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【结 构 式】

【分子编号】45909

【品名】1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane

【CA登记号】1132-95-2

【 分 子 式 】C12H24O2

【 分 子 量 】200.32136

【元素组成】C 71.95% H 12.08% O 15.97%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(III)

Treatment of erythromycin derivative (I) with hydroxylamine in isopropanol in the presence of HOAc affords oxime (II), which is then converted into the isopropoxycyclohexyl oxime form (IV) by reaction with 1,1-diisopropoxycyclohexane (III) and p-toluensulfonate (PPTS) in CH2Cl2. Regioselective protection of (IV) by means of N-(trimethylsilyl)-imidazole (Me3Si-Im) and chlorotrimethylsilane (TMSCl) in CH2Cl2 yields derivative (V), which is then converted into derivative (VI) by first methylation with methyl bromide and KOtBu in THF/methyl sulfoxide followed by deprotection with HOAc in acetonitrile. Oxime (VI) is then treated with sodium hydrosulfite (Na2S2O4) and formic acid in EtOH/H2O to provide derivative (VII).

参考文献 中间体
合成目标
【1】 Chu, D.; Grant, E.; Hlasta, D.; Henninger, T.; Khosla, C. (Kosan Biosciences, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0062783 .
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) 45907 (3R,4S,5R,6R,7R,9R,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]-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione C36H65NO13 详情 详情
(II) 45908 (3R,4S,5R,6R,7R,9R,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]-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-oxime C36H66N2O13 详情 详情
(III) 45909 1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane 1132-95-2 C12H24O2 详情 详情
(IV) 45910 (3R,4S,5R,6R,7R,9R,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]-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C45H82N2O14 详情 详情
(V) 45911 (3R,4S,5R,6R,7R,9R,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)-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C51H98N2O14Si2 详情 详情
(VI) 45912 (3R,4S,5R,6R,7R,9R,12R,13S,14R)-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]-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione 10-oxime C37H68N2O13 详情 详情
(VII) 45913 (3R,4S,5R,6R,7R,9R,12R,13S,14R)-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]-7-methoxy-3,5,7,9,11,13,14-heptamethyl-2,10-oxacyclotetradecanedione C37H67NO13 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

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3

该中间体在本合成路线中的序号：(II)

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4

该中间体在本合成路线中的序号：(XIII)

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).

参考文献 中间体
合成目标
【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
Extended Information