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【结 构 式】 
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【药物名称】 【化学名称】(2R,3R,4S)-3-(Acetamido)-4-amino-2-(1-ethylpropoxy)-3,4-dihydro-2H-pyran-6-carboxylic acid 【CA登记号】 【 分 子 式 】C13H22N2O5 【 分 子 量 】286.33069 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Anti-Influenza Virus Drugs, Antiviral Drugs, Neuraminidase (Sialidase) Inhibitors |
合成路线1
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 |
合成路线2
Aldehyde (XI) was further converted to unsaturated acid (XII) with sodium chlorite and sulfamic acid. Acid (XII) was converted to methyl ester (XIII) by treatment with N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU) and MeOH, and then cyclized to oxazoline (XIV) using trimethylsilyl triflate. Opening of the oxazoline (XIV) with trimethylsilyl azide in tert-butanol gave azide (XV), together with its epimer. Reduction of azide (XV) with SnCl2 gave amine (XVI). Finally, hydrolysis of the methyl ester of (XVI) with aqueous triethylamine afforded the target carboxylic acid.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XII) | 21978 | (2S,3R,4S)-3-(acetamido)-4-(acetoxy)-2-(1-ethylpropoxy)-3,4-dihydro-2H-pyran-6-carboxylic acid | C15H23NO7 | 详情 | 详情 | |
| (XIII) | 21979 | methyl (2R,3R,4S)-3-(acetamido)-4-(acetoxy)-2-(1-ethylpropoxy)-3,4-dihydro-2H-pyran-6-carboxylate | C16H25NO7 | 详情 | 详情 | |
| (XIV) | 21980 | methyl (3aR,4R,7aR)-4-(1-ethylpropoxy)-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate | C14H21NO5 | 详情 | 详情 | |
| (XV) | 21981 | methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-(1-ethylpropoxy)-3,4-dihydro-2H-pyran-6-carboxylate | C14H22N4O5 | 详情 | 详情 | |
| (XVI) | 21982 | methyl (2R,3R,4S)-3-(acetamido)-4-amino-2-(1-ethylpropoxy)-3,4-dihydro-2H-pyran-6-carboxylate | C14H24N2O5 | 详情 | 详情 |