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【结 构 式】 
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【分子编号】62297 【品名】(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}-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-hexame 【CA登记号】 |
【 分 子 式 】C41H74N2O13 【 分 子 量 】803.04424 【元素组成】C 61.32% H 9.29% N 3.49% O 25.9% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)The obtained 15 methylerythromycin A (XI) is chemically modified as follows. Treatment of ketone (XI) with hydroxylamine and AcOH provides oxime (XII), which is further converted into oxime acetal (XIV) by condensation with 1,1-diisopropoxycyclohexane (XIII) in the presence of PPTS. The sugar hydroxyl groups of (XIV) are then protected by silylation with trimethylsilyl chloride/trimethylsilyl imidazole to yield the 2',4''-bis-silyl ether (XV). Then, alkylation of the 6-hydroxyl group of (XV) with allyl t-butyl carbonate (XVI) in the presence of Pd(OAc)2 provides allyl ether (XVII). Further acidic hydrolysis of the acetal and silyl ether groups of (XVII) affords oxime (XVIII).
| 【1】 Macielag, M.; Abbanat, D.; Ashley, G.; Foleno, B.; Fu, H.; Li, Y.; Wira, E.; Bush, K.; Structure-activity studies of 15-methyl ketolides: Optimization of the heterocyclic substituent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1662. |
| 【2】 Hlasta, D.; Khosla, C.; Chu, D.T.W.; Ashley, G.; Henninger, T.C.; Grant, E.B. (Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0232918 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 62291 | (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}-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-hexamethyl-14-pr | C38H69NO13 | 详情 | 详情 | |
| (XII) | 62292 | (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}-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-hexamethyl-14-pr | C38H70N2O13 | 详情 | 详情 | |
| (XIII) | 45909 | 1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane | 1132-95-2 | C12H24O2 | 详情 | 详情 |
| (XIV) | 62293 | (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}-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-hexamethyl-14-pr | C47H86N2O14 | 详情 | 详情 | |
| (XV) | 62294 | (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)-7,12,13-trihydroxy-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3, | C53H102N2O14Si2 | 详情 | 详情 | |
| (XVI) | 62295 | allyl tert-butyl carbonate | C8H14O3 | 详情 | 详情 | |
| (XVII) | 62296 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-6-({(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-12,13-dihydroxy-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2- | C56H106N2O14Si2 | 详情 | 详情 | |
| (XVIII) | 62297 | (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}-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-hexame | C41H74N2O13 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)Removal of the oxime functionality of (XVIII) by means of sodium hydrosulfite and formic acid gives ketone (XIX). The C-3 sugar moiety is then cleaved under smooth acidic hydrolysis conditions yielding the des-cladinose analogue (XX). After protection of the 2'-hydroxyl group of the desosamine moiety of (XX) as the benzoate ester (XXI), its 3-hydroxyl is oxidized with either NCS/Me2S or with DMSO/EDC, producing the ketolide derivative (XXII). The C-11 secondary hydroxyl of (XXII) is then converted to mesylate (XXIII) by treatment with methanesulfonyl chloride in pyridine.
| 【1】 Macielag, M.; Abbanat, D.; Ashley, G.; Foleno, B.; Fu, H.; Li, Y.; Wira, E.; Bush, K.; Structure-activity studies of 15-methyl ketolides: Optimization of the heterocyclic substituent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1662. |
| 【2】 Hlasta, D.; Khosla, C.; Chu, D.T.W.; Ashley, G.; Henninger, T.C.; Grant, E.B. (Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0232918 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 62297 | (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}-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-hexame | C41H74N2O13 | 详情 | 详情 | |
| (XIX) | 62298 | (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}-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-hexame | C41H73NO13 | 详情 | 详情 | |
| (XX) | 62299 | (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}-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione | C33H59NO10 | 详情 | 详情 | |
| (XXI) | 62300 | (2S,3R,4S,6R)-2-{[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxacyclotetradecanyl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C40H63NO11 | 详情 | 详情 | |
| (XXII) | 62301 | (2S,3R,4S,6R)-2-{[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-14-propyloxacyclotetradecanyl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C40H61NO11 | 详情 | 详情 | |
| (XXIII) | 62303 | (2S,3R,4S,6R)-2-({(3R,5R,6R,7S,9R,11R,12R,13R,14R)-7-(allyloxy)-13-hydroxy-3,5,7,9,11,13-hexamethyl-12-[(methylsulfonyl)oxy]-2,4,10-trioxo-14-propyloxacyclotetradecanyl}oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C41H63NO13S | 详情 | 详情 |