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【结 构 式】 
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【药物名称】A-217213 【化学名称】11-Amino-11-deoxy-3-des(hexopyranosyloxy)-3-oxo-6-O-[3-(3-quinolinyl)-2-propynyl]erythromycin A 11-N,12-O-cyclic carbamate 【CA登记号】205111-68-8 【 分 子 式 】C42H57N3O10 【 分 子 量 】763.93669 |
【开发单位】Abbott (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Macrolides |
合成路线1
The title ketolide was synthesized starting from 2',4''-bis-O-trimethylsilylerythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I). Selective alkylation of (I) at the 6-hydroxyl group with propargyl bromide (II) furnished the propargyl ether (III). Then, acidic hydrolysis of the oxime ketal and the silyl ether groups of (III) provided (IV). Conversion of oxime (IV) into the corresponding ketone (V) was accomplished via diazotization with NaNO2 and HCl. The 2' and 4'' hydroxyl groups of (V) were then protected by esterification with acetic anhydride and DMAP to afford diacetate (VI). Treatment of (VI) with carbonyldiimidazole and NaH caused the elimination of the 11-hydroxyl group and formation of the 12-O-imidazolide (VII).
| 【1】 Or, Y.S.; Nilius, A.M.; Chu, D.T.W.; Zhang, X.; Wang, S.; Clark, R.F.; Ma, Z.; Structure-activity relationships leading to the discovery of A-217213, a novel 6-O-substituted ketolide with excellent activity against drug-resistant pathogens. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1171. |
| 【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) | 59651 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-({(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-14-ethyl-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-hexamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C52H100N2O14Si2 | 详情 | 详情 | |
| (II) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (III) | 59652 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-({(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-14-ethyl-12,13-dihydroxy-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-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C55H102N2O14Si2 | 详情 | 详情 | |
| (IV) | 28395 | (3R,4S,5R,6R,7S,9R,11S,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]-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione 10-oxime | C40H70N2O13 | 详情 | 详情 | |
| (V) | 59653 | (3R,4S,5R,6R,7S,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}-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione | C40H69NO13 | 详情 | 详情 | |
| (VI) | 59654 | (2S,3S,4R,6R)-6-{[(3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-7-(2-propynyloxy)oxacyclotetradecanyl]oxy}-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C44H73NO15 | 详情 | 详情 | |
| (VII) | 59655 | (2R,3S,7R,9S,10R,11R,12S,13R)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2R,4R,5S,6S)-5-(acetyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,5,7,9,11,13-hexamethyl-6,14-dioxo-9-(2-propynyloxy)oxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C48H73N3O15 | 详情 | 详情 |
合成路线2
Conversion of imidazolide (VII) into the cyclic carbamate (VIII) was carried out employing liquid ammonia in cold acetonitrile. The 3-cladinose moiety of (VIII) was then selectively removed by smooth acidic hydrolysis, yielding (IX). Subsequent oxidation of the 3-hydroxyl group of (IX) by means of N-chlorsuccinimide in the presence of dimethyl sulfide led to the ketolide compound (X). Palladium-catalyzed coupling of 3-bromoquinoline (XI) to the terminal acetylenic position of (X) furnished (XII). The title compound was finally obtained by methanolysis of the 2'-acetate group of (XII) at room temperature.
| 【1】 Or, Y.S.; Nilius, A.M.; Chu, D.T.W.; Zhang, X.; Wang, S.; Clark, R.F.; Ma, Z.; Structure-activity relationships leading to the discovery of A-217213, a novel 6-O-substituted ketolide with excellent activity against drug-resistant pathogens. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1171. |
| 【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 |
|---|---|---|---|---|---|---|
| (VII) | 59655 | (2R,3S,7R,9S,10R,11R,12S,13R)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2R,4R,5S,6S)-5-(acetyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,5,7,9,11,13-hexamethyl-6,14-dioxo-9-(2-propynyloxy)oxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C48H73N3O15 | 详情 | 详情 | |
| (VIII) | 59656 | (2S,3S,4R,6R)-6-{[(3aS,4R,7R,8S,9R,10R,11S,13R,15R,15aR)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-11-(2-propynyloxy)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl]oxy}-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C45H72N2O15 | 详情 | 详情 | |
| (IX) | 59657 | (2S,3R,4S,6R)-2-{[(3aS,4R,7R,8R,9S,10R,11S,13R,15R,15aR)-4-ethyl-8-hydroxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-11-(2-propynyloxy)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C35H56N2O11 | 详情 | 详情 | |
| (X) | 59658 | (2S,3R,4S,6R)-2-{[(3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-11-(2-propynyloxy)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C35H54N2O11 | 详情 | 详情 | |
| (XI) | 28432 | 3-bromoquinoline | 5332-24-1 | C9H6BrN | 详情 | 详情 |
| (XII) | 59659 | (2S,3R,4S,6R)-2-[((3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-11-{[3-(3-quinolinyl)-2-propynyl]oxy}tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C44H59N3O11 | 详情 | 详情 |