(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione -Drug Synthesis Database

【结构式】

【分子编号】33114

【品名】(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione

【CA登记号】

【分子式】C₄₇H₇₄ClFN₂O₁₃

【分子量】929.5613432

【元素组成】C 60.73% H 8.02% Cl 3.81% F 2.04% N 3.01% O 22.38%

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：(VII)

6-O-Methylerythromycin A (I) was protected as the 2'-acetate (II) and subsequently treated with chlorotrimethylsilane and pyridine to afford the 4''-O-silyl ether (III). Condensation of (III) with 1,1'-carbonyldiimidazole yielded the 12-O-acylimidazole derivative (IV), which was subsequently reacted with 3-chloro-4-fluorophenethyl amine (V) to form the 11,12-cyclic carbamate (VI). Deprotection of the acetate ester of (VI) on heating with methanol, followed by desilylation with tetrabutylammonium fluoride in THF yielded (VII).

参考文献中间体

合成目标

【1】 Randolph, J.; Haviv, F.; Bruncko, M.; Crawford, B.W.; Dalton, C.R.; Frey, L.M.; Kaminski, M.A.; Greer, J.; Sauer, D.R.; Mort, N.A. (Abbott Laboratories Inc.); 3',3'-N-Bis-substd. macrolide LHRH antagonists. US 5972898; WO 9950276 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	33108	(3R,4R,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; (3R,4R,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)	33109	(2S,3R,4S,6R)-4-(dimethylamino)-2-[((3R,4R,5R,6R,7R,9R,11R,12R,13S,14R)-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-dioxooxacyclotetradecanyl)oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate; (2S,3R,4S,6R)-4-(dimethylamino)-2-[((3R,4R,5R,6R,7R,9R,11R,12R,13S,14R)-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-dioxooxacyclotetradecanyl)oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate	C₄₀H₇₁NO₁₄	详情	详情
(III)	33110	(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,4R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-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-dioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate; (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,4R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-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-dioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate	C₄₃H₇₉NO₁₄Si	详情	详情
(IV)	33111	(2R,3S,7R,9R,10R,11R,12R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-12-([(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-6,14-dioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate; (2R,3S,7R,9R,10R,11R,12R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-12-([(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-6,14-dioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate	C₄₇H₇₉N₃O₁₄Si	详情	详情
(V)	33112	2-(3-chloro-4-fluorophenyl)-1-ethanamine; 3-chloro-4-fluorophenethylamine	C₈H₉ClFN	详情	详情
(VI)	33113	(2S,3R,4S,6R)-2-[[(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-4-ethyl-11-methoxy-8-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate; (2S,3R,4S,6R)-2-[[(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-4-ethyl-11-methoxy-8-([(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate	C₅₂H₈₄ClFN₂O₁₄Si	详情	详情
(VII)	33114	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione	C₄₇H₇₄ClFN₂O₁₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Treatment of (VII) with iodine and sodium acetate under irradiation of a halogen lamp produced N-demethylation to furnish (VIII). Further demethylation of (VIII) to give (IX) was achieved by a similar treatment with iodine and tripotassium phosphate. Finally, reductive condensation of (IX) with cyclopropanecarbaldehyde (X) in the presence of sodium cyanoborohydride yielded the bis(cyclopropylmethyl) derivative.

参考文献中间体

合成目标

【1】 Randolph, J.; Haviv, F.; Bruncko, M.; Crawford, B.W.; Dalton, C.R.; Frey, L.M.; Kaminski, M.A.; Greer, J.; Sauer, D.R.; Mort, N.A. (Abbott Laboratories Inc.); 3',3'-N-Bis-substd. macrolide LHRH antagonists. US 5972898; WO 9950276 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	33114	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione		C₄₇H₇₄ClFN₂O₁₃	详情	详情
(VIII)	33115	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-10-[[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-10-[[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione		C₄₆H₇₂ClFN₂O₁₃	详情	详情
(IX)	33116	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-4-amino-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione; (3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-4-amino-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(3-chloro-4-fluorophenethyl)-4-ethyl-8-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-11-methoxy-3a,7,9,11,13,15-hexamethyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione		C₄₅H₇₀ClFN₂O₁₃	详情	详情
(X)	26463	cyclopropanecarbaldehyde	1489-69-6	C₄H₆O	详情	详情

Extended Information