【结 构 式】 |
【药物名称】CGS-21680 【化学名称】2-[2-[4-(2-Carboxyethyl)phenyl]ethylamino]adenosin-5'-oic acid ethylamide 【CA登记号】120225-54-9 【 分 子 式 】C23H29N7O6 【 分 子 量 】499.53088 |
【开发单位】Novartis (Originator) 【药理作用】Antipsychotic Drugs, CARDIOVASCULAR DRUGS, DERMATOLOGIC DRUGS, Hypertension, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Wound-Healing Agents, Adenosine A2A Agonists |
合成路线1
The intermediate amine (V) was prepared via a Heck reaction between p-bromophenylacetonitrile (I) and tert-butyl acrylate (II) to afford the p-(cyanomethyl)cinnamate (III) . Catalytic double bond hydrogenation in (III) provided the saturated cyano ester (IV), which was then reduced to amine (V) by using NaBH4 in the presence of CoCl2. Alternatively, simultaneous double bond and cyano group reduction was accomplished by hydrogenation of (III) in the presence of Pd/C and HCl.
【1】 Hutchison, A.J.; Williams, M.; de Jesus, R.; Yokoyama, R.; Oei, H.H.; Ghai, G.R.; Webb, R.L.; Zoganas, H.C.; Stone, G.A.; Jarvis, M.F.; 2-(Arylalkylamino)adenosin-5'-uronamides: A new class of highly selective adenosine A2 receptor ligands. J Med Chem 1990, 33, 7, 1919. |
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) | 45829 | 2-(4-bromophenyl)acetonitrile; 4-Bromobenzyl cyanide | 16532-79-9 | C8H6BrN | 详情 | 详情 |
(II) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
(III) | 62371 | tert-butyl (E)-3-[4-(2-nitriloethyl)phenyl]-2-propenoate | C15H17NO2 | 详情 | 详情 | |
(IV) | 62372 | tert-butyl 3-[4-(2-nitriloethyl)phenyl]propanoate | C15H19NO2 | 详情 | 详情 | |
(V) | 62373 | tert-butyl 3-[4-(2-aminoethyl)phenyl]propanoate | C15H23NO2 | 详情 | 详情 |
合成路线2
Acetonide (VII) was prepared by treatment of 2-chloroadenosine (VI) with 2,2-dimethoxypropane and camphorsulfonic acid. Subsequent oxidation of (VII) with KMnO4 under basic conditions produced the carboxylic acid (VIII). After activation of (VIII) as the corresponding acid chloride (IX), reaction with ethylamine afforded amide (X). Condensation of amine (V) with the chloroadenosine derivative (X) at 130 C furnished the diaminopurine adduct (XI). Finally, simultaneous cleavage of the tert-butyl ester and acetonide groups of (XI) upon acidic treatment provided the title compound
【1】 Hutchison, A.J.; Williams, M.; de Jesus, R.; Yokoyama, R.; Oei, H.H.; Ghai, G.R.; Webb, R.L.; Zoganas, H.C.; Stone, G.A.; Jarvis, M.F.; 2-(Arylalkylamino)adenosin-5'-uronamides: A new class of highly selective adenosine A2 receptor ligands. J Med Chem 1990, 33, 7, 1919. |
【2】 Hutchison, A.J. (Novartis AG); Certain adenosine 5'-carboxamide derivs.. AU 8811233; EP 0277917; JP 1988201196 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(V) | 62373 | tert-butyl 3-[4-(2-aminoethyl)phenyl]propanoate | C15H23NO2 | 详情 | 详情 | |
(VI) | 62374 | (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H12ClN5O4 | 详情 | 详情 | |
(VII) | 62375 | [(3aR,4R,6R,6aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | C13H16ClN5O4 | 详情 | 详情 | |
(VIII) | 62376 | (3aR,4S,6R,6aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid | C13H14ClN5O5 | 详情 | 详情 | |
(IX) | 62377 | (3aR,4S,6R,6aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonyl chloride | C13H13Cl2N5O4 | 详情 | 详情 | |
(X) | 62378 | (3aR,4S,6R,6aR)-6-(6-amino-2-chloro-9H-purin-9-yl)-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide | C15H19ClN6O4 | 详情 | 详情 | |
(XI) | 62379 | tert-butyl 3-(4-{2-[(9-{(3aR,4R,6S,6aR)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-amino-9H-purin-2-yl)amino]ethyl}phenyl)propanoate | C30H41N7O6 | 详情 | 详情 |