(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate -Drug Synthesis Database

【结构式】

【分子编号】22299

【品名】(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate

【CA登记号】

【分子式】C₁₆H₁₈ClN₅O₇

【分子量】427.80112

【元素组成】C 44.92% H 4.24% Cl 8.29% N 16.37% O 26.18%

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：(I)

Diazotization of (I) with isoamyl nitrite in the presence of dipropyl disulfide afforded sulfide (III) through the intermediate diazonium salt (II). Further substitution of the chloro atom of (III) for ammonia provided 2-(propylthio)adenosine (IV). The 5'-hydroxyl group of (IV) was then phosphorylated by reaction with phosphoryl chloride in cold triethyl phosphate followed by aqueous work-up. The resulting 5'-monophosphate (V) was treated with carbonyl diimidazole and tri-n-butylamine to produce the phosphoryl imidazole intermediate (VI), which was finally condensed with dichloromethylenebis(phosphonic acid) (X). The target compound was isolated as the tetrasodium salt upon treatment with NaI in methanol-acetone.

参考文献中间体

合成目标

【1】 Ingall, A.H.; Dixon, J.; Bailey, A.; Coombs, M.E.; Cox, D.; McInally, J.I.; Hunt, S.F.; Kindon, N.D.; Teobald, B.J.; Willis, P.A.; Humphries, R.G.; Leff, P.; Clegg, J.A.; Smith, J.A.; Tomlinson, W.; Antagonists of the platelet P2T receptor: A novel approach to antithrombotic therapy. J Med Chem 1999, 42, 2, 213.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	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
(II)	22300	6-Chloro-9-(2'-O,3'-O,5'-O-Triacetyl-beta-D-ribofuranosyl)purine-2-diazonium cation	C₁₆H₁₈ClN₅O₇	详情	详情
(III)	22301	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[6-chloro-2-(propylsulfanyl)-9H-purin-9-yl]tetrahydro-3-furanyl acetate	C₁₉H₂₃ClN₄O₇S	详情	详情
(IV)	22302	(2R,3R,4S,5R)-2-[6-amino-2-(propylsulfanyl)-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol	C₁₃H₁₉N₅O₄S	详情	详情
(V)	22303	[(2R,3S,4R,5R)-5-[6-amino-2-(propylsulfanyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-2-furanyl]methyl dihydrogen phosphate	C₁₃H₂₀N₅O₇PS	详情	详情
(VI)	22304	[(2R,3S,4R,5R)-5-[6-amino-2-(propylsulfanyl)-9H-purin-9-yl]-3,4-dihydroxytetrahydro-2-furanyl]methyl hydrogen 1H-imidazol-1-ylphosphonate	C₁₆H₂₂N₇O₆PS	详情	详情
(X)	22305	dichloro(phosphono)methylphosphonic acid	CH₄Cl₂O₆P₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

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：(III)

Guanosine (I) was protected as the triacetate ester (II) and then chlorinated with POCl3 in the presence of dimethylaniline and tetraethylammonium chloride to give the 6-chloro derivative (III). Diazotization of (III) with tert-butyl nitrite, followed by a modified Sandmeyer reaction provided dichloro purine (IV). Substitution of the 6-chloro of (IV) by 2,2-diphenylethylamine (V) in the presence of diisopropylethylamine in refluxing isopropanol furnished the chloroadenosine derivative (VI), and subsequent removal of the acetate protecting groups of (VI) by hydrolysis with Na2CO3 in aqueous MeOH yielded the adenosine derivative (VII).

参考文献中间体

合成目标

【1】 Gregson, M.; Ayres, B.E.; Ewan, G.B.; Ellis, F.; Knight, J. (Glaxo Wellcome plc); 2,6-Diaminopurine derivs.. EP 0680488; JP 1996505864; US 5925624; WO 9417090 .
【2】 Keeling, S.E.; et al.; The discovery and synthesis of highly potent, A2A receptor agonists. Bioorg Med Chem Lett 2000, 10, 4, 403.

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)	25228	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate		C₁₆H₁₆Cl₂N₄O₇	详情	详情
(V)	38962	2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine	3963-62-0	C₁₄H₁₅N	详情	详情
(VI)	38960	(2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-3-furanyl acetate		C₃₀H₃₀ClN₅O₇	详情	详情
(VII)	38961	(2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol		C₂₄H₂₄ClN₅O₄	详情	详情

Extended Information