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【结 构 式】 
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【分子编号】10338 【品名】1-[(4S,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanone 【CA登记号】 |
【 分 子 式 】C33H42O5Si 【 分 子 量 】546.77898 【元素组成】C 72.49% H 7.74% O 14.63% Si 5.14% |
合成路线1
该中间体在本合成路线中的序号：(III)A new synthesis of neplanocin A has been reported: The triphenylmethyl (Tr) ether of 2,3-O-(isopropylidene)-D-ribose (I) is reduced with LiAlH4 to the corresponding diol, which without isolation is partially protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) to yield the secondary alcohol (II). The oxidation of (II) with oxalyl chloride affords the ketone (III), which is alkylated with the lithium derivative of trimethylsilyl (TMS) diazomethane in THF to give the carbene intermediate (IV), which cyclizes to the cyclopentene (V). The partial deprotection of (V) followed by oxidation with pyridinium dichromate (PDC) yields the cyclopentenone (VI), which is reduced with LiAlH4 in THF to the cyclopentanol (VII) as a single stereoisomer. The condensation of (VII) with adenine (VIII) under Mitsunobu's conditions (triphenylphosphine and diethylazodicarboxylate [DEAD]) in THF affords protected neplanocin A (VIII), which is finally deprotected with HCl in methanol.
| 【1】 Ohira, S.; Sawamoto, T.; Yamato, M.; Synthesis of (-)-neplanocin A via C-H insertion of alkylidenecarbene. Tetrahedron Lett 1995, 36, 9, 1537. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 62992 | [diazo(trimethylsilyl)methyl]lithium | C4H9LiN2Si | 详情 | 详情 | ||
| (I) | 10336 | (3aR,4S,6R,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]tetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C27H28O5 | 详情 | 详情 | |
| (II) | 10337 | (1R)-1-[(4R,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol | C33H44O5Si | 详情 | 详情 | |
| (III) | 10338 | 1-[(4S,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanone | C33H42O5Si | 详情 | 详情 | |
| (IV) | 62991 | 2-[(4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-propen-1-ol | C9H16O4 | 详情 | 详情 | |
| (V) | 10340 | ((3aR,6aR)-6-[[tert-Butyl(dimethyl)silyl]oxy]-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl trityl ether; ([(3aR,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy)(tert-butyl)dimethylsilane | C34H42O4Si | 详情 | 详情 | |
| (VI) | 10341 | (3aR,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C28H26O4 | 详情 | 详情 | |
| (VII) | 10342 | (3aS,4S,6aR)-2,2-Dimethyl-6-[(trityloxy)methyl]-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C28H28O4 | 详情 | 详情 | |
| (VIII) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The 4-hydroxyquinoline (III) was synthesized via Gould-Jacobs reaction from 4-iodoaniline (I) and diethyl ethoxymethylenemalonate (II). Displacement of the ethyl ester group with 4-chlorobenzylamine (IV) at 180 C furnished the chlorobenzyl amide (V). Subsequent palladium-catalyzed carbonylation of iodide (V) provided the methyl carboxylate (VI), which was further reduced to alcohol (VII) using LiAlH4. Methylation of the hydroxyquinoline (VII) with iodomethane gave rise to the N-methyl quinolone (VIII). After conversion of the alcohol function of (VIII) to the corresponding mesylate (IX), displacement with morpholine (X) yielded the target morpholinomethyl quinolone.
| 【1】 Turner, S.R.; Strohbach, J.W.; Scott, A.; Schnute, M.E.; Vaillancourt, V.A.; Thaisrivongs, S. (Pharmacia Corp.); 4-Oxo-1,4-dihydro-3-quinolinecarboxamides as antiviral agents. EP 1140851; WO 0040563 . |
| 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) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 44988 | ethyl 4-hydroxy-6-iodo-3-quinolinecarboxylate | C12H10INO3 | 详情 | 详情 | |
| (IV) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |
| (V) | 44989 | N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide | C17H12ClIN2O2 | 详情 | 详情 | |
| (VI) | 49889 | methyl 3-[[(4-chlorobenzyl)amino]carbonyl]-4-hydroxy-6-quinolinecarboxylate | C19H15ClN2O4 | 详情 | 详情 | |
| (VII) | 49890 | N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide | C18H15ClN2O3 | 详情 | 详情 | |
| (VIII) | 49891 | N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide | C19H17ClN2O3 | 详情 | 详情 | |
| (IX) | 49892 | (3-[[(4-chlorobenzyl)amino]carbonyl]-1-methyl-4-oxo-1,4-dihydro-6-quinolinyl)methyl methanesulfonate | C20H19ClN2O5S | 详情 | 详情 | |
| (X) | 10338 | 1-[(4S,5S)-5-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanone | C33H42O5Si | 详情 | 详情 |