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【结 构 式】 
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【分子编号】18638 【品名】(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 【CA登记号】 |
【 分 子 式 】C31H53N3O10 【 分 子 量 】627.77604 【元素组成】C 59.31% H 8.51% N 6.69% O 25.49% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Selective hydrolysis of the cladinose moiety of 6-O-methylerythromycin (I) with aqueous HCl gave (II), which was selectively acetylated at 2'-OH to provide acetate (III). Pfitzner-Moffat oxidation with DMSO, EDC, and pyridinum trifluoroacetate yielded 3-oxo compound (IV). Then, reaction with methanesulfonic anhydride in pyridine gave 11-O-mesylate (V), which on treatment with DBU in acetone produced the elimination product (VI). Subsequent condensation with carbonyldiimidazole in the presence of NaH afforded imidazole-carboxylate (VII). Then, reaction with hydrazine in aqueous acetonitrile provided a mixture of epimeric oxazolidinones (VIII) and (IX), which were separated by column chromatography.
| 【1】 Agouridas, C.; Denis, A.; Auger, J.M.; Benedetti, Y.; Bonnefoy, A.; Bretin, F.; Chantot, J.F.; Dussarat, A.; Fromentin, C.; D'Ambrieres, S.G.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.; Tessot, N.; Synthesis and antibacterial activity of ketolides (6-O-methyl-3-oxoerythromycin derivatives): A new class of antibacterials highly potent against macrolide-resistant and -susceptible respiratory pathogens. J Med Chem 1998, 41, 21, 4080. |
| 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) | 18631 | (3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione | C38H69NO13 | 详情 | 详情 | |
| (II) | 18632 | (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione | C30H55NO10 | 详情 | 详情 | |
| (III) | 18633 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C32H57NO11 | 详情 | 详情 | |
| (IV) | 18634 | (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 | |
| (V) | 18635 | (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 | |
| (VI) | 18636 | (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 | |
| (VII) | 18637 | (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 | |
| (VIII) | 18638 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone | C31H53N3O10 | 详情 | 详情 | |
| (IX) | 18639 | (3aS,4R,7R,9R,10R,11R,13R,15S,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone | C31H53N3O10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Wittig reaction of 4-quinolinecarboxaldehyde (X) with dioxolanylmethyl phosphonium salt (XI) using potassium tert-butoxide in THF produced olefin (XII), which was reduced by catalytic hydrogenation to afford (XIII). Hydrolysis of acetal (XIII) with HCl in acetone-H2O gave quinolinylpropanal (XIV). Finally, reductive alkylation of N-aminoisoxazolone (VIII) with aldehyde (XIV) using NaBH3CN/AcOH in MeOH provided the target compound.
| 【1】 Agouridas, C.; Denis, A.; Auger, J.M.; Benedetti, Y.; Bonnefoy, A.; Bretin, F.; Chantot, J.F.; Dussarat, A.; Fromentin, C.; D'Ambrieres, S.G.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.; Tessot, N.; Synthesis and antibacterial activity of ketolides (6-O-methyl-3-oxoerythromycin derivatives): A new class of antibacterials highly potent against macrolide-resistant and -susceptible respiratory pathogens. J Med Chem 1998, 41, 21, 4080. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 18638 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone | C31H53N3O10 | 详情 | 详情 | |
| (X) | 18640 | 4-quinolinecarbaldehyde | 4363-93-3 | C10H7NO | 详情 | 详情 |
| (XI) | 18641 | (1,3-dioxolan-2-ylmethyl)(triphenyl)phosphonium bromide | 52509-14-5 | C22H22BrO2P | 详情 | 详情 |
| (XII) | 18642 | 4-[(E)-2-(1,3-dioxolan-2-yl)ethenyl]quinoline | C14H13NO2 | 详情 | 详情 | |
| (XIII) | 18643 | 4-[2-(1,3-dioxolan-2-yl)ethyl]quinoline | C14H15NO2 | 详情 | 详情 | |
| (XIV) | 18644 | 3-(4-quinolinyl)propanal | C12H11NO | 详情 | 详情 |