-Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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.

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)