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【结 构 式】 
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【药物名称】Lurtotecan, OSI-211(Liposomal formulation), NX-211(Liposomal formulation), GW-211, GG-211, GI-147211C(diHCl), GI-147211 【化学名称】8(S)-Ethyl-8-hydroxy-15-(4-methylpiperazin-1-ylmethyl)-2,3,8,9,11,12-hexahydro-14H-1,4-dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12-dione 【CA登记号】149882-10-0, 155773-58-3 (diHCl) 【 分 子 式 】C28H30N4O6 【 分 子 量 】518.5745 |
【开发单位】GlaxoSmithKline (Originator), Gilead (Licensee), OSI (Licensee) 【药理作用】Breast Cancer Therapy, DRUG DELIVERY, Liposomes, Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Small Cell Lung Cancer Therapy, DNA Topoisomerase I Inhibitors |
合成路线1
Benzodioxan-6-amine (I) was protected as the corresponding acetanilide (II), which was subsequently subjected to Friedel-Crafts condensation with chloroacetyl chloride (III) in the presence of ZnCl2, yielding the chloro ketone (IV). Acidic hydrolysis of the acetamide function of (IV) provided amino ketone (V). Alternatively, intermediate (V) was prepared by direct acylation of aniline (I) employing chloroacetonitrile (VI) in the presence of BCl3. The 7-(chloromethyl)camptothecin derivative (VIII) was synthesized through a Friedlander condensation between amino ketone (V) and the known keto lactone (VII). Finally, displacement of the chloride of (VIII) with N-methylpiperazine (IX) gave rise to the title piperazinylmethyl camptothecin.
| 【1】 Luzzio, M.J.; et al.; Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 1995, 38, 3, 395. |
| 【2】 Luzzio, M.J.; Besterman, J.M.; Evans, M.G.; Myers, P.L. (GlaxoSmithKline plc); Water soluble camptothecin derivs.. EP 0540099; JP 1993222048; JP 2000109475; US 5559235 . |
| 【3】 Sternbach, D.D.; Lackey, K. (GlaxoSmithKline Inc.); Preparation of water soluble camptothecin derivs.. US 5342947 . |
| 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) | 54867 | 1,4-Benzodioxan-6-amine; 3,4-Ethylenedioxyaniline; 6-Amino-1,4-benzodioxane | 22013-33-8 | C8H9NO2 | 详情 | 详情 |
| (II) | 54868 | N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide | C10H11NO3 | 详情 | 详情 | |
| (III) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (IV) | 54869 | N-[7-(2-chloroacetyl)-2,3-dihydro-1,4-benzodioxin-6-yl]acetamide | C12H12ClNO4 | 详情 | 详情 | |
| (V) | 54870 | 1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone | C10H10ClNO3 | 详情 | 详情 | |
| (VI) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (VII) | 10841 | (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione | C13H13NO5 | 详情 | 详情 | |
| (VIII) | 54871 | (8S)-15-(chloromethyl)-8-ethyl-8-hydroxy-2,3-dihydro-11H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H,14H)-dione | C23H19ClN2O6 | 详情 | 详情 | |
| (IX) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
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3
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4
The silylated pyranopyridine (XXXIV) was prepared by an analoguos route to that of Scheme 3 starting from 2-methoxy-6-(trimethylsilyl)pyridine (XXX). Halogenation-desilylation of (XXXIV) by means of ICl-furnished iodide (XXXV). Subsequent demethylation of (XXXV) to give lactam (XXXVI) was performed employing either aqueous HI or iodotrimethylsane. Alkylation of lactam (XXXVI) with 1,4-dichloro-2-butyne (XXXVII) to (XXXVIII), followed by reaction with piperazine (IX), yielded (XXXIX). The cascade radical cyclization of (XXXIX) with isonitrile (XL) under sunlamp irradiation in the presence of hexamethyldistannane led to an inseparable mixture of the title compound and its regioisomer (XLI).
| 【1】 Josien, H.; et al.; A general synthetic approach to the (20S)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles. Chemistry (Weinheim) 1998, 4, 1, 67. |
| 【2】 Curran, D.P.; et al.; Cascade radical reactions of isonitriles: A second-generation synthesis of (20S)-camptothecin, topotecan, irinotecan, and GI-147211C. Angew Chem. Int Ed 1995, 34, 23-24, 2683. |
| 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 |
| (XIX) | 54879 | 2-(dimethylamino)ethyl(methyl)formamide | C6H14N2O | 详情 | 详情 | |
| (XXII) | 54882 | 2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol | 504-61-0 | C4H8O | 详情 | 详情 |
| (XXX) | 54890 | methyl 6-(trimethylsilyl)-2-pyridinyl ether; 2-methoxy-6-(trimethylsilyl)pyridine | C9H15NOSi | 详情 | 详情 | |
| (XXXI) | 54891 | 4-iodo-2-methoxy-6-(trimethylsilyl)nicotinaldehyde | C10H14INO2Si | 详情 | 详情 | |
| (XXXII) | 54892 | 3-{[(E)-2-butenyloxy]methyl}-4-iodo-2-methoxy-6-(trimethylsilyl)pyridine; (E)-2-butenyl [4-iodo-2-methoxy-6-(trimethylsilyl)-3-pyridinyl]methyl ether | C14H22INO2Si | 详情 | 详情 | |
| (XXXIII) | 35096 | 4-ethyl-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridine | C14H21NO2Si | 详情 | 详情 | |
| (XXXIV) | 54893 | (4S)-4-ethyl-4-hydroxy-8-methoxy-6-(trimethylsilyl)-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one | C14H21NO4Si | 详情 | 详情 | |
| (XXXV) | 54894 | (4S)-4-ethyl-4-hydroxy-6-iodo-8-methoxy-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one | C11H12INO4 | 详情 | 详情 | |
| (XXXVI) | 49255 | (4S)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C10H10INO4 | 详情 | 详情 | |
| (XXXVII) | 50923 | 1,4-Dichloro-2-butyne | 821-10-3 | C4H4Cl2 | 详情 | 详情 |
| (XXXVIII) | 54895 | (4S)-7-(4-chloro-2-butynyl)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C14H13ClINO4 | 详情 | 详情 | |
| (XXXIX) | 54886 | (4S)-4-ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol | C11H15NO4 | 详情 | 详情 | |
| (XL) | 54898 | C9H7NO2 | 详情 | 详情 | ||
| (XLI) | 54897 | (9S)-9-ethyl-9-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro-12H-[1,4]dioxino[2,3-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione | C28H30N4O6 | 详情 | 详情 |
合成路线5
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 |