|
【结 构 式】 
|
【药物名称】 【化学名称】1-Deoxy-1-[2-[2-(1H-imidazol-4-yl)ethylamino]-6-(2,2-diphenylethylamino)-9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamide trifluoroacetate 【CA登记号】167465-88-5 (as hydrochloride), 167298-03-5 (free base) 【 分 子 式 】C33H36F3N9O6 【 分 子 量 】711.70677 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Adenosine A2A Agonists |
合成路线1
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
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
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 |