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【结 构 式】 
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【药物名称】 【化学名称】(4S,5R,6R)-4-Amino-6-[N-(2-phenylethyl)-N-propylcarbamoyl]-5-(trifluoroacetamido)-5,6-dihydro-4H-pyran-2-carboxylic acid 【CA登记号】185381-95-7 【 分 子 式 】C20H24F3N3O5 【 分 子 量 】443.42658 |
【开发单位】Biota Scientific Management (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Anti-Influenza A Virus Drugs, Anti-Influenza Virus Drugs, Antiviral Drugs, Neuraminidase (Sialidase) Inhibitors |
合成路线1
Introduction of a Boc protecting group on derivative (I) by treatment with tert-butyldicarbonate and DMAP in dioxane affords 5-N-Boc derivative (II), which is then deacetylated by reaction with NaOMe in MeOH to provide compound (III). Conversion of trihydroxy derivative (III) into carboxylic acid (IV) is performed by first oxidation with sodium periodate in MeOH/H2O followed by treatment with sodium chlorite/potassium dihydrogen orthophosphate in tert-BuOH. Coupling of (IV) with secondary amine (V) by means of TBTU in THF yields phenethylpropyl carbamoyl derivative (VI), whose Boc group is removed by means of HCl in dioxane to give primary amine (VII). Condensation of (VII) with trifluoroacetic anhydride (VIII) in pyridine furnishes trifluoroacetylamino derivative (IX), whose azide group is reduced by means of PPh3 and Et3N in THF/H2O to yield 4-amino derivative (X). Finally, the desired product is obtained by saponification of the methyl ester group of (X) by heating with Et3N in H2O.
| 【1】 Smith, P.W.; et al.; Synthesis and influenza virus sialidase inhibitory activity of analogues of 4-guanidino-Neu5Ac2en (GG167) with modified 5-substituents. Eur J Med Chem 1996, 31, 2, 143. |
| 【2】 Fulton, H.E.; Jack, T.I.; Coomber, B.A.; Colman, P.; Wonacott, A.J.; Varghese, J.; Evans, D.N.; Wyatt, P.G.; Sialidase inhibitors related to zanamivir. Further SAR studies of 4-amino-4H-pyran-2-carboxylic acid-6-propylamides. Bioorg Med Chem Lett 2001, 11, 5, 669. |
| 【3】 Smith, P.; Sollis, S.; Cherry, P.; Howes, P. (Biota Scientific Management Pty Ltd.); 6-Carboxamido dihydropyran derivs.. US 5990156; WO 9636628 . |
| 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) | 15979 | methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C18H24N4O10 | 详情 | 详情 | |
| (II) | 50043 | methyl (2R,3R,4S)-3-[acetyl(tert-butoxycarbonyl)amino]-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C23H32N4O12 | 详情 | 详情 | |
| (III) | 50044 | methyl (2R,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate | C15H24N4O8 | 详情 | 详情 | |
| (IV) | 50045 | (2R,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]-6-(methoxycarbonyl)-3,4-dihydro-2H-pyran-2-carboxylic acid | C13H18N4O7 | 详情 | 详情 | |
| (V) | 50046 | N-phenethyl-1-propanamine; N-phenethyl-N-propylamine | C11H17N | 详情 | 详情 | |
| (VI) | 50047 | methyl (2R,3R,4S)-4-azido-3-[(tert-butoxycarbonyl)amino]-2-[[phenethyl(propyl)amino]carbonyl]-3,4-dihydro-2H-pyran-6-carboxylate | C24H33N5O6 | 详情 | 详情 | |
| (VII) | 50048 | methyl (2R,3R,4S)-3-amino-4-azido-2-[[phenethyl(propyl)amino]carbonyl]-3,4-dihydro-2H-pyran-6-carboxylate | C19H25N5O4 | 详情 | 详情 | |
| (VIII) | 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 |
| (IX) | 50049 | methyl (2R,3R,4S)-4-azido-2-[[phenethyl(propyl)amino]carbonyl]-3-[(2,2,2-trifluoroacetyl)amino]-3,4-dihydro-2H-pyran-6-carboxylate | C21H24F3N5O5 | 详情 | 详情 | |
| (X) | 50050 | methyl (2R,3R,4S)-4-amino-2-[[phenethyl(propyl)amino]carbonyl]-3-[(2,2,2-trifluoroacetyl)amino]-3,4-dihydro-2H-pyran-6-carboxylate | C21H26F3N3O5 | 详情 | 详情 |