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【结 构 式】 
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【药物名称】Korupensamine B 【化学名称】(R-biar)-6,8-Dihydroxy-5-(4-hydroxy-5-methoxy-7-methyl-1-naphthyl)-1(R),3(R)-dimethyl-1,2,3,4-tetrahydroisoquinoline 【CA登记号】 【 分 子 式 】C23H25NO4 【 分 子 量 】379.46 |
【开发单位】US Department of Health & Human Services (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases |
合成路线1
2-Bromo-5-isopropoxybenzoic acid (I) was treated with oxalyl chloride to give the corresponding acid chloride (II) and subsequently condensed with the enantiomerically pure tetrahydroisoquinoline (III), yielding ester (IV). Intramolecular biaryl coupling by means of palladium acetate and tri(o-tolylphosphine) produced lactone (V), existing as an interconvertible mixture of its two atropo-diastereomeric forms. Reductive ring cleavage of this lactone using several hydride transfer reagents gave a separable mixture of two atropisomeric diols, from which the R-biar atropisomer (VI) was isolated by chromatography. After protection of the phenolic hydroxyl group of (VI) as the isopropyl ether (VII), oxidation of the primary alcohol with pyridinium chlorochromate (PCC) gave aldehyde (VIII). Stobbe condensation of (VIII) with diethyl succinate (IX) and NaOEt afforded the benzylidene succinic derivative (X).
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 | |
| (I) | 35400 | 2-bromo-4-isopropoxybenzoic acid | C10H11BrO3 | 详情 | 详情 | |
| (II) | 35401 | 2-bromo-4-isopropoxybenzoyl chloride | C10H10BrClO2 | 详情 | 详情 | |
| (III) | 35402 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C21H27NO2 | 详情 | 详情 | |
| (IV) | 35403 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinyl 2-bromo-4-isopropoxybenzoate | C31H36BrNO4 | 详情 | 详情 | |
| (V) | 35404 | (2R,4R)-3-benzyl-5,10-diisopropoxy-2,4-dimethyl-1,2,3,4-tetrahydro-8H-isochromeno[4,3-f]isoquinolin-8-one | C31H35NO4 | 详情 | 详情 | |
| (VI) | 35405 | (1R,3R)-2-benzyl-5-[2-(hydroxymethyl)-4-isopropoxyphenyl]-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C31H39NO4 | 详情 | 详情 | |
| (VII) | 35406 | [2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]methanol | C34H45NO4 | 详情 | 详情 | |
| (VIII) | 35407 | 2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxybenzaldehyde | C34H43NO4 | 详情 | 详情 | |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 |
合成路线2
Further intramolecular Friedel-Crafts acylation in boiling acetic anhydride gave rise to naphthalene (XI). Reduction of the ethyl ester group of (XI) with LiAlH4 also produced the reductive cleavage of the phenolic acetate to furnish diol (XII). Conversion of the hydroxymethyl group of (XII) into the required methyl group was achieved by chlorination upon treatment with dibromotetrachloroethane and triphenylphosphine, followed by reductive dehalogenation to the methyl analogue (XIII) with LiAlH4. The free hydroxyl group of (XIII) was then methylated with dimethyl sulfate using phase-transfer catalysis to provide methyl ether (XIV), which was treated with BCl3 in order to eliminate the isopropyl protecting groups yielding the trihydroxy derivative (XV). Finally, hydrogenolysis of the N-benzyl protecting group of (XV) over Pd/C yielded the title compound.
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 | |
| (XI) | 35409 | ethyl 4-(acetoxy)-8-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxy-2-naphthoate | C42H51NO7 | 详情 | 详情 | |
| (XII) | 35410 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-3-(hydroxymethyl)-8-isopropoxy-1-naphthol | C38H47NO5 | 详情 | 详情 | |
| (XIII) | 35411 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-isopropoxy-3-methyl-1-naphthol | C38H47NO4 | 详情 | 详情 | |
| (XIV) | 35412 | 5-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-isopropoxy-3-methyl-1-naphthyl methyl ether; (1R,3R)-2-benzyl-6,8-diisopropoxy-5-(4-isopropoxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C39H49NO4 | 详情 | 详情 | |
| (XV) | 35413 | (1R,3R)-2-benzyl-5-(4-hydroxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C30H31NO4 | 详情 | 详情 |
合成路线3
The isoquinoline intermediate (IX) has been synthesized as follows: The reduction of methyl 3,5-dimethoxybenzoate (I) with LiAlH4 gives the benzyl alcohol (II), which is treated with Swern oxidant to yield the benzaldehyde (III). The treatment of (III) with the sequence outlined in the scheme the chiral secondary amine is obtained. The cyclization of (IV) with ammonium formate catalyzed by Pd, followed by a treatment with acetic anhydride and POCl3 afforded the dihydroisoquinoline (V), which is reduced with LiAlH4 to the tetrahydro derivative (VI). Cleavage of the methoxy groups of (VI) with BBr3 affords the dihydroxycompound (VII), which is benzylated with benzyl bromide and Cs2CO3 providing the fully benzylated tetrahydroisoquinoline (VIII). Finally, this compound is iodinated with I2 and Ag2SO4 furnishing the desired isoquinoline intermediate (IX).
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| 40727 | 2-phenyl-2-propanamine; 1-methyl-1-phenylethylamine | 585-32-0 | C9H13N | 详情 | 详情 | |
| (I) | 37841 | methyl 3,5-dimethoxybenzoate | 2150-37-0 | C10H12O4 | 详情 | 详情 |
| (II) | 35424 | (3,5-dimethoxyphenyl)methanol | 705-76-0 | C9H12O3 | 详情 | 详情 |
| (III) | 21720 | 3,5-dimethoxybenzaldehyde | 7311-34-4 | C9H10O3 | 详情 | 详情 |
| (IV) | 37842 | (2R)-1-(3,5-dimethoxyphenyl)-N-(1-methyl-1-phenylethyl)-2-propanamine; N-[(1R)-2-(3,5-dimethoxyphenyl)-1-methylethyl]-N-(1-methyl-1-phenylethyl)amine | C20H27NO2 | 详情 | 详情 | |
| (V) | 37843 | (3R)-6-methoxy-1,3-dimethyl-3,4-dihydro-8-isoquinolinyl methyl ether; (3R)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline | C13H17NO2 | 详情 | 详情 | |
| (VI) | 37844 | (1R,3R)-6-methoxy-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether; (1R,3R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C13H19NO2 | 详情 | 详情 | |
| (VII) | 37845 | (1R,3R)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C11H15NO2 | 详情 | 详情 | |
| (VIII) | 37846 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H33NO2 | 详情 | 详情 | |
| (IX) | 37847 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H32INO2 | 详情 | 详情 |
合成路线4
The intermediate naphthaleneboronic acid (XIX) has been obtained as follows: The bromination of the 3-methylphenyl methoxymethyl ether (X) with NBS gives the dibromo compound (XI), which is treated with sodium phenylsulfinate to afford the sulfone (XII). The condensation of (XII) with methyl crotonate (XIII) by means of LDA and KOH gives the butyric acid (XIV), which is cyclized to the tetralone (XV) by means of trifluoroacetic anhydride (TFAA). The aromatization of (XV) by means of t-BuOK or NaOH yields the 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol (XVI), which is methylated with dimethylsulfate to afford the methyl ether (XVII). The reaction of (XVII) with trimethyl borate and n-BuLi gives the boronic ester (XVIII), which is hydrolyzed with water and ammonium chloride yielding the desired naphthaleneboronic acid (XIX). Alternatively, the naphthaleneboronic acid (XIX) has been obtained as follows: The reaction of 2,4-dibromophenol methoxymethyl ether (XX) with n-BuLi and cyclohexyl(isopropyl)amine gives the benzyne intermediate (XXI), which, without isolation is cyclized with the lithium enolate of 3-methylcrotonic acid dimethylamide (XXII) to afford the previously described naphthol (XVI), which is purified by chromatography.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 37848 | 1-(methoxymethoxy)-3-methylbenzene; methoxymethyl 3-methylphenyl ether | C9H12O2 | 详情 | 详情 | |
| (XI) | 37849 | [4-bromo-3-(bromomethyl)phenoxy]methyl methyl ether; 1-bromo-2-(bromomethyl)-4-(methoxymethoxy)benzene | C9H10Br2O2 | 详情 | 详情 | |
| (XII) | 37850 | 2-bromo-5-(methoxymethoxy)benzyl phenyl sulfone; [2-bromo-5-(methoxymethoxy)benzyl](dioxo)phenyl-lambda(6)-sulfane | C15H15BrO4S | 详情 | 详情 | |
| (XIII) | 26361 | methyl (E)-2-butenoate | 623-43-8 | C5H8O2 | 详情 | 详情 |
| (XIV) | 37851 | 4-[2-bromo-5-(methoxymethoxy)phenyl]-3-methyl-4-(phenylsulfonyl)butyric acid | C19H21BrO6S | 详情 | 详情 | |
| (XV) | 37852 | 5-bromo-8-(methoxymethoxy)-3-methyl-4-(phenylsulfonyl)-3,4-dihydro-1(2H)-naphthalenone | C19H19BrO5S | 详情 | 详情 | |
| (XVI) | 37853 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol | C13H13BrO3 | 详情 | 详情 | |
| (XVII) | 37854 | 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthyl methyl ether; 5-bromo-1-methoxy-8-(methoxymethoxy)-3-methylnaphthalene | C14H15BrO3 | 详情 | 详情 | |
| (XVIII) | 37855 | dimethyl 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronate | C16H21BO5 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 | |
| (XX) | 37857 | (2,4-dibromophenoxy)methyl methyl ether; 2,4-dibromo-1-(methoxymethoxy)benzene | C8H8Br2O2 | 详情 | 详情 | |
| (XXI) | 37858 | 1-bromo-4-(methoxymethoxy)-1,3-cyclohexadien-5-yne; 4-bromo-1,3-cyclohexadien-5-yn-1-yl methoxymethyl ether | C8H7BrO2 | 详情 | 详情 | |
| (XXII) | 37859 | C8H14LiNO | 详情 | 详情 |
合成路线5
The condensation of the isoquinoline intermediate (IX) with the naphthaleneboronic acid intermediate (XIX) by means of palladium tetrakis(triphenylphosphine) and NaHCO3 in refluxing ethanol/toluene gives a 5:4 mixture of the (S) and (R) atropaisomers (XXIII), which, without separation, are treated with methanolic HCl to eliminate the methoxymethyl protecting groups and yield a mixture of (S) and (R) (XXIV). The debenzylation of this mixture by means of H2 over Pd/C in methanol/dichloromethane affords a mixture of the target (R-biar) compound, along with its (S-biar)-atropaisomer that are separated by HPLC.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S)-(XXIV) | 37861 | 4-[(1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-methoxy-6-methyl-1-naphthol | C44H43NO4 | 详情 | 详情 | |
| (R-biar) | 38308 | (1R,3R)-5-(4-hydroxy-5-methoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol | C23H25NO4 | 详情 | 详情 | |
| (S)-(XXIII) | 38319 | (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIII) | 63435 | 2-benzyl-6,8-bis(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl 2-benzyl-6-(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether | C46H47NO5 | 详情 | 详情 | |
| (R)-(XXIV) | 63438 | 4-{1,3-dimethyl-2-(phenylmethyl)-6,8-bis[(phenylmethyl)oxy]-1,2,3,4-tetrahydro-5-isoquinolinyl}-6-methyl-8-(methyloxy)-1-naphthalenol | C44H43NO4 | 详情 | 详情 | |
| (IX) | 37847 | benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline | C32H32INO2 | 详情 | 详情 | |
| (XIX) | 37856 | 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid | C14H17BO5 | 详情 | 详情 |