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【结 构 式】 
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【药物名称】 【化学名称】11-Deoxy-13-des(ethyl)-3-des(hexopyranosyloxy)-13-methyl-6-O-methyl-3-oxo-11-[4-(4-quinolinyl)butylamino]erythromycin A 11-N,12-O-cyclic carbamate 【CA登记号】229319-05-5 【 分 子 式 】C43H63N3O10 【 分 子 量 】781.99566 |
【开发单位】Kosan (Originator), R.W. Johnson (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Ketolides |
合成路线1
Treatment of erythromycin derivative (I) with hydroxylamine in isopropanol in the presence of HOAc affords oxime (II), which is then converted into the isopropoxycyclohexyl oxime form (IV) by reaction with 1,1-diisopropoxycyclohexane (III) and p-toluensulfonate (PPTS) in CH2Cl2. Regioselective protection of (IV) by means of N-(trimethylsilyl)-imidazole (Me3Si-Im) and chlorotrimethylsilane (TMSCl) in CH2Cl2 yields derivative (V), which is then converted into derivative (VI) by first methylation with methyl bromide and KOtBu in THF/methyl sulfoxide followed by deprotection with HOAc in acetonitrile. Oxime (VI) is then treated with sodium hydrosulfite (Na2S2O4) and formic acid in EtOH/H2O to provide derivative (VII).
| 【1】 Chu, D.; Grant, E.; Hlasta, D.; Henninger, T.; Khosla, C. (Kosan Biosciences, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0062783 . |
| 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) | 45907 | (3R,4S,5R,6R,7R,9R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-7,12,13-trihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione | C36H65NO13 | 详情 | 详情 | |
| (II) | 45908 | (3R,4S,5R,6R,7R,9R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-7,12,13-trihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-oxime | C36H66N2O13 | 详情 | 详情 | |
| (III) | 45909 | 1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane | 1132-95-2 | C12H24O2 | 详情 | 详情 |
| (IV) | 45910 | (3R,4S,5R,6R,7R,9R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-7,12,13-trihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C45H82N2O14 | 详情 | 详情 | |
| (V) | 45911 | (3R,4S,5R,6R,7R,9R,12R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-7,12,13-trihydroxy-4-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C51H98N2O14Si2 | 详情 | 详情 | |
| (VI) | 45912 | (3R,4S,5R,6R,7R,9R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-oxime | C37H68N2O13 | 详情 | 详情 | |
| (VII) | 45913 | (3R,4S,5R,6R,7R,9R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione | C37H67NO13 | 详情 | 详情 |
合成路线2
Acidolysis of (VII) with HCl furnishes des(hexopyranosyloxy) derivative (VIII), which is then acetylated with acetic anhydride in ethyl acetate to give protected derivative (IX). Compound (IX) is then oxidized by treatment with 3-ethylcarbodiimide (EDCI) and pyridinium trifluoroacetate in DMSO/CH2Cl2 to afford ketone (X). Mesylation of (X) with methanesulfonyl chloride (MsCl) in pyridine yields mesylated derivative (XI), which is then converted into the 10,11-anhydro form (XII) by reaction with 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) in acetone. Activation of compound (XII) by means of NaH and carbonyl diimidazole (CDI) in THF/DMF provides derivative (XIII), which is coupled with amine (XIV). Finally, treatment with refluxing MeOH furnishes the desired compound.
| 【1】 Chu, D.; Grant, E.; Hlasta, D.; Henninger, T.; Khosla, C. (Kosan Biosciences, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0062783 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIII) | 45919 | (2R,3S,7R,9R,10R,11R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-9-methoxy-2,3,5,7,9,11,13-heptamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C35H53N3O11 | 详情 | 详情 | |
| (VII) | 45913 | (3R,4S,5R,6R,7R,9R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione | C37H67NO13 | 详情 | 详情 | |
| (VIII) | 45914 | (3R,4S,5S,6R,7R,9R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione | C29H53NO10 | 详情 | 详情 | |
| (IX) | 45915 | (2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-2-[[(3R,4S,5S,6R,7R,9R,12R,13S,14R)-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,10-dioxooxacyclotetradecanyl]oxy]tetrahydro-2H-pyran-3-yl acetate | C31H55NO11 | 详情 | 详情 | |
| (X) | 45916 | (2S,3R,4S,6R)-2-[[(3R,5R,6R,7R,9R,12R,13S,14R)-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C31H53NO11 | 详情 | 详情 | |
| (XI) | 45917 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[((3R,5R,6R,7R,9R,12R,13R,14R)-13-hydroxy-7-methoxy-3,5,7,9,11,13,14-heptamethyl-12-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2,4,10-trioxooxacyclotetradecanyl)oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C34H59NO11S | 详情 | 详情 | |
| (XII) | 45918 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,13S,14R)-13-hydroxy-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C31H51NO10 | 详情 | 详情 | |
| (XIV) | 45920 | 4-(4-quinolinyl)butylamine; 4-(4-quinolinyl)-1-butanamine | C13H16N2 | 详情 | 详情 |