Cordycepin, 3-dA, -Drug Synthesis Database

【结构式】

【药物名称】Cordycepin, 3-dA

【化学名称】3'-Deoxyadenosine

【CA登记号】73-03-0

【分子式】C₁₀H₁₃N₅O₃

【分子量】251.24681

【开发单位】National Cancer Institute (Originator), OxiGene (Licensee)

【药理作用】Leukemia Therapy, Oncolytic Drugs

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The enantioselective epoxidation of allyl alcohol (I) with 2-phenylisopropyl hydroperoxide (II) and Ti(iPrO)4 in the presence of D-diisopropyl tartrate gives the chiral epoxide (III), which is esterified with pivaloyl chloride to yield the pivalate (IV). The opening of the epoxide ring of (IV) by means of lithium acetylide (V) and BF3/Et2O affords the alkynyl alcohol (VI), which is cyclized by means of Mo(CO)6 and trimethylamine oxide to provide the chiral dihydrofuran (VII). The oxidation of (VII) with OsO4 and 4-methylmorpholine-N-oxide (NMMO) gives the diol (VIII), which is treated with Ac2O to yield the diacetate (IX). The condensation of (IX) with N6-benzoyl-N6,7-bis(trimethylsilyl)adenine (X) by means of Tms-OTf affords the nucleoside (XI). Finally, this compound is deprotected by means of NaOMe in methanol.

参考文献中间体

【1】 Gleason, M.M.; McDonald, F.E.; Asymmetric synthesis of nucleosides via molybdenum-catalyzed alkynol cycloisomerization coupled with stereoselective glycosylations of deoxyfuranose glycals and 3-amidofuranose glycals. J Am Chem Soc 1996, 118, 28, 6648.
【2】 Gleason, M.M.; McDonald, F.E.; Asymmetric syntheses of stavudine (d4T) and cordycepin by cycloisomerization of alkynyl alcohols to endocyclic enol ethers. Angew Chem. Int Ed Engl 1995, 34, 3, 350.

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)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(II)	49206	alpha,alpha-Dimethylbenzyl hydroperoxide; Cumyl hydroperoxide; Cumene Hydroperoxide	80-15-9	C₉H₁₂O₂	详情	详情
(III)	16260	(R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol	57044-25-4	C₃H₆O₂	详情	详情
(IV)	12235	(2S)oxiranylmethyl pivalate		C₈H₁₄O₃	详情	详情
(V)	17461	ethynyllithium		C₂HLi	详情	详情
(VI)	12260	diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate		C₁₅H₁₅F₃O₆	详情	详情
(VII)	12226	(2S)-2,3-dihydro-2-furanylmethyl pivalate		C₁₀H₁₆O₃	详情	详情
(VIII)	49207	[(2S,4R,5R)-4,5-dihydroxytetrahydro-2-furanyl]methyl pivalate		C₁₀H₁₈O₅	详情	详情
(IX)	49208	[(2S,4R,5S)-4,5-bis(acetoxy)tetrahydro-2-furanyl]methyl pivalate		C₁₄H₂₂O₇	详情	详情
(X)	49209	N-(trimethylsilyl)-N-[7-(trimethylsilyl)-7H-purin-6-yl]benzamide		C₁₈H₂₅N₅OSi₂	详情	详情
(XI)	49210	[(2S,4R,5R)-4-(acetoxy)-5-[6-(benzoylamino)-9H-purin-9-yl]tetrahydro-2-furanyl]methyl pivalate		C₂₄H₂₇N₅O₆	详情	详情

合成路线2

The reaction of adenosine (I) 2-acetoxyisobutyryl bromide (A) in acetonitrile/water gives a mixture of the 3-bromo (II) and 2-bromo nucleosides (III), which is treated with Dowex (OH), Amberlite (OH) or methanolic NaOMe to yield the epoxide (IV). Finally, this compound is reduced with LiEt3BH in THF/DMSO or LiAlH4 in THF to afford a mixture of the 2'-deoxy nucleoside (V) and the target compound that are separated by chromatography. Alternatively, the mixture of the nucleosides (II) and (III) is debrominated by reaction with Bu3SnH and AIBN in refluxing toluene to give the same mixture of (V) and the target compound that is separated as before.

参考文献中间体

【1】 Russell, A.F.; et al.; Reactions of 2-acyloxyisobutyryl halides with nucleosides. II. Reactions of adenosine. J Am Chem Soc 1973, 95, 12, 4025.
【2】 Hansske, F.; Robins, M.J.; Regiospecific and stereoselective conversion of ribonucleosides to 3'-deoxynucleosides. A high yield three-stage synthesis of cordycepin from adenosine. Tetrahedron Lett 1985, 26, 36, 4295.
【3】 Bazin, H.; Chattopadhyaya, J.; A convenient preparation of 3'-deoxyadenosine (cordycepin) and 9-[3'(R)-deuterio-beta-D-2'(R)-pentofuranosyl]-adenine. Synthesis 1985, 1108.
【4】 Robins, M.J.; et al.; Nucleic acid related compounds. 88. Efficient conversions of ribonucleosides into their 2',3'-anhydro, 2'(and 3')-deoxy, 2',3'-didehydro-2',3'-dideoxy, and 2',3'-dideoxynucleoside analogues. J Org Chem 1995, 60, 24, 7902.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	49211	1-(bromocarbonyl)-2-methylpropyl acetate		C₇H₁₁BrO₃	详情	详情
(I)	11988	Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol	58-61-7	C₁₀H₁₃N₅O₄	详情	详情
(II)	49212	(2R,3S,4S,5R)-2-(6-amino-9H-purin-9-yl)-4-bromo-5-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate		C₁₈H₂₂BrN₅O₇	详情	详情
(III)	36390	(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-bromo-2-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate		C₁₈H₂₂BrN₅O₇	详情	详情
(IV)	48061	1-[3-(2,3-dihydro-1H-inden-5-yloxy)-2-[(2-methoxyethoxy)methyl]-3-oxopropyl]cyclopentanecarboxylic acid		C₂₂H₃₀O₆	详情	详情
(V)	49213	[(1S,2R,4R,5R)-4-(6-amino-9H-purin-9-yl)-3,6-dioxabicyclo[3.1.0]hex-2-yl]methanol		C₁₀H₁₁N₅O₃	详情	详情

合成路线3

The reaction of adenosine (I) with triethyl orthoacetate (II) by means of Ts-OH in acetonitrile gives the bicyclic dioxolane (III), which is treated with acetyl bromide in dichloroethane to yield the acetylated bromonucleoside (IV). The debromination of (IV) by means of Bu3SnH in toluene affords the acetylated target compound (V), which is finally deprotected with ammonia in methanol.

参考文献中间体

【1】 Norman, D.G.; Reese, C.B.; A convenient preparation of 3'-deoxyadenosine. Synthesis 1983, 304.

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)	11988	Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol	58-61-7	C₁₀H₁₃N₅O₄	详情	详情
(II)	12940	1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate	78-39-7	C₈H₁₈O₃	详情	详情
(III)	49214	[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2-ethoxy-2-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol		C₁₄H₁₉N₅O₅	详情	详情
(IV)	17629	[(2R,3S,4S,5R)-4-(acetoxy)-5-(6-amino-9H-purin-9-yl)-3-bromotetrahydro-2-furanyl]methyl acetate		C₁₄H₁₆BrN₅O₅	详情	详情
(V)	49215	[(2S,4R,5R)-4-(acetoxy)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate		C₁₄H₁₇N₅O₅	详情	详情

合成路线4

The reaction of adenosine (I) with 2-acetoxyisobutyryl bromide (A) gives the 3'-bromonucleoside (II) along with some 3'-bromo regioisomer (III). The reaction of the desired isomer (II) with HCl in methanol yields the intermediate acetylated 3'-bromonucleoside (V) and finally the 3'-bromo-3'-deoxyadenosine (VI). This compound is then debrominated by hydrogenation with H2 over Pd/C in ethanol/water.

参考文献中间体

【1】 Aman, S.; et al.; From adenosine to 3'-deoxyadenosine: Development and scale up. Org Process Res Dev 2000, 4, 6, 601.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	49211	1-(bromocarbonyl)-2-methylpropyl acetate		C₇H₁₁BrO₃	详情	详情
(I)	11988	Adenosine; (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol	58-61-7	C₁₀H₁₃N₅O₄	详情	详情
(II)	49212	(2R,3S,4S,5R)-2-(6-amino-9H-purin-9-yl)-4-bromo-5-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate		C₁₈H₂₂BrN₅O₇	详情	详情
(III)	36390	(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-bromo-2-[[(2,4,4-trimethyl-5-oxo-1,3-dioxolan-2-yl)oxy]methyl]tetrahydro-3-furanyl acetate		C₁₈H₂₂BrN₅O₇	详情	详情
(IV)	17629	[(2R,3S,4S,5R)-4-(acetoxy)-5-(6-amino-9H-purin-9-yl)-3-bromotetrahydro-2-furanyl]methyl acetate		C₁₄H₁₆BrN₅O₅	详情	详情
(V)	49216	(2R,3S,4R,5R)-2-(6-amino-9H-purin-9-yl)-4-bromo-5-(hydroxymethyl)tetrahydro-3-furanol		C₁₀H₁₂BrN₅O₃	详情	详情

Extended Information