|
【结 构 式】 
|
【药物名称】WHI-07, LS-194199 【化学名称】3'-Azido-5-bromo-5'-O-[4-bromophenoxy[1-(methoxycarbonyl)ethylamino]phosphoryl]-3'-deoxy-6-methoxy-5,6-dihydrothymidine 【CA登记号】339155-58-7 【 分 子 式 】C21H27Br2N6O9P 【 分 子 量 】698.26594 |
【开发单位】Parker Hughes Institute (Originator), Paradigm Pharmaceuticals (Not Determined) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Contraceptives, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Female Contraceptives, Vaginal Spermicides |
合成路线1
Treatment of 4-bromophenol (I) with phosphoryl chloride gave p-bromophenyl phosphoro- dichloridate (II), which was condensed with alanine methyl ester (III) to furnish alaninyl phosphorochloridate (IV). Further coupling of (IV) with 3'-azidothimidine (V) in the presence of N-methylimidazole afforded phosphate (VI). Then, addition of methyl hypobromite, (prepared from bromine and MeOH) provided the title compound as a diastereomeric mixture.
| 【1】 D'Cruz, O.; Jan, S.-T.; Shih, M.-J.; Chen, C.-L.; Uckun, F.M.; Venkatachalam, T.K.; Synthesis of dual function (5R,6R)- and (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-AZT-5'-(para-bromophenyl methoxyalaninyl phosphate) as novel spermicidal and anti-HIV agents. Antivir Chem Chemother 1999, 10, 1, 39. |
| 【2】 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 . |
| 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) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (II) | 25314 | Dichlorophoephoric acid 4-bromophenyl ester | C6H4BrCl2O2P | 详情 | 详情 | |
| (III) | 25315 | methyl 2-aminopropanoate; Alanine, methyl ester | 7625-53-8 | C4H9NO2 | 详情 | 详情 |
| (IV) | 25316 | methyl 2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate | C10H12BrClNO4P | 详情 | 详情 | |
| (V) | 25317 | 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | 101703-35-9 | C10H13N5O4 | 详情 | 详情 |
| (VI) | 25318 | methyl 2-[[[((2S,3S,5R)-3-azido-5-[[(propionylamino)carbonyl]amino]tetrahydro-2-furanyl)methoxy](4-bromophenoxy)phosphoryl]amino]propanoate | C20H24BrN6O8P | 详情 | 详情 |
合成路线2
In a related procedure, methyl hypobromite was added to 3'-azidothimidine (V) in MeOH, and the resulting mixture of diastereomeric 5-bromo-6-methoxypyrimidines (VII) and (VIII) was separated by column chromatography. Both the (5R,6R)- and the (5S,6S)-isomers (VII) and (VIII) were then coupled to phosphorochloridate (IV) to yield the title compound as seperated enantiomers.
| 【1】 D'Cruz, O.; Jan, S.-T.; Shih, M.-J.; Chen, C.-L.; Uckun, F.M.; Venkatachalam, T.K.; Synthesis of dual function (5R,6R)- and (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-AZT-5'-(para-bromophenyl methoxyalaninyl phosphate) as novel spermicidal and anti-HIV agents. Antivir Chem Chemother 1999, 10, 1, 39. |
| 【2】 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 25316 | methyl 2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate | C10H12BrClNO4P | 详情 | 详情 | |
| (V) | 25317 | 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | 101703-35-9 | C10H13N5O4 | 详情 | 详情 |
| (VII) | 25319 | (5R,6R)-1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-bromo-6-methoxy-5-methyldihydro-2,4(1H,3H)-pyrimidinedione | C11H16BrN5O5 | 详情 | 详情 | |
| (VIII) | 25320 | (5S,6S)-1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-bromo-6-methoxy-5-methyldihydro-2,4(1H,3H)-pyrimidinedione | C11H16BrN5O5 | 详情 | 详情 |