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【结 构 式】 
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【分子编号】21968 【品名】(2R,3R,4R,5S,6R)-3-(acetamido)-5-(acetoxy)-6-[(acetoxy)methyl]-2-chlorotetrahydro-2H-pyran-4-yl acetate 【CA登记号】3068-34-6 |
【 分 子 式 】C14H20ClNO8 【 分 子 量 】365.76744 【元素组成】C 45.97% H 5.51% Cl 9.69% N 3.83% O 34.99% |
合成路线1
该中间体在本合成路线中的序号：(III)The acetylation of N-acetyl-D-glucosamine (I) with Ac2O and pyridine gives the tetraacetoxy derivative (II), which is treated with dry HCl in acetic anhydride to yield 2-acetamido-3,4,6-tri-O-acetyl-1-chloro-2-deoxy-alpha-D-glucopyranose (III). The condensation of (III) with 7-benzyloxy-6-hydroxy-2H-1-benzopyran-2-one (IV) by means of NaOH and benzyl triethylammonium chloride in chloroform affords the acetylated glucoside (V), which is selectively deacetylated with NaOMe in hot methanol to provide the benzyl protected glucoside (VI). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in dimethoxyethane/water to furnish the target glycoside. The intermediate 7-benzyloxy-6-hydroxy-2H-1-benzopyran-2-one (IV) is obtained as follows: The reaction of Esculein (VII) with benzyl chloride, K2CO3, KI and 18-C-6 in hot DMF gives 7-benzyloxy-6-(D-glucopyranosyloxy)-2H-1-benzopyran-2-one (VIII), which is finally deglycosylated by means of HCl in methanol to afford the target intermediate (IV).
| 【1】 Watanabe, K.; Niimura, K.; Miyagawa, J. (Kureha Chemical Industry Co. Ltd.); Esculetin derivs. and method for manufacture thereof, use thereof, and pharmaceutical compsn.. EP 0654479; JP 1995179490; US 5736522 . |
| 【2】 Watanabe, K.; Niimura, K.; Yamazaki, T.; Maruoka, H. (Kureha Chemical Industry Co. Ltd.); Esculetin derivs., method for manufacture thereof, and pharmaceutical compsn.. CA 2166168; EP 0719770; JP 1996183785; US 5731293 . |
| 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) | 21967 | N-[(2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide | C8H15NO6 | 详情 | 详情 | |
| (II) | 53489 | (2R,3R,4R,5R,6R)-3-(acetylamino)-2,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-4-yl acetate | n/a | C16H23NO10 | 详情 | 详情 |
| (III) | 21968 | (2R,3R,4R,5S,6R)-3-(acetamido)-5-(acetoxy)-6-[(acetoxy)methyl]-2-chlorotetrahydro-2H-pyran-4-yl acetate | 3068-34-6 | C14H20ClNO8 | 详情 | 详情 |
| (IV) | 53490 | 7-Benzyl-O-esculetin; Esculetin-7-benzyl ether; 6,7-Dihydroxycoumarin-7-benzyl ether | 895-61-4 | C16H12O4 | 详情 | 详情 |
| (V) | 53491 | (2R,3R,4R,5R,6S)-5-(acetylamino)-4-(acetyloxy)-2-[(acetyloxy)methyl]-6-{[7-(benzyloxy)-2-oxo-2H-chromen-6-yl]oxy}tetrahydro-2H-pyran-3-yl acetate | n/a | C30H31NO12 | 详情 | 详情 |
| (VI) | 53492 | N-[(2S,3R,4R,5S,6R)-2-{[7-(benzyloxy)-2-oxo-2H-chromen-6-yl]oxy}-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide | n/a | C24H25NO9 | 详情 | 详情 |
| (VII) | 53493 | 7-hydroxy-6-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2H-chromen-2-one | n/a | C15H16O9 | 详情 | 详情 |
| (VIII) | 53494 | 7-(benzyloxy)-6-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2H-chromen-2-one | n/a | C22H22O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Chlorination and acetylation of N-acetyl glucosamine (I) with acetyl chloride afforded intermediate (II), which was cyclized to the oxazoline (III) with NaHCO3 and tetraethylammonium chloride. Opening of this heterocycle by treatment with 3-pentanol (IV) in the presence of p-toluenesulfonic acid yielded the b-glucoside (V). The primary hydroxyl group of (V) was subsequently deprotected by the following sequence, consisting of hydrolysis of the acetate esters with NaOMe in MeOH to give triol (VI), followed by protection of the primary alcohol as the trityl ether (VIII), acetylation of the secondary alcohols of (VIII), and finally deprotection of the trityl group with aqueous AcOH giving finally (X). Swern oxidation of the resulting primary alcohol (X) using DMSO and SO3-pyridine produced aldehyde (XI).
| 【1】 Smith, P.W.; Robinson, J.E.; Evans, D.N.; Sollis, S.L.; Trivedi, N.; Bethell, R.C.; Howes, P.D.; Sialidase inhibitors related to zanamivir: Synthesis and biological evaluation of 4H-pyran 6-ether and ketone. Bioorg Med Chem Lett 1999, 9, 4, 601. |
| 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) | 21967 | N-[(2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide | C8H15NO6 | 详情 | 详情 | |
| (II) | 21968 | (2R,3R,4R,5S,6R)-3-(acetamido)-5-(acetoxy)-6-[(acetoxy)methyl]-2-chlorotetrahydro-2H-pyran-4-yl acetate | 3068-34-6 | C14H20ClNO8 | 详情 | 详情 |
| (III) | 21969 | (3aR,5R,6R,7R,7aR)-6-(acetoxy)-5-[(acetoxy)methyl]-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]oxazol-7-yl acetate | C14H19NO8 | 详情 | 详情 | |
| (IV) | 21970 | 3-pentanol | 584-02-1 | C5H12O | 详情 | 详情 |
| (V) | 21971 | (2R,3R,4R,5R,6R)-3-(acetamido)-5-(acetoxy)-6-[(acetoxy)methyl]-2-(1-ethylpropoxy)tetrahydro-2H-pyran-4-yl acetate | C19H31NO9 | 详情 | 详情 | |
| (VI) | 21972 | N-[(2R,3R,4R,5S,6R)-2-(1-ethylpropoxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide | C13H25NO6 | 详情 | 详情 | |
| (VII) | 21973 | 1-[chloro[bis(4-methoxyphenyl)]methyl]-4-methoxybenzene; 4-[chloro[bis(4-methoxyphenyl)]methyl]phenyl methyl ether | 49757-42-8 | C22H21ClO3 | 详情 | 详情 |
| (VIII) | 21974 | N-((2R,3R,4R,5S,6R)-2-(1-ethylpropoxy)-4,5-dihydroxy-6-[[tris(4-methoxyphenyl)methoxy]methyl]tetrahydro-2H-pyran-3-yl)acetamide | C35H45NO9 | 详情 | 详情 | |
| (IX) | 21975 | (2R,3R,4R,5R,6R)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-[[tris(4-methoxyphenyl)methoxy]methyl]tetrahydro-2H-pyran-4-yl acetate | C39H49NO11 | 详情 | 详情 | |
| (X) | 21976 | (2R,3R,4R,5R,6R)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl acetate | C17H29NO8 | 详情 | 详情 | |
| (XI) | 21977 | (2R,3R,4R,5R,6S)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2H-pyran-4-yl acetate | C17H27NO8 | 详情 | 详情 |