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【结 构 式】

【分子编号】33832

【品名】[(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate

【CA登记号】

【 分 子 式 】C26H21BrO7

【 分 子 量 】525.35254

【元素组成】C 59.44% H 4.03% Br 15.21% O 21.32%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

The silylation of 1,2,4-triazole-3-carboxylic acid methyl ester (VII) with hexamethyldisylazane (HMDS) gives 1-(trimethylsilyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XII), which is condensed with 2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl bromide (XIII) by means of PNPP at 160 C to afford the previously described intermediate 1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (XI).

1 Laguna, N; Robins, R.K.; Witkowski, J.T. (ICN Pharmaceuticals, Inc.); 1,2,4-Triazole nucleosides. DE 2220246; US 3798209 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 33827 methyl 1H-1,2,4-triazole-3-carboxylate 4928-88-5 C4H5N3O2 详情 详情
(XI) 33830 methyl 1-[(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl]-1H-1,2,4-triazole-3-carboxylate C30H25N3O9 详情 详情
(XII) 33831 methyl 1-(trimethylsilyl)-1H-1,2,4-triazole-3-carboxylate C7H13N3O2Si 详情 详情
(XIII) 33832 [(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate C26H21BrO7 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

Condensation of 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl bromide (X) with diaminomaleonitrile (XI) yields the ribofuranosyl diamine (XII), which is alternatively prepared by N-protection of diamine (XI) with TMSCl in the presence of HMDS in refluxing acetonitrile and subsequent coupling of the obtained bis(silylamine) (XIII) with the D-ribofuranosyl acetate (XIV) by means of TMSOTf in CH2Cl2. Cyclization of diamine (XII) with HC(OEt)3 in the presence of NaOMe in anisole affords the 4,5-dicyanoimidazole derivative (XV), which undergoes regioselective addition of NaOMe in MeOH to give imidate (XVI). Finally, Hofmann rearrangement of imidate (XVI) with NaOCl in the presence of NaOH yields imidazolecarbonitrile (V) .
Alternatively, formylation of diaminomaleonitrile (XI) with HCOOH in benzene leads to N-formyldiaminomaleonitrile (XVII) , which is then silylated with TMSCl in the presence of HMDS to yield the protected amine (XVIII). Finally, amine (XVIII) is condensed with the ribofuranosyl acetate (XIV) in the presence of TMSOTf in CH2Cl2 to give compound (XIX), which undergoes cyclization using AcOH in refluxing benzene yielding nitrile (XV) .

1 Ferris, J.P., Devadas, B., Huang, C.H., Ren, W.Y. Novel synthesis of 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxamide and 5-amino-1-(beta-D-ribopyranosyl)imidazole-4-carboxamide. J Org Chem 1985, 50(6): 747-54.
2 Ohtsuka, Y. Chemistry of diaminomaleonitrile. 1. Selective preparations of monoformyldiaminomaleonitrile and imidazoles by reaction with formicacid. J Org Chem 1976, 41(4): 713-4.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 37430 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carbonitrile C9H12N4O4 详情 详情
(X) 33832 [(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate C26H21BrO7 详情 详情
(XI) 16903 (Z)-2,3-diamino-2-butenedinitrile;diaminomaleonitrile 1187-42-4 C4H4N4 详情 详情
(XII) 68818 (2R,3R,4S,5R)-2-((benzoyloxy)methyl)-5-(((Z)-1,3-diamino-1-cyanoprop-1-en-2-yl)amino)tetrahydrofuran-3,4-diyl dibenzoate C30H24N4O7 详情 详情
(XIII) 68815 (Z)-4-amino-2,3-bis((trimethylsilyl)amino)but-2-enenitrile C10H20N4Si2 详情 详情
(XIV) 26984 (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate C28H24O9 详情 详情
(XV) 68819 (2R,3R,4S,5R)-2-(5-(aminomethyl)-4-cyano-1H-imidazol-1-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate C31H22N4O7 详情 详情
(XVI) 68821 methyl 4-cyano-1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-imidazole-5-carbimidate C11H14N4O5 详情 详情
(XVII) 68816 N-formyldiaminomaleonitrile;(Z)-N-(1,3-diamino-1-cyanoprop-1-en-2-yl)formamide C5H4N4O 详情 详情
(XVIII) 68817 (Z)-N-(3-amino-1-cyano-2-((trimethylsilyl)amino)prop-1-en-1-yl)formamide C8H12N4OSi 详情 详情
(XIX) 68820 (2R,3R,4S,5R)-2-(((Z)-3-amino-1-cyano-2-formamidoprop-1-en-1-yl)amino)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate C31H24N4O8 详情 详情

合成路线3

该中间体在本合成路线中的序号:(X)

Methylation of D-ribose (XX) with MeOH using HCl yields methyl Dribofuranoside (XXI), which is then benzoylated with BzCl in CHCl3/pyr to give the protected intermediate (XXII). Bromination of methyl ether (XXII) with HBr in AcOH furnishes bromide (X). Acetylation of methyl ether (XXII) with Ac2O and AcOH produces acetate (XIV) .

1 Recondo, E.F., Rinderknecht, H. Eine neue, einfache Synthese des 1-OAcetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranosides. Helv Chim Acta 1959, 42(4): 1171.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 33832 [(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate C26H21BrO7 详情 详情
(XIV) 26984 (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate C28H24O9 详情 详情
(XX) 10016 D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal 50-69-1 C5H10O5 详情 详情
(XXI) 41258 (2R,3S,4R)-2-(hydroxymethyl)-5-methoxytetrahydro-3,4-furandiol C6H12O5 详情 详情
(XXII) 12247 [(2R,3R,4R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-furanyl]methyl benzoate C27H24O8 详情 详情
Extended Information