fut 1998, 23, 6, 591. |
| 【2】 Agouridas, C.; Denis, A.; Auger, J.-M.; et al.; Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens. Bioorg Med Chem Lett 1999, 9, 21, 3075. |
| 【3】 Agouridas, C.; Chantot, J.-F.; Denis, A.; Gouin d'Ambrieres, S.; Le Martret, O. (Aventis Pharma SA); Novel erythromycin derivs., method for their preparation and their use as drugs. EP 0680967; FR 2719587; JP 1996053489; JP 1999152296; US 5635485; WO 9529929 . |
| 【4】 Agouridas, C.; Chantot, J.F.; Denis, A.; Gouin d'Ambrieres, S.; Le Martret, O. (Aventis Pharma SA); Novel erythromycin derivs., their process of preparation and their application as medicines. FR 2732684 . |
| 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) | 17157 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C32H55NO11 | 详情 | 详情 | |
| (II) | 17158 | (2S,3R,4S,6R)-4-(dimethylamino)-2-([(3R,5R,6R,7R,9R,11R,12R,13R,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-12-[(methylsulfonyl)oxy]-2,4,10-trioxooxacyclotetradecanyl]oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate | C33H57NO13S | 详情 | 详情 | |
| (III) | 17159 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,13S,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C32H53NO10 | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 17161 | (2R,3S,7R,9R,10R,11R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C36H55N3O11 | 详情 | 详情 | |
| (VI) | 17162 | 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylamine; 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]-1-butanamine | 173838-63-6 | C12H16N4 | 详情 | 详情 |
| (VII) | 17163 | N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione | 5394-18-3 | C12H12BrNO2 | 详情 | 详情 |
| (VIII) | 17164 | 3-(1H-imidazol-4-yl)pyridine | C8H7N3 | 详情 | 详情 | |
| (IX) | 17165 | 2-[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]-1H-isoindole-1,3(2H)-dione | 173838-67-0 | C20H18N4O2 | 详情 | 详情 |