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【结 构 式】 
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【分子编号】19159 【品名】(1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,12,15,16-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 【CA登记号】 |
【 分 子 式 】C35H50O11Si 【 分 子 量 】674.8609 【元素组成】C 62.29% H 7.47% O 26.08% Si 4.16% |
合成路线1
该中间体在本合成路线中的序号：(XII)Protection of 14b-hydroxy-10-deacetylbaccatin (XI) with triethylsilyl chloride in pyridine-DMF provided the 7-silyl ether (XII). This compound was condensed with phosgene in CH2Cl2 to give cyclic carbonate (XIII), which was deprotonated with lithium hexamethyldisilazide (LiHMDS) in THF at -40 C, and then selectively acetylated at the 10 hydroxyl group with AcCl. The resulting baccatin derivative (XIV) was coupled with azetidinone (X) in the presence of LiHMDS in THF at -40 C to provide ester (XV), which was then desilylated by treatment with HF. Finally, the resulting isobutenyl compound (XVI) was hydrogenated in the presence of Pd/C to produce the target isobutyl derivative.
| 【1】 Ojima, I.; et al.; Syntheses and structure-activity relationships of taxoids derived from 14beta-hydroxy-10-deacetylbaccatin III. J Med Chem 1997, 40, 3, 267. |
| 【2】 Takahashi, N.; et al.; Growth inhibition of gastric cancer cells by troglitazone, a ligand for peroxisome proliferator-activated receptor. Dig Dis Week (May 16 1999, Orlando) 1999, Abst 3684. |
| 【3】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 | |
| (XI) | 19158 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,9,12,15,16-pentahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C29H36O11 | 详情 | 详情 | |
| (XII) | 19159 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,12,15,16-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C35H50O11Si | 详情 | 详情 | |
| (XIII) | 19160 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-12,15-dihydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C36H48O12Si | 详情 | 详情 | |
| (XIV) | 19161 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C38H50O13Si | 详情 | 详情 | |
| (XV) | 19162 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-2-[(triisopropylsilyl)oxy]-4-hexenoyl]oxy)-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C59H89NO17Si2 | 详情 | 详情 | |
| (XVI) | 19163 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methyl-4-hexenoyl]oxy)-9-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C44H55NO17 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Semisynthesis of the first synthon: The diterpene 14beta-hydroxy-10-deacetylbaccatin III (I) was extracted in a highly purified form from the needles of Taxus wallichiana cultivated in the Himalayan region. It was then converted in 7-O-(triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate (IV) according to the following scheme: 14beta-hydroxy-10-deacetylbaccatin III (I) was dissolved in anhydrous DMF and treated with N-methylimidazole and chlorotriethylsilane to provide 7-O-(triethylsilyl)-10-deacetyl-14beta-hydroxybaccatin III (II) in an almost quantitative yield. Compound (II) was dissolved in a mixture of methylene chloride and dry pyridine and added slowly to a cooled phosgene solution giving 7-O-(triethylsilyl-10-deacetyl-14beta-hydroxybaccatin III-1,14-carbonate (III). After acetylation of compound (III) in pyridine and acetyl chloride, the synthon (IV) was obtained and was ready for coupling.
| 【1】 Laccabue, D.; Pratesi, G.; BAY 59-8862. Drugs Fut 2001, 26, 6, 533. |
| 【2】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 . |
| 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) | 19158 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,9,12,15,16-pentahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C29H36O11 | 详情 | 详情 | |
| (II) | 19159 | (1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,12,15,16-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C35H50O11Si | 详情 | 详情 | |
| (III) | 19160 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-12,15-dihydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C36H48O12Si | 详情 | 详情 | |
| (IV) | 19161 | (1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate | C38H50O13Si | 详情 | 详情 |