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【结 构 式】 
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【药物名称】A-184656 【化学名称】6-Deoxy-3-des(cladinosyloxy)-3-oxo-6-[3-(3-quinolinyl)-2(E)-propenyloxy]erythromycin A 【CA登记号】205110-20-9 【 分 子 式 】C41H60N2O10 【 分 子 量 】740.94275 |
【开发单位】Abbott (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Macrolides |
合成路线1
Alkylation of silylated erythromycin oxime (I) with allyl bromide in the presence of t-BuOK provided allyl ether (II). After acid hydrolysis of the cyclo hexylidene ketal of (II), the oxime group was removed by treatment with NaHSO3 and formic acid to afford ketone (IV). Subsequent cleavage of the 3-O-cladinose unit of (IV) by hydrolysis with HCl furnished ketolide (V). The 2'-hydroxyl group of (V) was then protected by benzoylation with benzoic anhydride yielding (VI).
| 【1】 Flamm, R.K.; Raney, P.M.; Nilius, A.M.; Bui, M.; Or, Y.S.; Wang, S.; Plattner, J.J.; Ma, Z.; Clark, R.; Chu, D.T.W.; Synthesis and antibacterial activity of 6-O-substituted ketolides. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-126. |
| 【2】 Or, Y.S.; Ma, Z.; Clark, R.F.; Chu, D.T.; Plattner, J.J. (Abbott Laboratories Inc.); 6-O-Substd. ketolides having antibacterial activity. EP 0929563; US 5866549; WO 9809978 . |
| 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) | 28388 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-7,12,13-trihydroxy-4-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C54H104N2O12Si2 | 详情 | 详情 | |
| (II) | 28389 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-12,13-dihydroxy-4-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C57H108N2O12Si2 | 详情 | 详情 | |
| (III) | 28390 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-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]-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-oxime | C40H72N2O13 | 详情 | 详情 | |
| (IV) | 28391 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-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]-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione | C40H71NO13 | 详情 | 详情 | |
| (V) | 28429 | (3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione | C32H57NO10 | 详情 | 详情 | |
| (VI) | 28430 | (2S,3R,4S,6R)-2-[[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C39H61NO11 | 详情 | 详情 |
合成路线2
Oxidation of the 3-hydroxyl group of (VI) by means of N-chlorosuccinimide in the presence of Me2S and Et3N produced ketone (VII). A 3-quinolinyl moiety was further introduced on the allyl group of (VII) by treatment with 3-bromoquinoline (VIII) in the presence of Pd(OAc)2 and tri-o-tolyl phosphine to yield (IX). Finally, the benzoate ester of (IX) was cleaved by treatment with boiling MeOH.
| 【1】 Flamm, R.K.; Raney, P.M.; Nilius, A.M.; Bui, M.; Or, Y.S.; Wang, S.; Plattner, J.J.; Ma, Z.; Clark, R.; Chu, D.T.W.; Synthesis and antibacterial activity of 6-O-substituted ketolides. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-126. |
| 【2】 Or, Y.S.; Ma, Z.; Clark, R.F.; Chu, D.T.; Plattner, J.J. (Abbott Laboratories Inc.); 6-O-Substd. ketolides having antibacterial activity. EP 0929563; US 5866549; WO 9809978 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 28430 | (2S,3R,4S,6R)-2-[[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C39H61NO11 | 详情 | 详情 | |
| (VII) | 28431 | (2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C39H59NO11 | 详情 | 详情 | |
| (VIII) | 28432 | 3-bromoquinoline | 5332-24-1 | C9H6BrN | 详情 | 详情 |
| (IX) | 28433 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[((3R,5R,6R,7S,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-7-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]oxacyclotetradecanyl)oxy]-6-methyltetrahydro-2H-pyran-3-yl benzoate | C48H64N2O11 | 详情 | 详情 |