A-198401, -Drug Synthesis Database

【结构式】

【药物名称】A-198401

【化学名称】11-Amino-3'-N-(cyclopropylmethyl)-3'-N-demethyl-11-deoxy-3-O-deshexopyranosyl-11-[2-(3,4-dichlorophenyl)ethyl]-6-O-methyl-3-O-[4(S)-methyl-2-oxooxazolidin-3-ylcarbonyl]erythromycin A 11-N,12-O-cyclic carbamate

【CA登记号】256375-42-5, 361981-34-2 (deleted CAS)

【分子式】C₄₇H₆₉Cl₂N₃O₁₃

【分子量】954.99228

【开发单位】Abbott (Originator)

【药理作用】Oncolytic Drugs, GnRH (LHRH) Antagonists, Macrolides

合成路线1 合成路线2

合成路线1

Protection of 2'-O-acetyl-6-O-methylerythromycin A (I) with chlorotrimethylsilane afforded the 4''-O-trimethylsilyl derivative (II). Subsequent treatment with carbonyldiimidazole and NaH produced the dehydrated imidazolide (III), which was converted to the cyclic carbamate (V) upon reaction with 4-chlorophenethyl amine (IV). Acid hydrolysis of the cladinose moiety gave alcohol (VI), and further condensation with carbonyldiimidazole yielded imidazolide (VII).

参考文献中间体

【1】 Waid, P.; Dalton, C.R.; Randolph, J.T.; Greer, J.; Nichols, C.J.; Haviv, F.; Mort, N.A.; Sauer, D.R. (Abbott Laboratories Inc.); Macrolide LHRH antagonists. WO 0012522 .

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)	38154	(2S,3R,4S,6R)-4-(dimethylamino)-2-[((3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-4-[[(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
(II)	38155	(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-4-([(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
(III)	38156	(2R,3S,7R,9R,10R,11R,12S,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-12-([(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
(IV)	29459	4-chlorophenethylamine; 2-(4-chlorophenyl)-1-ethanamine	156-41-2	C₈H₁₀ClN	详情	详情
(V)	38157	(2S,3R,4S,6R)-2-[[(3aS,4R,7R,8S,9R,10R,11R,13R,15R,15aR)-1-(4-chlorophenethyl)-4-ethyl-11-methoxy-8-([(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		C₅₂H₈₅ClN₂O₁₄Si	详情	详情
(VI)	38158	(2S,3R,4S,6R)-2-[[(3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-1-(4-chlorophenethyl)-4-ethyl-8-hydroxy-11-methoxy-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		C₄₁H₆₃ClN₂O₁₁	详情	详情
(VII)	38159	(3aS,4R,7R,8S,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(4-chlorophenethyl)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl 1H-imidazole-1-carboxylate		C₄₅H₆₅ClN₄O₁₂	详情	详情

合成路线2

Coupling of this imidazolide (VII) with the lithium salt of (S)-4-methyloxazolidine-2-one (VIII) at low temperature, followed by acid hydrolysis of the acetate ester furnished carbamate (IX). Mono-N-demethylation of (IX) to give secondary amine (X) was achieved by photochemical reaction with iodine and NaOAc. Finally, reductive alkylation with cyclopropanecarboxaldehyde (XI) in the presence of NaBH3CN produced the title cyclopropylmethylamino derivative.

参考文献中间体

【1】 Waid, P.; Dalton, C.R.; Randolph, J.T.; Greer, J.; Nichols, C.J.; Haviv, F.; Mort, N.A.; Sauer, D.R. (Abbott Laboratories Inc.); Macrolide LHRH antagonists. WO 0012522 .

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)	38159	(3aS,4R,7R,8S,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(4-chlorophenethyl)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl 1H-imidazole-1-carboxylate		C₄₅H₆₅ClN₄O₁₂	详情	详情
(VIII)	38160	(4S)-4-methyl-1,3-oxazolidin-2-one		C₄H₇NO₂	详情	详情
(IX)	38161			C₄₄H₆₆ClN₃O₁₃	详情	详情
(X)	38162			C₄₃H₆₄ClN₃O₁₃	详情	详情
(XI)	26463	cyclopropanecarbaldehyde	1489-69-6	C₄H₆O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)