(2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide -Drug Synthesis Database

【结构式】

【分子编号】22401

【品名】(2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

【CA登记号】

【分子式】C₁₂H₁₅IN₆O₄

【分子量】434.19361

【元素组成】C 33.2% H 3.48% I 29.23% N 19.36% O 14.74%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

2-Iodoadenosine (I) was protected as the ketal (II) on treatment with p-toluenesulfonic in an excess of acetone. This compound was oxidized to the acid (III) with potassium permanganate in aqueous alkaline solution. Deprotection of the ketal was accomplished on heating in 50% formic acid to give IV, which was then esterified in ethanolic solution by means of dropwise addition of thionyl chloride. The resulting ethyl ester (V) was dissolved in liquid ethylamine to afford amide (VI). Finally, VI was coupled with 1-phenyl-2-propyn-1-ol (VII) in the presence of triethylamine and a trace of bis(triphenylphosphine)palladium dichloride and cuprous iodide, to yield the title compound.

参考文献中间体

合成目标

【1】 Dionisotti, S.; Ongini, E.; Camaioni, E.; Volpini, R.; Zocchi, C.; Conti, A.; Vittori, S.; Monopoli, A.; Cristalli, G.; 2-Alkynyl derivatives of adenosine-5'-N-ethylurona. J Med Chem 1994, 37, 11, 1720.
【2】 Cristalli, G. (Schering Corp.); Adenosine derivs. having A2 agonist activity. US 5593975; WO 9322328 .

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)	22396	(2R,3R,4S,5R)-2-(6-amino-2-iodo-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol	35109-88-7	C₁₀H₁₂IN₅O₄	详情	详情
(II)	22397	[(3aR,4R,6R,6aR)-6-(6-amino-2-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol		C₁₃H₁₆IN₅O₄	详情	详情
(III)	22398	(3aR,4S,6R,6aR)-6-(6-amino-2-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid		C₁₃H₁₄IN₅O₅	详情	详情
(IV)	22399	(2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furancarboxylic acid		C₁₀H₁₀IN₅O₅	详情	详情
(V)	22400	ethyl (2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furancarboxylate		C₁₂H₁₄IN₅O₅	详情	详情
(VI)	22401	(2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide		C₁₂H₁₅IN₆O₄	详情	详情
(VII)	22402	1-phenyl-2-propyn-1-ol	4187-87-5	C₉H₈O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The intermediate iodopurine (IX) was prepared as follows. Acetylation of guanosine (I) afforded the triacetate ester (II). Subsequent chlorination of (II) to the 6-chloropurine (III) was accomplished by treatment with phosphoryl chloride and N,N-dimethylaniline. Diazotization of (III) with isoamyl nitrite in the presence of CuI furnished the 6-chloro-2-iodopurine (IV). Displacement of the 6-chloro group of (IV) in liquid ammonia with concomitant ammonolysis of the acetate esters gave rise to the 6-amino derivative (V). The dioxolane ketal (VI) was then formed by treatment of (V) with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid. After oxidation of the primary alcohol of (VI) with alkaline KMnO4 to give (VII), its ketal hydrolysis using 50% formic acid produced the carboxylic acid (VIII). The required N-ethyl amide (IX) was then obtained by esterification with SOCl2/EtOH, followed by treatment with liquid ethylamine.

参考文献中间体

合成目标

【1】 Linden, J.M.; MacDonald, T.; Glover, D.K.; Beller, G.A. (University of Virginia); Induction of pharmacological stress with adenosine receptor agonists. JP 2003502433; WO 0078774 .

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)	38958	Guanosine; 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one	118-00-3	C₁₀H₁₃N₅O₅	详情	详情
(II)	38959	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₉N₅O₈	详情	详情
(III)	22299	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₈ClN₅O₇	详情	详情
(IV)	59471	(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-iodo-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₆ClIN₄O₇	详情	详情
(V)	22396	(2R,3R,4S,5R)-2-(6-amino-2-iodo-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol	35109-88-7	C₁₀H₁₂IN₅O₄	详情	详情
(VI)	22397	[(3aR,4R,6R,6aR)-6-(6-amino-2-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol		C₁₃H₁₆IN₅O₄	详情	详情
(VII)	22398	(3aR,4S,6R,6aR)-6-(6-amino-2-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid		C₁₃H₁₄IN₅O₅	详情	详情
(VIII)	22399	(2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-3,4-dihydroxytetrahydro-2-furancarboxylic acid		C₁₀H₁₀IN₅O₅	详情	详情
(IX)	22401	(2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide		C₁₂H₁₅IN₆O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

1,4-Cyclohexanedimethanol (X) was converted to the mono-tosylate (XI), which was then condensed with lithium acetylide ethylenediamine complex to furnish (4-propargylcyclohexyl)methanol (XII). This procedure was further improved with the protection of diol (X) as the mono-silyl ether (XIII). Tosylation of (XIII) and subsequent reaction with lithium acetylide afforded (XIV), which was then desilylated to (XII) by means of tetrabutylammonium fluoride. Alcohol (XII) was oxidized by Jones reagent to the corresponding carboxylic acid (XV). This was converted into the methyl ester (XVI) by treatment with trimethylsilyl diazomethane. Finally, palladium-catalyzed coupling of the iodopurine (IX) with acetylene (XVI) gave rise to the title compound.

参考文献中间体

合成目标

【1】 Sullivan, G.W.; Rieger, J.M.; Brown, M.L.; Macdonald, T.L.; Linden, J.; Design, synthesis, and evaluation of novel A2A adenosine receptor agonists. J Med Chem 2001, 44, 4, 531.
【2】 Linden, J.M.; MacDonald, T.; Glover, D.K.; Beller, G.A. (University of Virginia); Induction of pharmacological stress with adenosine receptor agonists. JP 2003502433; WO 0078774 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	22401	(2S,3S,4R,5R)-5-(6-amino-2-iodo-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide	C₁₂H₁₅IN₆O₄	详情	详情
(X)	59472	[4-(hydroxymethyl)cyclohexyl]methanol	C₈H₁₆O₂	详情	详情
(XI)	59473	[4-(hydroxymethyl)cyclohexyl]methyl 4-methylbenzenesulfonate	C₁₅H₂₂O₄S	详情	详情
(XII)	59474	[4-(2-propynyl)cyclohexyl]methanol	C₁₀H₁₆O	详情	详情
(XIII)	59475	[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methanol	C₁₄H₃₀O₂Si	详情	详情
(XIV)	59476	tert-butyl(dimethyl)silyl [4-(2-propynyl)cyclohexyl]methyl ether; tert-butyl(dimethyl){[4-(2-propynyl)cyclohexyl]methoxy}silane	C₁₆H₃₀OSi	详情	详情
(XV)	59477	4-(2-propynyl)cyclohexanecarboxylic acid	C₁₀H₁₄O₂	详情	详情
(XVI)	59478	methyl 4-(2-propynyl)cyclohexanecarboxylate	C₁₁H₁₆O₂	详情	详情

Extended Information