|
【结 构 式】 
|
【药物名称】Protaxel, BP-179 【化学名称】3(S)-Benzamido-2(R)-hydroxybenzenepropionic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4-[(2,3-dihydroxypropoxy)carbonyloxy]-11-hydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl ester 【CA登记号】186040-50-6 【 分 子 式 】C51H57NO18 【 分 子 量 】972.01884 |
【开发单位】Biophysica Foundation (Originator), Interpharma Praha (Codevelopment) 【药理作用】Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, ONCOLYTIC DRUGS, Ovarian Cancer Therapy, Prostate Cancer Therapy, P-Glycoprotein (MDR-1) Inhibitors, Taxanes |
合成路线1
Acylation of paclitaxel (I) with 2,3-O-isopropylideneglyceryl chloroformate (II) produced the 2',7-bis-carbonate (III). Subsequent acid hydrolysis of the acetonide groups of (III) furnished the corresponding bis-(dihydroxypropyl)carbonate (IV). The 2'-ester of (IV) was then selectively hydrolyzed using a phosphate buffer at pH 6.5.
| 【1】 Seligson, A.L.; et al.; A new prodrug of paclitaxel: Synthesis of Protaxel. Anti-Cancer Drugs 2001, 12, 4, 305. |
| 【2】 Sovak, M.; Douglass, J.G.; Bressi, J.C.; Seligson, A. (Biophysica Foundation); Novel taxoids. JP 1998509461; US 5801191; WO 9638138 . |
| 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) | 10595 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 33069-62-4 | C47H51NO14 | 详情 | 详情 |
| (II) | 56226 | 4-{[(chlorocarbonyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolane | C7H11ClO4 | 详情 | 详情 | |
| (III) | 56227 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-({[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl}oxy)-3-phenylpropanoyl]oxy}-9-({[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl}oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C61H71NO22 | 详情 | 详情 | |
| (IV) | 56228 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-2-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-3-phenylpropanoyl)oxy]-9-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C55H63NO22 | 详情 | 详情 |
合成路线2
In an alternative method, paclitaxel (I) was acylated with allyl chloroformate (V) to afford the bis-carbonate (VI). Dihydroxylation of both allyl groups of (VI) was accomplished by treatment with tert-butyl hydroperoxide producing (IV). The 2'-ester of (IV) was finally removed upon stirring in a NaHCO3-neutralized solution at room temperature.
| 【1】 Seligson, A.L.; et al.; A new prodrug of paclitaxel: Synthesis of Protaxel. Anti-Cancer Drugs 2001, 12, 4, 305. |
| 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) | 10595 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 33069-62-4 | C47H51NO14 | 详情 | 详情 |
| (IV) | 56228 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-2-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-3-phenylpropanoyl)oxy]-9-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C55H63NO22 | 详情 | 详情 | |
| (V) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (VI) | 56229 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-9-{[(allyloxy)carbonyl]oxy}-15-{[(2R,3S)-2-{[(allyloxy)carbonyl]oxy}-3-(benzoylamino)-3-phenylpropanoyl]oxy}-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C55H59NO18 | 详情 | 详情 |