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【结 构 式】

【分子编号】38961

【品名】(2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol

【CA登记号】

【 分 子 式 】C24H24ClN5O4

【 分 子 量 】481.93856

【元素组成】C 59.81% H 5.02% Cl 7.36% N 14.53% O 13.28%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VII)

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).

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

合成路线2

该中间体在本合成路线中的序号:(XIII)

Alternatively, condensation of 2,6-dichloropurine (VIII) with protected ribose (IX) at 140 C gave the ribofuranosyl purine (X). Subsequent displacement of the 6-chloro of (V) by amine (V), followed by hydrolysis of the benzoate esters afforded the intermediate (VII).

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
(VIII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(IX) 26984 (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate C28H24O9 详情 详情
(X) 32565 (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate C31H22Cl2N4O7 详情 详情
(XI) 38962 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine 3963-62-0 C14H15N 详情 详情
(XII) 38963 ((2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl benzoate C45H36ClN5O7 详情 详情
(XIII) 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

合成路线3

该中间体在本合成路线中的序号:(VII)

Protection of the 2',3'-diol group of adenosine (VII) as the corresponding acetonide (XII) was effected by treatment with 2,2-dimethoxypropane and p-toluenesulfonic acid. The primary alcohol group of (XII) was then oxidized to carboxylic acid (XIII) using KMnO4. After conversion of (XIII) to acid chloride by means of refluxing SOCl2, coupling with ethylamine furnished amide (XIV). Displacement of the 2-chloro of (XIV) by histamine (XV) in hot DMSO produced adduct (XVI). The acetonide group of (XVI) was finally deprotected using aqueous trifluoroacetic acid.

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
(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
(XII) 38964 ((3aR,4R,6R,6aR)-6-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol C27H28ClN5O4 详情 详情
(XIII) 38965 (3aR,4S,6R,6aR)-6-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid C27H26ClN5O5 详情 详情
(XIV) 38966 (3aR,4S,6R,6aR)-6-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide C29H31ClN6O4 详情 详情
(XV) 38967 2-(1H-imidazol-4-yl)ethylamine; 2-(1H-imidazol-4-yl)-1-ethanamine 51-45-6 C5H9N3 详情 详情
(XVI) 38968 (3aR,4S,6R,6aR)-6-(6-[(2,2-diphenylethyl)amino]-2-[[2-(1H-imidazol-4-yl)ethyl]amino]-9H-purin-9-yl)-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide C34H39N9O4 详情 详情
Extended Information