(3R,4S,5R,6R,7R,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]-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione -Drug Synthesis Database

【结构式】

【分子编号】18631

【品名】(3R,4S,5R,6R,7R,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]-7-methoxy-3,5,7,9,11,13-hexamethyl-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%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Selective hydrolysis of the cladinose moiety of 6-O-methylerythromycin (I) with aqueous HCl gave (II), which was selectively acetylated at 2'-OH to provide acetate (III). Pfitzner-Moffat oxidation with DMSO, EDC, and pyridinum trifluoroacetate yielded 3-oxo compound (IV). Then, reaction with methanesulfonic anhydride in pyridine gave 11-O-mesylate (V), which on treatment with DBU in acetone produced the elimination product (VI). Subsequent condensation with carbonyldiimidazole in the presence of NaH afforded imidazole-carboxylate (VII). Then, reaction with hydrazine in aqueous acetonitrile provided a mixture of epimeric oxazolidinones (VIII) and (IX), which were separated by column chromatography.

参考文献中间体

合成目标

【1】 Agouridas, C.; Denis, A.; Auger, J.M.; Benedetti, Y.; Bonnefoy, A.; Bretin, F.; Chantot, J.F.; Dussarat, A.; Fromentin, C.; D'Ambrieres, S.G.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.; Tessot, N.; Synthesis and antibacterial activity of ketolides (6-O-methyl-3-oxoerythromycin derivatives): A new class of antibacterials highly potent against macrolide-resistant and -susceptible respiratory pathogens. J Med Chem 1998, 41, 21, 4080.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	18631	(3R,4S,5R,6R,7R,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]-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione	C₃₈H₆₉NO₁₃	详情	详情
(II)	18632	(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione	C₃₀H₅₅NO₁₀	详情	详情
(III)	18633	(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-4,12,13-trihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate	C₃₂H₅₇NO₁₁	详情	详情
(IV)	18634	(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate	C₃₂H₅₅NO₁₁	详情	详情
(V)	18635	(2S,3R,4S,6R)-4-(dimethylamino)-2-([(3R,5R,6R,7R,9R,11R,12R,13R,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-12-[(methylsulfonyl)oxy]-2,4,10-trioxooxacyclotetradecanyl]oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate	C₃₃H₅₇NO₁₃S	详情	详情
(VI)	18636	(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,13S,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate	C₃₂H₅₃NO₁₀	详情	详情
(VII)	18637	(2R,3S,7R,9R,10R,11R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate	C₃₆H₅₅N₃O₁₁	详情	详情
(VIII)	18638	(3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone	C₃₁H₅₃N₃O₁₀	详情	详情
(IX)	18639	(3aS,4R,7R,9R,10R,11R,13R,15S,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone	C₃₁H₅₃N₃O₁₀	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety, yielding (IV). The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent oxidation of the 3-hydroxyl group of (V) under modified Swern conditions furnished ketone (VI). Finally, methanolysis of the acetate ester group of (VI) provided the title compound.

参考文献中间体

合成目标

【1】 Alihodzic, S.; et al.; Synthesis and antibacterial activity of isomeric 15-membered azalides. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2001, Abst 1177.
【2】 Kobrehel, G.; Lazarevski, G.; Kelneric, Z. (Pliva dd); 15-Membered lactams ketolides with antibacterial activity. EP 1070077; JP 2002510701; US 6110965; WO 9951616 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	18631	(3R,4S,5R,6R,7R,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]-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione	C₃₈H₆₉NO₁₃	详情	详情
(II)	55084	(3R,4S,5R,6R,7R,9R,11S,12R,13S,14R)-6-{[(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}-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-oxime	C₃₈H₇₀N₂O₁₃	详情	详情
(III)	55085	(2R,3S,4R,5R,8R,10R,11R,12R,13S,14R)-11-{[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4-dihydroxy-13-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-10-methoxy-3,5,8,10,12,14-hexamethyl-1-oxa-7-azacyclopentadecane-6,15-dione	C₃₈H₇₀N₂O₁₃	详情	详情
(IV)	55086	(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-{[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4,13-trihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-1-oxa-7-azacyclopentadecane-6,15-dione	C₃₀H₅₆N₂O₁₀	详情	详情
(V)	55087	(3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,13-trihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-6,15-dioxo-1-oxa-7-azacyclopentadecan-11-yl]oxy}-6-methyltetrahydro-2H-pyran-3-yl acetate	C₃₂H₅₈N₂O₁₁	详情	详情
(VI)	55088	(3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12R,14R)-2-ethyl-3,4-dihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-6,13,15-trioxo-1-oxa-7-azacyclopentadecan-11-yl]oxy}-6-methyltetrahydro-2H-pyran-3-yl acetate	C₃₂H₅₆N₂O₁₁	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety. The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent acylation of the 3-hydroxyl group of (V) with the mixed anhydride prepared from 4-nitrophenylacetic acid (VI) and pivaloyl chloride furnished ester (VII). Finally, methanolysis of the acetate ester group of (VII) provided the title compound.

参考文献中间体

合成目标

【1】 Alihodzic, S.; et al.; Synthesis and antibacterial activity of isomeric 15-membered azalides. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2001, Abst 1177.
【2】 Kobrehel, G.; Lazarevski, G.; Kelneric, Z. (Pliva dd); 15-Membered lactams ketolides with antibacterial activity. EP 1070077; JP 2002510701; US 6110965; WO 9951616 .
【3】 Kobrehel, G.; Lazarevski, G.; Alihodzic, S.; Mutak, S. (Pliva dd); Novel 8a- and 9a-15-membered lactams. EP 1181298; WO 0063223 .

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)	18631	(3R,4S,5R,6R,7R,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]-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione		C₃₈H₆₉NO₁₃	详情	详情
(II)	55084	(3R,4S,5R,6R,7R,9R,11S,12R,13S,14R)-6-{[(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}-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-oxime		C₃₈H₇₀N₂O₁₃	详情	详情
(III)	55085	(2R,3S,4R,5R,8R,10R,11R,12R,13S,14R)-11-{[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4-dihydroxy-13-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-10-methoxy-3,5,8,10,12,14-hexamethyl-1-oxa-7-azacyclopentadecane-6,15-dione		C₃₈H₇₀N₂O₁₃	详情	详情
(IV)	55086	(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-{[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4,13-trihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-1-oxa-7-azacyclopentadecane-6,15-dione		C₃₀H₅₆N₂O₁₀	详情	详情
(V)	55087	(3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,13-trihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-6,15-dioxo-1-oxa-7-azacyclopentadecan-11-yl]oxy}-6-methyltetrahydro-2H-pyran-3-yl acetate		C₃₂H₅₈N₂O₁₁	详情	详情
(VI)	30305	2-(4-nitrophenyl)acetic acid	104-03-0	C₈H₇NO₄	详情	详情
(VII)	55089	(2R,3S,4R,5R,8R,10R,11R,12R,13S,14R)-11-{[(3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4-dihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-6,15-dioxo-1-oxa-7-azacyclopentadecan-13-yl 2-(4-nitrophenyl)acetate		C₄₀H₆₃N₃O₁₄	详情	详情

Extended Information