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【结 构 式】

【分子编号】54479

【品名】(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

【CA登记号】

【 分 子 式 】C40H63NO11

【 分 子 量 】733.94036

【元素组成】C 65.46% H 8.65% N 1.91% O 23.98%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

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).

参考文献 中间体
合成目标
【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：(VIII)

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).

参考文献 中间体
合成目标
【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
Extended Information