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【结 构 式】 
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【分子编号】61006 【品名】[{4-[(9-ethyl-2-fluoro-9H-purin-6-yl)amino]phenyl}(hydroxy)phosphoryl]methylphosphonic acid 【CA登记号】 |
【 分 子 式 】C14H16FN5O5P2 【 分 子 量 】415.2576672 【元素组成】C 40.49% H 3.88% F 4.58% N 16.87% O 19.26% P 14.92% |
合成路线1
该中间体在本合成路线中的序号：(IX)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 |
合成路线2
该中间体在本合成路线中的序号：(VI)The oxidation of Josamycin (I) with CrO3 and pyridine, followed by reaction with Ac2O, AcCl and methanol gives the macrocyclic dimethyl acetal (II), which is treated with NaBH4 and a Ru catalyst to promote a ring contraction yielding the 14-member macrocycle (III). The reduction of the double bond of (III) with H2 over PtO2 affords the saturated macrocycle (IV), which is treated first with MsCl and TEA and then with NaN3 to afford the azido macrocycle (V). The treatment of (V) with TFA provides the azido aldehyde (VI), which is finally reduced to the corresponding amine and simultaneously methylated by means of H2 over Pd/C in the presence of formaldehyde to furnish the target 14-member macrocyclic lactone.
| 【1】 Vo, N.H.; Wang, J.; Haley, T.; Napper, A.; Phan, L.T.; Or, Y.; 9-Amino derivatives of novel 14-membered ring macrolide antibiotics derived from leucomycins: Chemistry and in vitro biological activities. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1664. |
| 【2】 Or, Y.S.; Wang, J.; Phan, L.T.; Vo, N. (Enanta Pharmaceuticals, Inc.); 9-Amino-14-membered macrolides derived from leucomycins. US 6436906; WO 0281493 . |
| 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) | 62001 | (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,6R)-6-{[(4R,5R,6S,8R,9R,10R,16R)-4-(acetyloxy)-10-hydroxy-5-methoxy-9,16-dimethyl-2-oxo-8-(2-oxoethyl)oxa-11,13-cyclohexadecadien-6-yl]oxy}-4-(dimethylamino)-5-hydroxy-2-methyltetrahydro-2H-pyran-3-yl]oxy}-4-hydroxy-2,4-dimethyltetrahydro-2H-pyran-3-yl 3-methylbutanoate | C42H69NO15 | 详情 | 详情 | |
| (II) | 62002 | (2S,3S,4R,6R)-6-{[(2R,3S,4S,5R,6R)-5-(acetyloxy)-6-{[(4R,5R,6S,8R,9R,16R)-4-(acetyloxy)-8-(2,2-dimethoxyethyl)-5-methoxy-9,16-dimethyl-2,10-dioxooxa-11,13-cyclohexadecadien-6-yl]oxy}-4-(dimethylamino)-2-methyltetrahydro-2H-pyran-3-yl]oxy}-4-hydroxy-2,4-dimethyltetrahydro-2H-pyran-3-yl 3-methylbutanoate | C46H75NO17 | 详情 | 详情 | |
| (III) | 62003 | (2S,3S,4R,6R)-6-{[(2R,3S,4S,5R,6R)-5-(acetyloxy)-6-{[(4R,5R,6S,8R,9R,10R,14R)-4-(acetyloxy)-8-(2,2-dimethoxyethyl)-10-hydroxy-5-methoxy-9,14-dimethyl-2-oxooxa-11-cyclotetradecen-6-yl]oxy}-4-(dimethylamino)-2-methyltetrahydro-2H-pyran-3-yl]oxy}-4-hydroxy-2,4-dimethyltetrahydro-2H-pyran-3-yl 3-methylbutanoate | C44H75NO17 | 详情 | 详情 | |
| (IV) | 62004 | (2S,3S,4R,6R)-6-{[(2R,3S,4S,5R,6R)-5-(acetyloxy)-6-{[(4R,5R,6S,8R,9R,10R,14R)-4-(acetyloxy)-8-(2,2-dimethoxyethyl)-10-hydroxy-5-methoxy-9,14-dimethyl-2-oxooxacyclotetradecanyl]oxy}-4-(dimethylamino)-2-methyltetrahydro-2H-pyran-3-yl]oxy}-4-hydroxy-2,4-dimethyltetrahydro-2H-pyran-3-yl 3-methylbutanoate | C44H77NO17 | 详情 | 详情 | |
| (V) | 62005 | (2S,3S,4R,6R)-6-{[(2R,3S,4S,5R,6R)-5-(acetyloxy)-6-{[(4R,5R,6S,8R,9R,10S,14R)-4-(acetyloxy)-10-azido-8-(2,2-dimethoxyethyl)-5-methoxy-9,14-dimethyl-2-oxooxacyclotetradecanyl]oxy}-4-(dimethylamino)-2-methyltetrahydro-2H-pyran-3-yl]oxy}-4-hydroxy-2,4-dimethyltetrahydro-2H-pyran-3-yl 3-methylbutanoate | C44H76N4O16 | 详情 | 详情 | |
| (VI) | 61006 | [{4-[(9-ethyl-2-fluoro-9H-purin-6-yl)amino]phenyl}(hydroxy)phosphoryl]methylphosphonic acid | C14H16FN5O5P2 | 详情 | 详情 |