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【结 构 式】

【药物名称】

【化学名称】5'-O-[[2-(Adenin-9yl)-1,2-dideoxy-5-O-(phosphonooxy)-D-arabinofuranos-3-yloxy](hydroxy)phosphoryl]-2-deoxycytidine

【CA登记号】

【 分 子 式 】C19H26N8O12P2

【 分 子 量 】620.41307

【开发单位】National Cancer Institute (Originator), University of Iowa (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Integrase Inhibitors

合成路线1

Demethylation of compound (XI) by means of BBr3 in refluxing dichloromethane gives 5-hydroxytetralinyl derivative (XII), which is then condensed with bromoacetic acid ethyl ester (XIII) by means of K2CO3 in DMF or acetonitrile to furnish (ethoxycarbonylmethoxy)tetraline derivative (XIV). Finally, the target product is obtained by saponification of the ethyl ester group of (XIV) by means of NaOH in 1,2-dimethoxyethane.

1 Wenzel, T.; Nair, V.; Self-complementary oligodeoxyribonucleotides incorporating L-related isodeoxynucleosides: Synthesis, physical characterization, enzymology, and CD studies. Bioconjugate Chem 1998, 9, 6, 683.
2 Nair, V.; Taktakishvili, M.; Pommier, Y.; Neamati, N.; Recognition and inhibition of HIV integrase by a novel dinucleotide. Bioorg Med Chem Lett 2000, 10, 3, 249.
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) 46810 (2R,3S,4S)-2-(hydroxymethyl)tetrahydro-3,4-furandiol C5H10O4 详情 详情
(II) 46811 (2R,3S,4S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)tetrahydro-3,4-furandiol C21H28O4Si 详情 详情
(III) 46812 (2R,3R,4S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydro-3-furanol C24H34O4SSi 详情 详情
(IV) 46813 tert-butyl(diphenyl)silyl ((2R,3R,4S)-3-[[tert-butyl(diphenyl)silyl]oxy]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydro-2-furanyl)methyl ether; tert-butyl[((2R,3R,4S)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydro-3-furanyl)oxy]diphenylsilane C40H52O4SSi2 详情 详情
(V) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(VI) 46814 (2R,3S,4R)-4-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol C10H13N5O3 详情 详情
(VII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(VIII) 46815 N-[9-[(3R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-3-furanyl]-9H-purin-6-yl]benzamide C17H17N5O4 详情 详情
(IX) 46816 N-[9-((3R,4S,5R)-5-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]-4-hydroxytetrahydro-3-furanyl)-9H-purin-6-yl]benzamide C38H35N5O6 详情 详情
(X) 46817 sodium [((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)oxophosphoranolate C44H38ClN5NaO9P 详情 详情
(XI) 46818 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-(hydroxymethyl)tetrahydro-3-furanyl acetate C18H19N3O6 详情 详情
(XII) 46819 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate C62H56ClN8O14P 详情 详情
(XIII) 46820 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[[(2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-(hydroxymethyl)tetrahydro-3-furanyl]oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate C41H38ClN8O12P 详情 详情
(XIV) 46821 cyanomethyl dihydrogen phosphate C2H4NO4P 详情 详情

合成路线2

The condensation of the cyclic sulfite (I) with N6-benzoyladenine (II) gives the isoadenosine (III), which is condensed with 2-chlorophenylphosphono-bis-triazolide (ClPTr) to yield the phosphate diester (IV). The condensation of (IV) with the deoxycytidine (V) by means of triisopropylbenzenesulfonyl tetrazolide (TPS-TAZ) affords the phosphoric ester (VI), which is treated with dichloroacetic acid (Cl2HOAc) in order to eliminate the dimethoxytrityl protecting group and provide the hydroxymethyl derivative (VII). The phosphorylation of (VII) by means of 2-cyanoethyl phosphate (VIII) gives the protected intermediate (IX), which is finally treated with hot NH4OH to yield the target bis nucleoside phosphate.

1 Taktakishvili, M.; Nair, V.; Pal, s.; Neamati, N.; Pommier, Y.; Recognition and inhibition of HIV integrase by novel dinucleotides. J Am Chem Soc 2000, 122, 24, 5671.
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) 50021 (3aR,4R)-4-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydrofuro[3,4-d][1,3]dioxol-2-one C27H26O7 详情 详情
(II) 10035 N-(9H-Purin-6-yl)benzamide; N6-Benzoyladenine 4005-49-6 C12H9N5O 详情 详情
(III) 46816 N-[9-((3R,4S,5R)-5-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]-4-hydroxytetrahydro-3-furanyl)-9H-purin-6-yl]benzamide C38H35N5O6 详情 详情
(IV) 46817 sodium [((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)oxophosphoranolate C44H38ClN5NaO9P 详情 详情
(V) 46818 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-(hydroxymethyl)tetrahydro-3-furanyl acetate C18H19N3O6 详情 详情
(VI) 46819 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[((2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[[bis(4-methoxyphenyl)(phenyl)methoxy]methyl]tetrahydro-3-furanyl)oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate C62H56ClN8O14P 详情 详情
(VII) 46820 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[[[(2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-(hydroxymethyl)tetrahydro-3-furanyl]oxy](2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate C41H38ClN8O12P 详情 详情
(VIII) 50022 2-cyanoethyl dihydrogen phosphate C3H6NO4P 详情 详情
(IX) 50023 (2R,3S,5R)-5-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-2-([[([(2R,3S,4R)-4-[6-(benzoylamino)-9H-purin-9-yl]-2-[(phosphonooxy)methyl]tetrahydro-3-furanyl]oxy)(2-chlorophenoxy)phosphoryl]oxy]methyl)tetrahydro-3-furanyl acetate C41H39ClN8O15P2 详情 详情
Extended Information