|
【结 构 式】 
|
【分子编号】19161 【品名】(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 【CA登记号】 |
【 分 子 式 】C38H50O13Si 【 分 子 量 】742.8927 【元素组成】C 61.44% H 6.78% O 28% Si 3.78% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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：(IV)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 |
合成路线3
该中间体在本合成路线中的序号：(IV)Coupling reaction of the two synthons: (4S,5R)-3-(tert-Butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyloxazolidine-5-carboxylic acid (XIV) was dissolved in methylene chloride and added to 7-O-(triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate (IV) in toluene, in the presence of DMAP and DCC, to yield 7-O-(triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate 13-[3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-5-oxazolidinecarboxylate] (XV) (Scheme 26450201c). Deprotection reaction of the coupling product 7-O-(Triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate 13-[3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-5-oxazolidinecarboxylate] (XV) was dissolved in anhydrous methanol containing a catalytic amount of dry HCl at 0 C. After work-up and crystallization from ethanol/water, 13-[N-(tert-butoxycarbonyl)-b-isobutylisoserinyl]-14beta-hydroxybaccatin III-1,14-carbonate (BAY 59-8862) was obtained.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XIV) | 47538 | (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-5-carboxylic acid | C21H31NO7 | 详情 | 详情 | |
| (XV) | 47539 | 5-[(1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-2-(benzoyloxy)-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-15-yl] 3-(tert-butyl) (4S,5R)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-3,5-dicarboxylate | C59H79NO19Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Lithium enolate (II), generated from chiral ester (I) and LDA at -84 C, was cyclocondensed with imine (III) to furnish azetidinone (IV). After removal of the triisopropylsilyl group of (IV) using HF in pyridine, the resulting lactam was treated with CH2I2 and Et2Zn in 1,2-dichloroethane to give the dimethylcyclopropyl azetidinone (V). The C-3 hydroxyl group was reprotected as the triisopropylsilyl ether (VI). Then, the N-p-methoxyphenyl group of (VI) was removed by oxidative treatment with ceric ammonium nitrate at -10 C, and the resulting azetidinone was N-protected with Boc2O to afford tert-butyl carbamate (VII).
| 【1】 Lin, S.; et al.; Syntheses and biological activity of advanced second-generation taxoids. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 315. |
| 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) | 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 | |
| (II) | 21730 | 2-(Triisopropylsilyloxy)-1-(2(S)-phenyl-1(R)-cyclohexyl)vinyl-1-ol lithium salt | C23H37LiO3Si | 详情 | 详情 | |
| (IV) | 21740 | (3R,4S)-1-(4-hydroxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C22H35NO3Si | 详情 | 详情 | |
| (V) | 21741 | (3R,4S)-4-[(1S)-2,2-dimethylcyclopropyl]-3-hydroxy-1-(4-methoxyphenyl)-2-azetidinone | C15H19NO3 | 详情 | 详情 | |
| (VI) | 21742 | (3R,4S)-4-[(1S)-2,2-dimethylcyclopropyl]-1-(4-methoxyphenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C24H39NO3Si | 详情 | 详情 | |
| (VII) | 21743 | tert-butyl (2S,3R)-2-[(1S)-2,2-dimethylcyclopropyl]-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C22H41NO4Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)Protection of the C-7 hydroxyl group of 14-b-hydroxy-10-deacetyl baccatin III (VIII) with triethylsilyl chloride and imidazole yielded silyl ether (IX). Then, the 1,14-diol of (IX) was converted to cyclic carbonate (X) by treatment with diphosgene in the presence of pyridine. Subsequent selective acetylation of (X) at C-10 hydroxyl group with acetyl chloride in the presence of LiN(SiMe3)2 afforded ester (XI). The title taxoid was then obtained by further coupling of (XI) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine.
| 【1】 Toyoshi, T.; Nomura, T.; Ogawa, A.; et al.; A four-week intravenous toxicity study of flecainide acetate in rats with a two-week recovery phase. Clin Rep 1994, 28, 6, 13. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 21743 | tert-butyl (2S,3R)-2-[(1S)-2,2-dimethylcyclopropyl]-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C22H41NO4Si | 详情 | 详情 | |
| (VIII) | 21744 | (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 | |
| (IX) | 19169 | tert-butyl N-[3-(aminomethyl)benzyl]carbamate; tert-butyl 3-(aminomethyl)benzylcarbamate | 108467-99-8 | C13H20N2O2 | 详情 | 详情 |
| (X) | 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 | |
| (XI) | 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 |