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【结 构 式】 
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【分子编号】54474 【品名】(3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-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-propyl-2,10-oxacyclotetradecanedione 【CA登记号】 |
【 分 子 式 】C38H69NO13 【 分 子 量 】747.9648 【元素组成】C 61.02% H 9.3% N 1.87% O 27.81% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 15-methylerythromycin A (I) with hydroxylamine, cyclohexanone di-isopropylacetal (II) and PPTS gives the substituted oxime (III), which is regioselectively silylated with Tms-Cl and imidazole to yield the disilylated compound (IV). The alkylation of (IV) with allyl bromide (V) and tBu-OK affords the 6-O-allyl derivative (VI),which is treated with HOAc and HCOOH to cleave the oxime group and furnish the 6-O-allyl-15-methylerythromycin A (VII). The cleavage of the 3-O-carbohydrate moiety of (VII) by means of aq. HCl, followed by benzoylation with Bz2O, gives the benzoyl intermediate (VIII), which is oxidized with NCS and Me2S and dehydrated with Ms-Cl, pyridine and DBU to yield the ketolide (IX). The fluorination of (IX) by means of (PhSO2)2N-F and tBu-OK affords the 2-fluoro derivative (X).
| 【1】 Macielag, M.; et al.; Structure-antibacterial activty relationships of ketolides derived from 15-methylerythromycin A. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1174. |
| 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) | 54474 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-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-propyl-2,10-oxacyclotetradecanedione | C38H69NO13 | 详情 | 详情 | |
| (II) | 45909 | 1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane | 1132-95-2 | C12H24O2 | 详情 | 详情 |
| (III) | 54475 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-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-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C47H86N2O14 | 详情 | 详情 | |
| (IV) | 54476 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-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-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C53H102N2O14Si2 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 54477 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-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-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C56H106N2O14Si2 | 详情 | 详情 | |
| (VII) | 54478 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-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-propyl-2,10-oxacyclotetradecanedione | C41H73NO13 | 详情 | 详情 | |
| (VIII) | 54479 | (2S,3S,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-isopropyl-6-methylmorpholinyl benzoate | C40H63NO11 | 详情 | 详情 | |
| (IX) | 54480 | (2S,3S,6R)-2-{[(3R,5R,6R,7S,9R,13S,14R)-7-(allyloxy)-13-hydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate | C40H59NO10 | 详情 | 详情 | |
| (X) | 54481 | (2S,3S,6R)-2-{[(3S,5S,6R,7S,9R,13S,14R)-7-(allyloxy)-3-fluoro-4,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate | C40H60FNO10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 15-methylerythromycin A (I) with hydroxylamine, cyclohexanone di-isopropylacetal (II) and PPTS gives the substituted oxime (III), which is regioselectively silylated with Tms-Cl and imidazole to yield the disilylated compound (IV). The alkylation of (IV) with allyl bromide (V) and tBu-OK affords the 6-O-allyl derivative (VI),which is treated with HOAc and HCOOH to cleave the oxime group and furnish the 6-O-allyl-15-methylerythromycin A (VII). The cleavage of the 3-O-carbohydrate moiety of (VII) by means of aq. HCl, followed by benzoylation with Bz2O, gives the benzoyl intermediate (VIII), which is oxidized with NCS and Me2S and dehydrated with Ms-Cl, pyridine and DBU to yield the ketolide (IX). The fluorination of (IX) by means of (PhSO2)2N-F and tBu-OK affords the 2-fluoro derivative (X).
| 【1】 Macielag, M.; et al.; Structure-antibacterial activty relationships of ketolides derived from 15-methylerythromycin A. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1174. |
| 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) | 54474 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-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-propyl-2,10-oxacyclotetradecanedione | C38H69NO13 | 详情 | 详情 | |
| (II) | 45909 | 1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane | 1132-95-2 | C12H24O2 | 详情 | 详情 |
| (III) | 54475 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-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-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C47H86N2O14 | 详情 | 详情 | |
| (IV) | 54476 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-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-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C53H102N2O14Si2 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 54477 | (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-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-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] | C56H106N2O14Si2 | 详情 | 详情 | |
| (VII) | 54478 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-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-propyl-2,10-oxacyclotetradecanedione | C41H73NO13 | 详情 | 详情 | |
| (VIII) | 54479 | (2S,3S,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-isopropyl-6-methylmorpholinyl benzoate | C40H63NO11 | 详情 | 详情 | |
| (IX) | 54480 | (2S,3S,6R)-2-{[(3R,5R,6R,7S,9R,13S,14R)-7-(allyloxy)-13-hydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate | C40H59NO10 | 详情 | 详情 | |
| (X) | 54481 | (2S,3S,6R)-2-{[(3S,5S,6R,7S,9R,13S,14R)-7-(allyloxy)-3-fluoro-4,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate | C40H60FNO10 | 详情 | 详情 |