|
【结 构 式】 
|
【药物名称】Luzopeptin E2 【化学名称】2-(Hexahydro-3-pyridazinecarboxylic acid)-7-(hexahydro-3-pyridazinecarboxylic acid)antibiotic BBM 928C 【CA登记号】93079-89-1 【 分 子 式 】C60H78N14O20 【 分 子 量 】1315.37246 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antibiotics, Antibiotics and Alkaloids, ANTIINFECTIVE THERAPY, Antineoplastic Antibiotics, ONCOLYTIC DRUGS |
合成路线1
The reaction of the acetyl-protected dipeptide (I) with N2H4 in acetonitrile followed by treatment with Boc2O, 4-dimethylaminopyridine (DMAP) and Et3N in dichloromethane affords the Boc-protected dipeptide (II). Oxazolone cleavage of (II) by means of Cs2CO3 in MeOH yields the methyl ester (III), which is converted into the crotyl ester (V) by a first hydrolysis with LiOH in THF/H2O followed by treatment with crotyl bromide (IV) and Et3N in acetone. Removal of the allyl moiety from peptide (VI) by means of Pd(PPh3)4 and dimedone in THF allows obtention of the carboxylic acid derivative (VII), which is then esterified with (V) by means of dicyclohexylcarbodiimide (DCC) and DMAP in CH2Cl2 to furnish (VIII). Removal of the crotyl moiety from (VIII) by means of Pd(PPh3)4 and dimedone in THF gives (IX), whose azide group is reduced with PPh3 in THF/H2O to afford amine (X). Self-assembling of (X) by spontaneous cyclodimerization when treated with 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (DEC) and 1-hydroxy-7-aza-1H-benzotriazole (HOAt) produces dimer (XI), which is reduced by hydrogenation over PtO2 in EtOAc to provide (XII).
| 【1】 Ciufolini, M.A.; et al.; Total synthesis of luzopeptin E2. Angew Chem. Int Ed Engl 2000, 39, 14, 2493. |
| 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) | 43044 | methyl (3S)-2-[[(4R)-3-acetyl-2-oxo-1,3-oxazolidin-4-yl]carbonyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C12H15N3O6 | 详情 | 详情 | |
| (II) | 43045 | methyl (3S)-2-[[(4R)-3-(tert-butoxycarbonyl)-2-oxo-1,3-oxazolidin-4-yl]carbonyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C15H21N3O7 | 详情 | 详情 | |
| (III) | 43046 | methyl (3S)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C14H23N3O6 | 详情 | 详情 | |
| (IV) | 35252 | (E)-1-bromo-2-butene | 29576-14-5 | C4H7Br | 详情 | 详情 |
| (V) | 43047 | (E)-2-butenyl (3S)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C17H27N3O6 | 详情 | 详情 | |
| (VI) | 43048 | allyl (2S,3S)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoate | C15H24N4O5 | 详情 | 详情 | |
| (VII) | 43049 | (2S,3S)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoic acid | C12H20N4O5 | 详情 | 详情 | |
| (VIII) | 43050 | (E)-2-butenyl (3S)-2-[(2R)-3-([(2S)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate | C29H46N8O10 | 详情 | 详情 | |
| (IX) | 43051 | (3S)-2-[(2R)-3-([(2S)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid | C25H40N8O10 | 详情 | 详情 | |
| (X) | 43052 | (3S)-2-[(2R)-3-([(2S)-2-[[2-[(2-aminoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid | C25H42N6O10 | 详情 | 详情 | |
| (XI) | 43053 | tert-butyl (4aS,13S,17R,23aS,32S,36R)-36-[(tert-butoxycarbonyl)amino]-13,32-bis(1-hydroxy-1-methylethyl)-9,12,28,31-tetramethyl-5,8,11,14,18,24,27,30,33,37-decaoxo-4,4a,5,6,7,8,9,10,11,12,13,14,17,18,23,23a,24,25,26,27,28,29,30,31,32,33,36,37-octaco | C48H76N12O18 | 详情 | 详情 | |
| (XII) | 43054 | tert-butyl (4aS,13S,17R,23aS,32S,36R)-36-[(tert-butoxycarbonyl)amino]-13,32-bis(1-hydroxy-1-methylethyl)-9,12,28,31-tetramethyl-5,8,11,14,18,24,27,30,33,37-decaoxodotriacontahydro-1H,16H,20H,35H-dipyridazino[6,1-l:6,1-b_1_][1,17,4,7,10,13,20,23,26,2 | C48H80N12O18 | 详情 | 详情 |
合成路线2
Boc groups of (XII) are cleaved with TFA in CH2Cl2 to furnish intermediate (XIII). Quinoline (XV) is protected with benzyl bromide and K2CO3 in acetone to give the benzyl-protected derivative (XVI), which is converted into the carboxylic acid (XVII) by treatment with NaOCl in dioxane. Debenzylation of (XVII) by hydrogenolysis over Pd/C in EtOAc yields intermediate (XIV), which finally acylates the primary amino groups in (XIII) by means of DEC, 1-hydroxy-1H-benzotriazole (HOBt) and NaHCO3 in DMF.
| 【1】 Ciufolini, M.A.; et al.; Total synthesis of luzopeptin E2. Angew Chem. Int Ed Engl 2000, 39, 14, 2493. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 43054 | tert-butyl (4aS,13S,17R,23aS,32S,36R)-36-[(tert-butoxycarbonyl)amino]-13,32-bis(1-hydroxy-1-methylethyl)-9,12,28,31-tetramethyl-5,8,11,14,18,24,27,30,33,37-decaoxodotriacontahydro-1H,16H,20H,35H-dipyridazino[6,1-l:6,1-b_1_][1,17,4,7,10,13,20,23,26,2 | C48H80N12O18 | 详情 | 详情 | |
| (XIII) | 43055 | (4aS,13S,17R,23aS,32S,36R)-17,36-diamino-13,32-bis(1-hydroxy-1-methylethyl)-9,12,28,31-tetramethylicosahydro-1H,16H,20H,35H-dipyridazino[6,1-l:6,1-b_1_][1,17,4,7,10,13,20,23,26,29]dioxaoctaazacyclodotriacontine-5,8,11,14,18,24,27,30,33,37(17H,36H)-d | C38H64N12O14 | 详情 | 详情 | |
| (XIV) | 43056 | 1-(3-hydroxy-6-methoxy-2-quinolinyl)-1-ethanone | C12H11NO3 | 详情 | 详情 | |
| (XV) | 43057 | 1-[3-(benzyloxy)-6-methoxy-2-quinolinyl]-1-ethanone | C19H17NO3 | 详情 | 详情 | |
| (XVI) | 43058 | 3-(benzyloxy)-6-methoxy-2-quinolinecarboxylic acid | C18H15NO4 | 详情 | 详情 | |
| (XVII) | 43059 | 3-hydroxy-6-methoxy-2-quinolinecarboxylic acid | C11H9NO4 | 详情 | 详情 |