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【结 构 式】 
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【分子编号】35096 【品名】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 【CA登记号】 |
【 分 子 式 】C14H21NO2Si 【 分 子 量 】263.41178 【元素组成】C 63.84% H 8.04% N 5.32% O 12.15% Si 10.66% |
合成路线1
该中间体在本合成路线中的序号：(XXXIII)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2
该中间体在本合成路线中的序号：(I)The known enol ether (I) was dihydroxylated with OsO4 and then oxidatively cleaved to the keto formate (II) by means of Pb(OAc)4. Reformatskii reaction of (II) with (tert-butoxycarbonyl)methylzinc bromide gave hydroxyester (III). Further cyclization of (III) using trifluroacetic acid produced lactone (IV). Halogenation with iodine monochloride afforded iodopyridine (V). Then, cleavage of the methyl ether of (V) employing trimethylsilyl iodide generated the pyridone lactone (VI), which was N-alkylated with 3-(trimethylsilyl)propargyl bromide (VII), yielding (VIII). Radical annulation of (VIII) with isonitrile (IX) in the presence hexamethylditin furnished the pentacyclic system (X). Finally, removal of the N-Boc protecting group of (X) yielded the title compound.
| 【1】 Bom, D.; et al.; Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J Med Chem 1999, 42, 16, 3018. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | ||
| (I) | 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 | |
| (II) | 35097 | [2-methoxy-4-propionyl-6-(trimethylsilyl)-3-pyridinyl]methyl formate | C14H21NO4Si | 详情 | 详情 | |
| (III) | 35098 | tert-butyl 3-[3-[(formyloxy)methyl]-2-methoxy-6-(trimethylsilyl)-4-pyridinyl]-3-hydroxypentanoate | C20H33NO6Si | 详情 | 详情 | |
| (IV) | 35099 | 5-ethyl-5-hydroxy-9-methoxy-7-(trimethylsilyl)-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C15H23NO4Si | 详情 | 详情 | |
| (V) | 35100 | 5-ethyl-5-hydroxy-7-iodo-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H14INO4 | 详情 | 详情 | |
| (VI) | 35101 | 5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H12INO4 | 详情 | 详情 | |
| (VII) | 35105 | (3-bromo-1-propynyl)(trimethyl)silane | 38002-45-8 | C6H11BrSi | 详情 | 详情 |
| (VIII) | 35106 | 5-ethyl-5-hydroxy-7-iodo-8-[3-(trimethylsilyl)-2-propynyl]-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C17H22INO4Si | 详情 | 详情 | |
| (IX) | 35107 | Carbamic acid, (4-cyanophenyl)-, 1,1-dimethylethyl ester (9CI); tert-butyl 4-cyanophenylcarbamate | 143090-18-0 | C12H14N2O2 | 详情 | 详情 |
| (X) | 35108 | tert-butyl 5-ethyl-5-hydroxy-3,15-dioxo-12-(trimethylsilyl)-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino[1,2-b]quinolin-10-ylcarbamate | C29H35N3O6Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The known enol ether (I) was dihydroxylated with OsO4 and then oxidatively cleaved to the keto formate (II) by means of Pb(OAc)4. Reformatskii reaction of (II) with (tert-butoxycarbonyl)methylzinc bromide gave hydroxyester (III). Further cyclization of (III) using trifluroacetic acid produced lactone (IV). Halogenation with iodine monochloride afforded iodopyridine (V). Then, cleavage of the methyl ether of (V) employing trimethylsilyl iodide generated the pyridone lactone (VI), which was N-alkylated with 3-(tert-butyldimethylsilyl)propargyl bromide (VII), yielding (VIII). Finally, radical annulation of (VIII) with phenyl isonitrile (IX) in the presence hexamethylditin furnished the title pentacyclic compound.
| 【1】 Bom, D.; et al.; Novel A,B,E-ring-modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J Med Chem 1999, 42, 16, 3018. |
| 【2】 Burke, T.G.; Curran, D.P.; Bom, D. (University of Kentucky; University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. WO 0061146 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40586 | bromo[2-(tert-butoxy)-2-oxoethyl]zinc | C6H11BrO2Zn | 详情 | 详情 | ||
| (I) | 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 | |
| (II) | 35097 | [2-methoxy-4-propionyl-6-(trimethylsilyl)-3-pyridinyl]methyl formate | C14H21NO4Si | 详情 | 详情 | |
| (III) | 35098 | tert-butyl 3-[3-[(formyloxy)methyl]-2-methoxy-6-(trimethylsilyl)-4-pyridinyl]-3-hydroxypentanoate | C20H33NO6Si | 详情 | 详情 | |
| (IV) | 35099 | 5-ethyl-5-hydroxy-9-methoxy-7-(trimethylsilyl)-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C15H23NO4Si | 详情 | 详情 | |
| (V) | 35100 | 5-ethyl-5-hydroxy-7-iodo-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one | C12H14INO4 | 详情 | 详情 | |
| (VI) | 35101 | 5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H12INO4 | 详情 | 详情 | |
| (VII) | 35102 | (3-bromo-1-propynyl)(tert-butyl)dimethylsilane | C9H17BrSi | 详情 | 详情 | |
| (VIII) | 35103 | 8-[3-[tert-butyl(dimethyl)silyl]-2-propynyl]-5-ethyl-5-hydroxy-7-iodo-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C20H28INO4Si | 详情 | 详情 | |
| (IX) | 35104 | Benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |