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【结 构 式】 
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【分子编号】54877 【品名】{7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol 【CA登记号】 |
【 分 子 式 】C18H22IN3O3 【 分 子 量 】455.29557 【元素组成】C 47.49% H 4.87% I 27.87% N 9.23% O 10.54% |
合成路线1
该中间体在本合成路线中的序号：(XVII)In a different strategy, the dioxinoquinoline system (XII) was prepared by acylation of amino ketone (X) with methyl malonyl chloride (XI), followed by intramolecular Knoevenagel condensation of the intermediate keto malonamide. Chlorination of (XII) with POCl3 afforded the dichloro derivative (XIII), which was subsequently condensed with N-methylpiperazine (IX) to give (XIV). Reduction of the ester group of (XIV) by means of DIBAL provided alcohol (XV). Replacement of the 7-chloro of (XV) by an iodide group required previous oxidation of (XV) to the more reactive aldehyde (XVI). Treatment of (XVI) with NaI and HCl led to the corresponding iodo aldehyde, which was further reduced to alcohol (XVII) using NaBH4.
| 【1】 Fang, F.G.; Xie, S.; Lowery, M.W. (GlaxoSmithKline Inc.); Intermediates in pharmaceutical camptothecin preparation. WO 9529917 . |
| 【2】 Huie, E.M.; Fang, F.G.; Xie, S.; Comins, D.L. (GlaxoSmithKline Inc.; North Carolina State University); Preparation of a camptothecin deriv. by intramolecular cyclisation. WO 9529919 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (X) | 54870 | 1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone | C10H10ClNO3 | 详情 | 详情 | |
| (XI) | 50272 | Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate | 37517-81-0 | C4H5ClO3 | 详情 | 详情 |
| (XII) | 54872 | methyl 9-(chloromethyl)-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate | C14H12ClNO5 | 详情 | 详情 | |
| (XIII) | 54873 | methyl 7-chloro-9-(chloromethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate | C14H11Cl2NO4 | 详情 | 详情 | |
| (XIV) | 54874 | methyl 7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate | C19H22ClN3O4 | 详情 | 详情 | |
| (XV) | 54875 | {7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol | C18H22ClN3O3 | 详情 | 详情 | |
| (XVI) | 54876 | 7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehyde | C18H20ClN3O3 | 详情 | 详情 | |
| (XVII) | 54877 | {7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol | C18H22IN3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)Lithiation of 2-methoxypyridine (XVIII), followed by formylation with N-formyl-N,N',N'-trimethylethylenediamine (XIX), produced the pyridine carbaldehyde (XX), which was further iodinated to (XXI) by lithiation and subsequent treatment with iodine. Reductive condensation of aldehyde (XXI) with crotyl alcohol (XXII) in the presence of triethylsilane and trifluoroacetic acid yielded the crotyl ether (XXIII). Cyclization of (XXIII) under Heck reaction conditions led to a mixture of the ethylidene pyranopyridine (XXIV) and the major isomerized analogue (XXV). Sharpless asymmetric dihydroxylation of this reaction mixture afforded the alpha-hydroxy lactol (XXVI), which was further oxidixed to hydroxy lactone (XXVII) employing iodine and CaCO3. Demethylation of ether (XXVII) under acidic conditions generated lactam (XXVIII). Mitsunobu coupling between lactam (XXVIII) and (hydroxymethyl)quinoline (XVII) furnished adduct (XXIX). The title compound was finally obtained by Heck cyclization of (XXIX) in the presence of palladium acetate and triphenylphosphine.
| 【1】 Fang, F.G.; et al.; Convergent catalytic asymmetric synthesis of camptothecin analog GI147211C. Tetrahedron 1997, 53, 32, 10953. |
| 【2】 Fang, F.G.; Xie, S.; Lowery, M.W. (GlaxoSmithKline Inc.); Intermediates in pharmaceutical camptothecin preparation. WO 9529917 . |
| 【3】 Huie, E.M.; Fang, F.G.; Xie, S.; Comins, D.L. (GlaxoSmithKline Inc.; North Carolina State University); Preparation of a camptothecin deriv. by intramolecular cyclisation. WO 9529919 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 54877 | {7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol | C18H22IN3O3 | 详情 | 详情 | |
| (XVIII) | 54878 | 2-Methoxypyridine; Methyl 2-pyridyl ether | 1628-89-3 | C6H7NO | 详情 | 详情 |
| (XIX) | 54879 | 2-(dimethylamino)ethyl(methyl)formamide | C6H14N2O | 详情 | 详情 | |
| (XX) | 54880 | 2-methoxynicotinaldehyde | C7H7NO2 | 详情 | 详情 | |
| (XXI) | 54881 | 4-iodo-2-methoxynicotinaldehyde | C7H6INO2 | 详情 | 详情 | |
| (XXII) | 54882 | 2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol | 504-61-0 | C4H8O | 详情 | 详情 |
| (XXIII) | 54883 | (E)-2-butenyl (4-iodo-2-methoxy-3-pyridinyl)methyl ether; 3-{[(E)-2-butenyloxy]methyl}-4-iodo-2-methoxypyridine | C11H14INO2 | 详情 | 详情 | |
| (XXIV) | 54884 | 4-[(E)ethylidene]-3,4-dihydro-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-[(E)ethylidene]-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine | C11H13NO2 | 详情 | 详情 | |
| (XXV) | 54885 | 4-ethyl-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine | C11H13NO2 | 详情 | 详情 | |
| (XXVI) | 54886 | (4S)-4-ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol | C11H15NO4 | 详情 | 详情 | |
| (XXVII) | 54887 | (4S)-4-ethyl-4-hydroxy-8-methoxy-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one | C11H13NO4 | 详情 | 详情 | |
| (XXVIII) | 54888 | (4S)-4-ethyl-4-hydroxy-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C10H11NO4 | 详情 | 详情 | |
| (XXIX) | 54889 | (4S)-4-ethyl-4-hydroxy-7-({7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methyl)-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C28H31IN4O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)In a further procedure, hydrolysis of the methoxy pyranopyridine (XXV) employing iodotrimethylsilane gave lactam (XLII). This was condensed with the (hydroxymethyl)quinoline (XVII) under Mitsunobu conditions to afford adduct (XLIII). The hexacyclic system (XLIV) was then obtained by intramolecular Heck condensation of (XLIII) using palladium acetate and triphenylphosphine. Asymmetric dihydroxylation of (XLIV) yielded the alpha-hydroxy lactol (XLV). Finally, Swern oxidation of lactol (XLV) furnished the title lactone.
| 【1】 Fang, F.G.; Xie, S. (GlaxoSmithKline Inc.); Method for preparing camptothecin derivs.. WO 9716454 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 54877 | {7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol | C18H22IN3O3 | 详情 | 详情 | |
| (XXV) | 54885 | 4-ethyl-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine | C11H13NO2 | 详情 | 详情 | |
| (XLII) | 54899 | 4-ethyl-1,7-dihydro-8H-pyrano[3,4-c]pyridin-8-one | C10H11NO2 | 详情 | 详情 | |
| (XLIII) | 54900 | 4-ethyl-7-({7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methyl)-1,7-dihydro-8H-pyrano[3,4-c]pyridin-8-one | C28H31IN4O4 | 详情 | 详情 | |
| (XLIV) | 54901 | 8-ethyl-15-[(4-methyl-1-piperazinyl)methyl]-2,3,11,14-tetrahydro-12H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-12-one | C28H30N4O4 | 详情 | 详情 | |
| (XLV) | 54902 | (8S)-8-ethyl-8,9-dihydroxy-15-[(4-methyl-1-piperazinyl)methyl]-2,3,8,9,11,14-hexahydro-12H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-12-one | C28H32N4O6 | 详情 | 详情 |