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【结 构 式】 
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【分子编号】48761 【品名】8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde 【CA登记号】 |
【 分 子 式 】C18H19NO4 【 分 子 量 】313.3532 【元素组成】C 68.99% H 6.11% N 4.47% O 20.42% |
合成路线1
该中间体在本合成路线中的序号：(VII)The intermediate tricyclic carbaldehyde has been obtained by two different methods: 1. The dicarboxylic ester (I) is methylated with Me-I and Ag2O in dioxane to give the dimethoxy compound (II), which is reduced with LiAlH4 in THF to obtain the dicarbinol (III). Monoesterification of (III) with benzoyl chloride and pyridine in dichloromethane yields the monobenzoate (IV), which is oxidized with DMP to afford the carbaldehyde (V). The Grignard reaction of (V) with methylmagnesium bromide and MeLi in THF provides the diol (VI), which is oxidized with oxalyl chloride to furnish the desired intermediate carbaldehyde (VII). 2. The reaction of the tricyclic ketone (VIII) with phosphonium bromide (IX) by means of tBu-OK in THF gives methylene derivative (X), which by hydroboration with BH3 and H2O2 in THF yields the carbinol (XI). The oxidation of (XI) with DPP affords the carbaldehyde (XII), which is condensed with the 1-aminopyrrolidine (XIII) to afford the hydrazone (XIV). The acylation of (XIV) with acetyl chloride and LDA in THF provides the acetyl derivative (XV), which is finally treated with oxalic acid go give the desired intermediate carbaldehyde (VII).
| 【1】 Kita, Y.; et al.; Total synthesis of the antitumor antribiotic (±)-fredericamycin A by a linear approach. Chemistry (Weinheim) 2000, 6, 21, 3897. |
| 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) | 48755 | dimethyl 9-hydroxy-3-methyl-1-oxo-1,2,6,7-tetrahydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate | C17H17NO6 | 详情 | 详情 | |
| (II) | 48756 | dimethyl 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate | C19H21NO6 | 详情 | 详情 | |
| (III) | 48757 | [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methanol | C17H21NO4 | 详情 | 详情 | |
| (IV) | 48758 | [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methyl benzoate | C24H25NO5 | 详情 | 详情 | |
| (V) | 48759 | (8-formyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methyl benzoate | C24H23NO5 | 详情 | 详情 | |
| (VI) | 48760 | 1-[8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanol | C18H23NO4 | 详情 | 详情 | |
| (VII) | 48761 | 8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C18H19NO4 | 详情 | 详情 | |
| (VIII) | 48762 | 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinolin-8-one | C15H15NO3 | 详情 | 详情 | |
| (IX) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (X) | 48763 | 1,9-dimethoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinoline; 1-methoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinolin-9-yl methyl ether | C16H17NO2 | 详情 | 详情 | |
| (XI) | 48764 | (1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methanol | C16H19NO3 | 详情 | 详情 | |
| (XII) | 46913 | (2R)-2-(methoxymethyl)pyrrolidinylamine; (2R)-2-(methoxymethyl)-1-pyrrolidinamine | 59983-39-0 | C6H14N2O | 详情 | 详情 |
| (XIII) | 48765 | 1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C16H17NO3 | 详情 | 详情 | |
| (XIV) | 48766 | N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-N-[(2R)-2-(methoxymethyl)pyrrolidinyl]amine; (2R)-N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-2-(methoxymethyl)-1-pyrrolidinamine | C22H29N3O3 | 详情 | 详情 | |
| (XV) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (XVI) | 48767 | 1-[1,9-dimethoxy-8-([[(2R)-2-(methoxymethyl)pyrrolidinyl]imino]methyl)-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanone | C24H31N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of carbaldehyde (VII) with phenylsulfanylacetylene (XVII) by means of LiHMDS in toluene gives the intermediate lithium alcoxide (XVIII), which is condensed with benzoyl chloride (XIX) to yield the ester (XX). The migration of the aroyl group of (XX) to the methyl ketone group under basic medium (LiHMDS) affords diketone (XXI), which is oxidized with DMP, complexed with Co2(CO)8 and debenzylated, providing the cobalt complex (XXII). The cycloaddition of (XXII) by means of Me2SiCl2, chloranil in refluxing toluene, followed by protection of the peri-OH groups with tBu2Si(OTf)2 and oxidation of the sulfanyl group with MCPBA, gives the polycyclic spiro compound (XXIII). The reaction of (XXIII) with chloroacetate (XXIV) by means of Ts-OH yields the chloroacetoxy compound (XXV). Selective demethylation of (XXV) with trimethylsilyl iodide affords the pyridinone (XXVI), which is oxidized with SeO2 in dioxane to provide the carbaldehyde (XXVII). The condensation of (XXVII) with phosphonium bromide (XXVIII) by means of BuLi in THF furnishes the alkylated precursor (XXIX), which is finally deprotected by means of BBr3 in dichloromethane and oxidized by air to afford the target compound.
| 【1】 Kita, Y.; et al.; Total synthesis of the antitumor antribiotic (±)-fredericamycin A by a linear approach. Chemistry (Weinheim) 2000, 6, 21, 3897. |
| 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) | 48761 | 8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde | C18H19NO4 | 详情 | 详情 | |
| (XVII) | 48768 | ethynyl phenyl sulfide; 1-(ethynylsulfanyl)benzene | C8H6S | 详情 | 详情 | |
| (XVIII) | 48769 | C26H24LiNO4S | 详情 | 详情 | ||
| (XIX) | 48770 | 2-(benzyloxy)-4,5-dimethoxybenzoyl chloride | C16H15ClO4 | 详情 | 详情 | |
| (XX) | 48771 | 1-(8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)-3-(phenylsulfanyl)-2-propynyl 2-(benzyloxy)-4,5-dimethoxybenzoate | C42H39NO8S | 详情 | 详情 | |
| (XXI) | 48772 | 1-[2-(benzyloxy)-4,5-dimethoxyphenyl]-3-[8-[1-hydroxy-3-(phenylsulfanyl)-2-propynyl]-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1,3-propanedione | C42H39NO8S | 详情 | 详情 | |
| (XXII) | 48773 | 1-[1,9-dimethoxy-3-methyl-8-[3-(phenylsulfanyl)-2-propynoyl]-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-3-(2-hydroxy-4,5-dimethoxyphenyl)-1,3-propanedione | C35H31NO8S | 详情 | 详情 | |
| (XXIII) | 48774 | C44H45NO9S | 详情 | 详情 | ||
| (XXIV) | 48775 | 1-ethoxyvinyl 2-chloroacetate | C6H9ClO3 | 详情 | 详情 | |
| (XXV) | 48776 | C40H42ClNO10 | 详情 | 详情 | ||
| (XXVI) | 48777 | C39H40ClNO10 | 详情 | 详情 | ||
| (XXVII) | 48778 | C39H38ClNO11 | 详情 | 详情 | ||
| (XXVIII) | 48753 | (E)-2-butenyl(triphenyl)phosphonium bromide | C22H22BrP | 详情 | 详情 | |
| (XXIX) | 48779 | C43H44ClNO10 | 详情 | 详情 |