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【结 构 式】 
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【药物名称】Alvocidib hydrochloride, Flavopiridol, HL-275, MDL-107826A, HMR-1275, NSC-649890, L86-8275 【化学名称】(-)-cis-2-(2-Chlorophenyl)-5,7-dihydroxy-8-(3-hydroxy-1-methylpiperidin-4-yl)-4H-1-benzopyran-4-one 【CA登记号】131740-09-5, 146426-40-6 (free base), 131739-92-9 (racemic;HCl salt) 【 分 子 式 】C21H21Cl2NO5 【 分 子 量 】438.31122 |
【开发单位】Aventis Pharma (Originator), National Cancer Institute (Codevelopment) 【药理作用】Breast Cancer Therapy, Colorectal Cancer Therapy, Head and Neck Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Melanoma Therapy, Multiple Myeloma Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Prostate Cancer Therapy, Renal Cancer Therapy, Solid Tumors Therapy, Apoptosis Inducers, CDK2 Inhibitors, Inhibitors of Signal Transduction Pathways, Vascular Endothelial Growth Factor (VEGF) Inhibitors |
合成路线1
The condensation of acetophenone (I) with 2-chlorobenzoyl chloride (II) in pyridine gives the corresponding ester (III), which is treated with KOH in hot pyridine yielding the diketone (IV). The cyclization of (IV) with H2SO4 in acetic acid at 100 C affords the benzopyranone (V). The hydrolysis of the acetate group of (V) with NaOH in methanol/water affords the piperidinol (VI), which is finally demethylated with pyridinium hydrochloride at 210-20 C. Alternatively, the ester (III) can be cyclized directly to benzopyranone (V) by means of NaH in hot dioxane.
| 【1】 Naik, R.G.; Lal, B.; Rupp, R.H.; Sedlacek, H.H.; Dickneite, G.; Czech, J. (Aventis SA); Use of 4H-1-benzopyran-4-one derivs., 4H-1-benzopyran-4-one derivs. and medicines containing same. AU 8943841; DE 3836676; EP 0366061; JP 1990178225; US 5284856 . |
| 【2】 Tabaka, A.C.; et al.; Application of modified flavone closure for the preparation of racemic L86-8275. Org Process Res Dev 1999, 3, 4, 256. |
| 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) | 38042 | (3R,4R)-4-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-1-methylpiperidinyl acetate | C18H25NO6 | 详情 | 详情 | |
| (II) | 14000 | o-Chlorobenzoyl chloride; 2-Chlorobenzoyl chloride | 609-65-4 | C7H4Cl2O | 详情 | 详情 |
| (III) | 38043 | 2-acetyl-6-[(3R,4R)-3-(acetoxy)-1-methylpiperidinyl]-3,5-dimethoxyphenyl 2-chlorobenzoate | C25H28ClNO7 | 详情 | 详情 | |
| (IV) | 38044 | (3R,4R)-4-[3-[3-(2-chlorophenyl)-3-oxopropanoyl]-2-hydroxy-4,6-dimethoxyphenyl]-1-methylpiperidinyl acetate | C25H28ClNO7 | 详情 | 详情 | |
| (V) | 38045 | (3R,4R)-4-[2-(2-chlorophenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl]-1-methylpiperidinyl acetate | C25H26ClNO6 | 详情 | 详情 | |
| (VI) | 38046 | 2-(2-chlorophenyl)-8-[(3R,4R)-3-hydroxy-1-methylpiperidinyl]-5,7-dimethoxy-4H-chromen-4-one | C23H24ClNO5 | 详情 | 详情 |