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【结 构 式】 
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【分子编号】21743 【品名】tert-butyl (2S,3R)-2-[(1S)-2,2-dimethylcyclopropyl]-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate 【CA登记号】 |
【 分 子 式 】C22H41NO4Si 【 分 子 量 】411.65738 【元素组成】C 64.19% H 10.04% N 3.4% O 15.55% Si 6.82% |
合成路线1
该中间体在本合成路线中的序号：(VII)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 |
|---|---|---|---|---|---|---|
| (II) | 21730 | 2-(Triisopropylsilyloxy)-1-(2(S)-phenyl-1(R)-cyclohexyl)vinyl-1-ol lithium salt | C23H37LiO3Si | 详情 | 详情 | |
| (IV) | 21732 | (3R,4S)-1-(4-methoxyphenyl)-4-[(E)-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2
该中间体在本合成路线中的序号：(VII)The C-7 hydroxyl group of 10-deacetyl baccatin III (VIII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (IX). Subsequent selective acetylation of (IX) at C-10 hydroxyl group with acetyl chloride in the presence of LiN(SiMe3)2 afforded ester (X). The title taxoid was then obtained by further coupling of (X) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine.
| 【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 |
|---|---|---|---|---|---|---|
| (VII) | 21743 | tert-butyl (2S,3R)-2-[(1S)-2,2-dimethylcyclopropyl]-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C22H41NO4Si | 详情 | 详情 | |
| (VIII) | 10467 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 32981-86-5 | C29H36O10 | 详情 | 详情 |
| (IX) | 21737 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-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 | C35H50O10Si | 详情 | 详情 | |
| (X) | 10473 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-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 | C37H52O11Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)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) | 19151 | (1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate | C23H38O3Si | 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) | 21732 | (3R,4S)-1-(4-methoxyphenyl)-4-[(E)-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4
该中间体在本合成路线中的序号：(VII)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：(VII)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 |