A-177775, -Drug Synthesis Database

【结构式】

【药物名称】A-177775

【化学名称】3'-N-Cyclopentyl-3'-N-demethyl-11-deoxy-11-[2-(3,4-dichlorophenyl)ethylamino]-6-O-methylerythromycin A 11-N,12-O-(cyclic carbamate)

【CA登记号】

【分子式】C₅₁H₈₀Cl₂N₂O₁₃

【分子量】1000.11785

【开发单位】Abbott (Originator)

【药理作用】Oncolytic Drugs, Prostate Cancer Therapy, GnRH (LHRH) Antagonists

合成路线1 合成路线2

合成路线1

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 3,4-dichlorophenethyl 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

【1】 Kaminski, M.A.; Crawford, B.W.; Dalton, C.R.; Mort, N.A.; Sauer, D.R.; Bruncko, M.; Greer, J.; Frey, L.M.; Randolph, J.; Haviv, F. (Abbott Laboratories Inc.); Macrolide LHRH antagonists. US 5955440; WO 9950275 .

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)	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)	33678	3,4-dichlorophenethylamine; 2-(3,4-dichlorophenyl)-1-ethanamine	21581-45-3	C₈H₉Cl₂N	详情	详情
(VI)	33676	(2S,3R,4S,6R)-2-[[(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3,4-dichlorophenethyl)-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		C₅₂H₈₄Cl₂N₂O₁₄Si	详情	详情
(VII)	33677	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3,4-dichlorophenethyl)-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		C₄₇H₇₄Cl₂N₂O₁₃	详情	详情

合成路线2

N-Demethylation by treatment with iodine and sodium acetate under irradiation of a halogen lamp produced secondary amine (VIII). Finally, reductive condensation of (VIII) with cyclopentanone (IX) in the presence of sodium cyanoborohydride yielded the title cyclopentylamino compound.

参考文献中间体

【1】 Kaminski, M.A.; Crawford, B.W.; Dalton, C.R.; Mort, N.A.; Sauer, D.R.; Bruncko, M.; Greer, J.; Frey, L.M.; Randolph, J.; Haviv, F. (Abbott Laboratories Inc.); Macrolide LHRH antagonists. US 5955440; WO 9950275 .

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)	33677	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3,4-dichlorophenethyl)-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		C₄₇H₇₄Cl₂N₂O₁₃	详情	详情
(VIII)	33679	(3aS,4R,7R,8R,9R,10R,11R,13R,15R,15aR)-1-(3,4-dichlorophenethyl)-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		C₄₆H₇₂Cl₂N₂O₁₃	详情	详情
(IX)	15113	cyclopentanone	120-92-3	C₅H₈O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)