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【结 构 式】 
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【分子编号】15979 【品名】methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate 【CA登记号】 |
【 分 子 式 】C18H24N4O10 【 分 子 量 】456.40952 【元素组成】C 47.37% H 5.3% N 12.28% O 35.05% |
合成路线1
该中间体在本合成路线中的序号：(V)1) The esterification of N-acetylneuraminic acid (I) with methanol/HCl gives the corresponding methyl ester (II), which is acetylated with acetic anhydride, pyridine and dimethylaminopyridine (DMAP) yielding the pentaacetate (III). The reaction of (III) with trimethylsilyl trifluoromethanesulfonate in ethyl acetate affords the 2,3-didehydro derivative (IV), which is treated with trimethylsilyl azide in butanol to give the 4-azido derivative (V). The selective deacetylation of (V) with sodium methoxide in methanol yields N-acetyl-4-azido-2,4-dideoxy-2,3-didehydroneuraminic acid methyl ester (VI), which is reduced with H2 over Lindlar catalyst (Pd-Pb) in water and treated with Dowex 8x2 resin to afford the N-acetyl-4-amino-2,4-dideoxy-2,3-didehydroneuraminic acid (VII). The reaction of (VII) with BrCN and sodium acetate in methanol gives the corresponding 4-cyanoamino derivative (VIII), which is converted into the final product by reaction with ammonium formate in aqueous NH4OH. 2) The amino derivative (VII) can be converted directly into the final product by reaction with amidinosulfonic acid (X), NaOH and K2CO3 in water. 3) The amino derivative (VII) can also be converted directly into the final product by reaction with pyrazole-1-carboxamidine (XI) and triethylamine in water.
| 【1】 Chandler, M.; Bamford, M.J.; Conroy, R.; et al.; Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-Ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-gluco-nononic acid. J Chem Soc - Perkins Trans I 1995, 9, 7, 1173-80. |
| 【2】 von Itzstein, M.; Wu, W.-Y.; Jin, B.; The synthesis of 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid: A potent influenza virus sialidase inhibitor. Carbohydr Res 1994, 259, 2, 301-5. |
| 【3】 Fromtling, R.; Castaner, J.; Zanamivir. Drugs Fut 1996, 21, 4, 375. |
| 【4】 Weir, N.G.; Chandler, M.; Bamford, M.J. (Glaxo Wellcome plc); Synthesis of N-acetyl neuraminic acid derivs. WO 9407885 . |
| 【5】 Patel, V. (Glaxo Wellcome plc); Synthesis of N-acetyl neuraminic acid derivs. WO 9407886 . |
| 【6】 Chandler, M.; Weir, N. (Glaxo Wellcome plc); Preparation of N-acetyl neuraminic derivs. WO 9312105 . |
| 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) | 15975 | (2S,4S,5R,6R)-5-(acetamido)-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydro-2H-pyran-2-carboxylic acid | 131-48-6 | C11H19NO9 | 详情 | 详情 |
| (II) | 15976 | methyl (2S,4S,5R,6R)-5-(acetamido)-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydro-2H-pyran-2-carboxylate | 50998-13-5 | C12H21NO9 | 详情 | 详情 |
| (III) | 15977 | methyl (2R,4S,5S,6R)-5-(acetamido)-2,4-bis(acetoxy)-6-[(1S,2R)-1,2,3-tris(acetoxy)propyl]tetrahydro-2H-pyran-2-carboxylate | C22H31NO14 | 详情 | 详情 | |
| (IV) | 15978 | methyl (3aS,4R,7aR)-2-methyl-4-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate | C18H23NO10 | 详情 | 详情 | |
| (V) | 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 | |
| (VI) | 15980 | methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate | C12H18N4O7 | 详情 | 详情 | |
| (VII) | 15981 | (2R,3R,4S)-3-(acetamido)-4-amino-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid | C11H18N2O7 | 详情 | 详情 | |
| (VIII) | 15982 | (2R,3R,4S)-3-(acetamido)-4-(cyanoamino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid | C12H17N3O7 | 详情 | 详情 | |
| (IX) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (X) | 15984 | amino(imino)methanesulfonic acid | CH4N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)4) The selective deacetylation of 4-O,5-N,7-O,8-O,9-O-pentaacetyl-2,3-didehydro-2-deoxyneuraminic acid (XI) with boron trifluoride ethearate in benzene/methanol gives the 4-deacetyl derivative (XII), which is treated with trifluoromethanesulfonic anhydride in dichloromethane and with sodium azide in DMF to obtain the 4-azido-4-deoxy derivative (XIII). The reduction of (XIII) with H2S in pyridine affords the corresponding 4-amino derivative (XIV), which is finally condensed with S-methylisothiourea in water and saponified through Dowex 50W x 8 in aqueous NH4OH.
| 【1】 Von Itzstein, L.M.; Wu, W.-Y.; Phan, T.; Danylec, B.; Derivs. and analogues of 2-deoxy-2,3-didehydro-N-acetyl neuraminic acid and their use as antiviral agents. EP 0786458; WO 9116320 . |
| 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) | 15985 | methyl (2R,3S,4S)-3-(acetamido)-4-(acetoxy)-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C20H27NO12 | 详情 | 详情 | |
| (XII) | 15986 | methyl (2R,3R,4S)-3-(acetamido)-4-hydroxy-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C18H25NO11 | 详情 | 详情 | |
| (XIII) | 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 | |
| (XIV) | 15988 | methyl (2R,3R,4S)-3-(acetamido)-4-amino-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate | C18H26N2O10 | 详情 | 详情 | |
| (XV) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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 |