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【结 构 式】 
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【药物名称】AP-23317 【化学名称】[4-[2-(4-Aminocyclohexylamino)-9-ethyl-9H-purin-6-ylamino]phenyl](hydroxy)phosphorylmethyl]phosphonic acid 【CA登记号】344585-41-7 (trans-isomer) 【 分 子 式 】C20H29N7O5P2 【 分 子 量 】509.44563 |
【开发单位】Ariad Pharmaceuticals (Originator) 【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Osteoporosis, Src Kinase Inhibitors |
合成路线1
2-Amino-6-chloropurine (I) is converted into the 2-fluoro analogue (II) by diazotization in the presence of fluoroboric acid. Subsequent alkylation of (II) with EtOH under Mitsunobu conditions provides the 9-ethyl purine (III).
| 【1】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III (Ariad Pharmaceuticals Inc.); Novel purines. WO 0144260 . |
| 【2】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. WO 0144259 . |
| 【3】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. US 2002068721 . |
合成路线2
Reaction of phosphinylmethyl phosphonate (IV) with 1-iodo-4-nitrobenzene (V) in the presence of Pd(PPh3)4 affords the nitrophenyl phosphinoyl derivative (VI). Reduction of the nitro group of (VI) to the corresponding aniline (VII) is accomplished by treatment with SnCl2 in ethanol. Then, hydrolysis of the triethyl ester (VII) under acidic conditions furnishes phosphonic acid (VIII). Displacement of the 6-chloro group of purine (III) with the aminophenyl phosphonic acid (VIII) in hot DMSO gives rise to the 6-anilino purine (IX). Finally, displacement of the remaining halogen atom of (IX) with trans-1,4-diaminocyclohexane (X) leads to the title 2,6-diaminopurine compound.
| 【1】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. US 2002068721 . |
| 【2】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. WO 0144259 . |
| 【3】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III (Ariad Pharmaceuticals Inc.); Novel purines. WO 0144260 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 61001 | 6-chloro-9-ethyl-2-fluoro-9H-purine | C7H6ClFN4 | 详情 | 详情 | |
| (IV) | 61002 | diethyl [ethoxy(oxo)phosphoranyl]methylphosphonate | C7H18O5P2 | 详情 | 详情 | |
| (V) | 21845 | 1-iodo-4-nitrobenzene | 636-98-6 | C6H4INO2 | 详情 | 详情 |
| (VI) | 61003 | diethyl [ethoxy(4-nitrophenyl)phosphoryl]methylphosphonate | C13H21NO7P2 | 详情 | 详情 | |
| (VII) | 61004 | diethyl [(4-aminophenyl)(ethoxy)phosphoryl]methylphosphonate | C13H23NO5P2 | 详情 | 详情 | |
| (VIII) | 61005 | [(4-aminophenyl)(hydroxy)phosphoryl]methylphosphonic acid | C7H11NO5P2 | 详情 | 详情 | |
| (IX) | 61006 | [{4-[(9-ethyl-2-fluoro-9H-purin-6-yl)amino]phenyl}(hydroxy)phosphoryl]methylphosphonic acid | C14H16FN5O5P2 | 详情 | 详情 | |
| (X) | 43407 | 4-aminocyclohexylamine; 1,4-cyclohexanediamine | 3114-70-3 | C6H14N2 | 详情 | 详情 |