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【结 构 式】 
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【药物名称】AZD-6126, ZD-6126, ANG-453 【化学名称】5(S)-Acetamido-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl dihydrogen phosphate 【CA登记号】219923-05-4 【 分 子 式 】C20H24NO8P 【 分 子 量 】437.38998 |
【开发单位】Angiogene Pharmaceuticals (Originator), AstraZeneca (Licensee) 【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Angiogenesis Inhibitors, Antimitotic Drugs, Microtubule-Stabilizing Agents |
合成路线1
The title phosphate ester was prepared from N-acetylcolchinol (I). Treatment of (I) with di-tert-butyl diethylphosphoramidite in the presence of tetrazole provided the phosphite ester (II), which was subsequently oxidized to phosphate (III) by means of MCPBA. The tert-butyl phosphate ester of (III) was finally cleaved using trifluoroacetic acid.
| 【1】 Dougherty, G. (Angiogene Pharmaceuticals Ltd.); Use of colchinol derivs. as vascular damaging agents. WO 9902166 . |
| 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) | 47283 | N-[(5S)-3-hydroxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide | C20H23NO5 | 详情 | 详情 | |
| (II) | 47284 | (5S)-5-(acetamido)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl di(tert-butyl) phosphite | C28H40NO7P | 详情 | 详情 | |
| (III) | 47285 | (5S)-5-(acetamido)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl di(tert-butyl) phosphate | C28H40NO8P | 详情 | 详情 |
合成路线2
The reaction of colchicin (I) with aq. HCl at 100 C gives the monodemethylated compound (II), which is treated with H2O2 at 60 C to yield the dibenzocycloheptene derivative (III). The condensation of (III) with N,N-diethylphosphoramidic acid di-tert-butyl ester (IV) by means of tetrazole affords the phosphoric acid triester (V), which is finally treated with MCPBA to provide the target phosphoric acid monoester.
| 【1】 Blakey, D.C.; Davis, P.D.; Dougherty, G.J.; et al.; ZD6126: A novel vascular-targeting agent that causes selective destruction of tumor vasculature. Cancer Res 2002, 62, 24, 7247. |
| 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) | 18479 | N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide | 64-86-8 | C22H25NO6 | 详情 | 详情 |
| (II) | 58655 | N-[(7S)-10-hydroxy-1,2,3-trimethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide | C21H23NO6 | 详情 | 详情 | |
| (III) | 47283 | N-[(5S)-3-hydroxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide | C20H23NO5 | 详情 | 详情 | |
| (IV) | 58656 | C12H28NO3P | 详情 | 详情 | ||
| (V) | 47285 | (5S)-5-(acetamido)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl di(tert-butyl) phosphate | C28H40NO8P | 详情 | 详情 |