(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 -Drug Synthesis Database

【结构式】

【分子编号】28395

【品名】(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

【CA登记号】

【分子式】C₄₀H₇₀N₂O₁₃

【分子量】787.00148

【元素组成】C 61.05% H 8.97% N 3.56% O 26.43%

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：(III)

Alkylation of protected erythromycin (I) at the 6-hydroxyl group with propargyl bromide provided ether (II). Hydrolysis of the cyclohexylidene ketal group of (II) with concomitant desilylation with AcOH gave (III). The oxime function of (III) was then hydrolyzed using either sodium bisulfite and formic acid or sodium nitrite and HCl to afford the title ketone.

参考文献中间体

合成目标

【1】 Bui, M.H.; Plattner, J.J.; Ramney, p.M.; Nilius, A.M.; Chu, D.T.W.; Or, Y.S.; Wang, S.; Clark, R.F.; Henry, R.F.; Ma, Z.; Novel 6-O-substituted erythromycin A derivatives. Synthesis and antibacterial activity. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-125.
【2】 Or, Y.S.; Chu, D.T.; Clark, R.F.; Ma, Z. (Abbott Laboratories Inc.); 6-O-Substd. erythromycins and method for making them. EP 0918783; EP 1007530; JP 2000509712; US 6075011; WO 9742204; WO 9742206 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(I)	28388	(3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-7,12,13-trihydroxy-4-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime]		C₅₄H₁₀₄N₂O₁₂Si₂	详情	详情
(II)	28394	(3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-6-([(2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-14-ethyl-12,13-dihydroxy-4-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)methyl]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-7-(2-propynyloxy)-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime]		C₅₇H₁₀₆N₂O₁₂Si₂	详情	详情
(III)	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

合成路线2

该中间体在本合成路线中的序号：(IV)

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).

参考文献中间体

合成目标

【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

Extended Information