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【结 构 式】 
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【分子编号】17162 【品名】4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylamine; 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]-1-butanamine 【CA登记号】173838-63-6 |
【 分 子 式 】C12H16N4 【 分 子 量 】216.286 【元素组成】C 66.64% H 7.46% N 25.9% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |
合成路线2
该中间体在本合成路线中的序号：(X)In an alternative synthesis, compound (IV) was protected as the silyl ether (V) and then fluorinated by means of N-fluorosulfonimide and potassium tert-butoxide. The resulting fluorinated derivative (VI) was desilylated by means of tetrabutylammonium fluoride to yield (VII), which was further protected as the 2'-acetate ester (VIII). Treatment of (VIII) with 1,1'-carbonyl diimidazole produced the acyl imidazole (IX). Subsequent condensation of (IX) with amine (X) gave rise to the corresponding 11,12-cyclic carbamate, which was finally deacetylated upon treatment with MeOH.
| 【1】 Bonnefoy, A.; Denis, A.; Novel fluoroketolides: Synthesis and antibacterial activity. Drugs Fut 2001, 26, 10, 975. |
| 【2】 Fromentin, C.; Denis, A.; Piltan, G.; Bretin, F.; Bonnet, A.; Agouridas, C.; Bonnefoy, A.; beta-Keto-ester chemistry and ketolides. Synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3 enol-ether ketolides. Bioorg Med Chem Lett 2000, 10, 17, 2019. |
| 【3】 Spinnewyn, B.; Auguet, M.; Denis, A.; et al.; Synthesis and antibacterial activity of 2-halogeno, 2-methyl, and 2,3 enol-ether ketolides using beta-keto-ester chemistry. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2152. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 33655 | (3R,5R,6R,7R,9R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C30H51NO9 | 详情 | 详情 | |
| (V) | 33656 | (3R,5R,6R,7R,9R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C33H59NO9Si | 详情 | 详情 | |
| (VI) | 33657 | (3S,5R,6R,7R,9R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-3-fluoro-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C33H58FNO9Si | 详情 | 详情 | |
| (VII) | 33658 | (3S,5R,6R,7R,9R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-3-fluoro-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyloxa-11-cyclotetradecene-2,4,10-trione | C30H50FNO9 | 详情 | 详情 | |
| (VIII) | 33659 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3S,5R,6R,7R,9R,13S,14R)-14-ethyl-3-fluoro-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 | C32H52FNO10 | 详情 | 详情 | |
| (IX) | 33660 | (2R,3S,7R,9R,10R,11R,13S)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-13-fluoro-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C36H54FN3O11 | 详情 | 详情 | |
| (X) | 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 |